Pharmacology

Lessons from Practice Childhood hepatotoxicity with paracetamol doses less than 150 mg/kg per day MJA 1999; 171: 497 Paracetamol is widely used as an antipyretic and analgesic. Adverse effects are regarded as unlikely at doses below 150 mg/kg per day.1 However, lower doses have resulted in hepatotoxicity,2 and there is growing evidence of the potential for hepatotoxicity in children given multiple therapeutic or supratherapeutic doses of paracetamol.3-6The nomogram devised by Rumack and Matthews7 was based on data obtained from previously well adult patients who had taken a single large dose of paracetamol. The relevance of this to children given multiple doses in the context of a febrile illness is unknown, particularly as the metabolism in this population appears to be quite different.8 It has been suggested that the therapeutic index for paracetamol may be as low as 1.7,9 and that sick children under the age of two years given in excess of 90 mg/kg per day for more than one day should be regarded as being at higher risk.6 The product information recommends a maximum daily dose of 60 mg/kg, but it is not uncommon for children to receive doses in excess of 90 mg/kg per day in the hospital setting.10 Although the number of reported cases of hepatotoxicity induced by therapeutic doses of paracetamol is small, it is possible that cases have gone unrecognised. It is important to administer the drug with caution and according to current dosage guidelines. Case reports Case 1: Six days before transfer to our hospital, a previously well four-year-old, 20 kg girl had commenced a course of cefaclor for otitis media, and over 72 hours she received about 2400 mg of paracetamol in divided doses. She was admitted to her local hospital with fever (39ºC), abdominal pain, vomiting and diarrhoea. Her aspartate transaminase (AST) level was 2050 U/L (normal range, < 45 U/L). She was tachypnoeic and hypoxic, and over the next 17 hours received 2800 mg (140 mg/kg) paracetamol. Her condition deteriorated. Results of liver function tests were: AST, 4580 U/L (Figure A); alanine transaminase, 2785 U/L (normal range, < 55 U/L); and serum bilirubin, 27 µmol/L (normal range, < 15 µmol/L). The international normalised ratio of prothrombin time was 4.2, and activated partial thromboplastin time, 47 s (control, < 42 s). Left lower lobe pneumonia was diagnosed, and treatment commenced with fresh frozen plasma, vitamin K, and antibiotics. The AST level rose to 11 475 U/L. The paracetamol level 22 hours after the last documented dose of the drug was 55 µmol/L. N-acetylcysteine (150 mg/kg) was administered intravenously. After the child was transferred to our hospital, intravenous N-acetylcysteine was continued (10 mg/kg/h for 32 h). Abdominal ultrasound revealed a large homogeneous liver and a small amount of ascites. Serology for hepatitis A and B, Epstein-Barr virus, cytomegalovirus and Mycoplasma pneumoniae was negative. Respiratory syncytial virus was detected in a nasopharyngeal aspirate. Blood cultures were negative. Stool examination revealed no viral agent. The patient was discharged after seven days, with an AST level of 171 U/L. Three months later she was completely well, with normal liver function tests. Case 2: A 12-year-old, 43 kg boy with Duchenne's muscular dystrophy was admitted for posterior spinal fusion and tendon-release surgery. He was anaesthetised using propofol and nitrous oxide, and during the operation required transfusion for a one-litre blood loss. He returned to the ward on a morphine infusion (20 µg/kg/h) and cephazolin (1 g eight-hourly). Over the next 24 hours he received a total dose of 3000 mg (70 mg/kg) paracetamol rectally. Similar total doses were given over the next five days, with a maximum of 4650 mg (108 mg/kg) in any 24-hour period. Liver function tests taken the day after surgery revealed an AST level of 193 U/L (Figure B) and a gamma-glutamyl transpeptidase (GGT) level of 43 U/L (normal range, < 40 U/L). He developed paralytic ileus 48 hours after surgery; this resolved with intravenous hydration. On day seven, he became irritable and disoriented and was pale, icteric and lethargic. Results of investigations were: serum bilirubin, 120 µmol/L; GGT, 68 U/L; AST, 7377 U/L; and ammonia, 88 µmol/L (normal range, < 50 µmol/L). His serum paracetamol level was 528 µmol/L. The haemoglobin level was 68 g/L and he received two units of packed cells. Serology for hepatitis B and C was negative. The paracetamol level was 206 µmol/L 34 hours after the last dose, but, as the liver enzyme levels were falling and the child's conscious state improving, N-acetylcysteine was not administered. He was discharged 22 days after surgery with an AST level of 113 U/L. Back to text Jenny L Hynson,* Mike South** * Consultant Paediatrician ** Associate Professor, and Director Department of General Paediatrics, Royal Children's Hospital Flemington Road, Parkville, VIC 3052 Rumack BH. Acetaminophen overdose in young children. Am J Dis Child 1984; 138: 428-433. Schoidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337: 1112-1117. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22-27. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127: 888-894. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300-304. Kearns GL, Leeder JS, Wasserman GS. Acetaminophen overdose with therapeutic intent [editorial]. J Pediatr 1998; 132: 5-8. Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871-876. Penna A, Buchanan N. Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol 1991; 32: 143-149. Heubi JE, Bien JP. Acetaminophen use in children: more is not better [editorial]. J Pediatr 1997; 130: 175-177. Penna AC, Dawson KP, Penna CM. Is prescribing paracetamol "pro re nata" acceptable? J Paediatr Child Health 1993; 29: 104-106.

Research Vancomycin and teicoplanin use in Victorian hospitals Marion B Robertson, Jonathan G A Dartnell and Tony M Korman, on behalf of the Victorian Drug Usage Evaluation Group MJA 1999; 171: 127-131 See also Ferguson, Grayson et al & Collignon Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Pharmacology Abstract Objective: To determine patterns of prescribing of glycopeptide antibiotics (vancomycin and teicoplanin) in Victorian hospitals and identify areas for targeted intervention. Design: A concurrent, observational, multisite evaluation of drug use. Setting: Thirty-five Victorian hospitals, 1-14 September 1997. Study population: Patients commencing a glycopeptide antibiotic course. Main outcome measures: Rate of glycopeptide antibiotic use; indications; duration of use; main hospitals using glycopeptide antibiotics. Results: 293 patients (269 adults and 24 neonates) commenced on 302 glycopeptide antibiotic courses: 296 intravenous (IV) vancomycin courses and three each of oral vancomycin and parenteral teicoplanin. The overall rate of use was 10.3 courses per 1000 inpatient separations. Of 271 IV vancomycin courses for adults, 176 (65%) were for treatment -- 120 empirically. The median duration of treatment courses was 4.7 days (interquartile range, 2.0-8.2 days). A flucloxacillin-resistant organism was confirmed for 44% of treatment courses. Ninety-five IV vancomycin courses were for prophylaxis, including for cardiac (54%) and vascular surgery (21%); 82% of prophylactic courses were administered for less than 24 hours. Of all the glycopeptide antibiotic courses, 69% were administered at five major metropolitan hospitals. Conclusions: Glycopeptide antibiotic use in Victoria is concentrated in the major metropolitan hospitals. Prolonged durations of vancomycin therapy, including for surgical prophylaxis and empirical therapy not subsequently confirmed by microbiology findings, would be suitable targets for interventional strategies. Introduction The emergence of resistant strains of Staphylococcus aureus and coagulase-negative staphylococci has resulted in increased use of the glycopeptide antibiotics vancomycin and teicoplanin.1 These antibiotics are the only effective treatments for infections with these pathogens, but the emergence of vancomycin-resistant enterococci (VRE) threatens their utility.1,2 VRE can cause serious life-threatening infections, and can transfer their resistance in vitro to other pathogens, such as Staphylococcus, rendering the bacteria resistant to currently available antimicrobials.3,4The emergence of VRE has been linked to both overuse and inappropriate use of antibiotics such as vancomycin, teicoplanin and extended-spectrum cephalosporins.2,4 There is also a strong relationship with the use of glycopeptide antibiotics in animals.5 Australian studies have reported inappropriate use of vancomycin ranging from 42% to 65% in individual hospitals.6,7 Responding to these concerns, consensus guidelines have been disseminated to all Victorian hospitals.8 The aim of this study was to examine patterns of prescribing vancomycin and teicoplanin in Victorian hospitals in order to identify potential areas for targeted intervention to improve use of these antibiotics. Methods This study was conducted by the Victorian Drug Usage Evaluation Group, a multidisciplinary group that aims to promote and improve coordination of drug use evaluation activities as a means to improve drug use. All Victorian public and private hospital pharmacy departments listed in the Society of Hospital Pharmacists of Australia directory9 were invited to participate. All patients at participating hospitals who commenced a course (Box 1) of oral or intravenous (IV) vancomycin or teicoplanin between 1-14 September 1997 inclusive were enrolled. Pharmacists at each hospital collected data concerning: demographic details, the indication for antibiotic therapy as determined from the medical record or by consultation with the prescriber, site and source of infection, beta-lactam hypersensitivity, and past history of methicillin-resistant S. aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE), microbiology results of specimens taken up to seven days before or concurrent with vancomycin or teicoplanin therapy, administration of antibiotics before, during and immediately after vancomycin or teicoplanin therapy, and specialist consultation and advice. Prescription data were collected until the end of the course, until the day of discharge or death, or until 28 September 1997. Each hospital provided details of the number of inpatient separations between 1-14 September 1997. This was used to estimate the number of glycopeptide antibiotic courses commenced per 1000 inpatient separations. Data were evaluated by the Mann-Whitney rank sum test of the equivalence of medians of samples not drawn from a normally distributed population. Proportions were compared using the χ2 test. Data are presented as proportions, medians and interquartile ranges. Results Hospitals: Thirty-five hospitals participated in the study: 33 of 58 public and two of 14 private hospitals invited to participate. Twenty hospitals were in the Melbourne metropolitan area and 15 in regional areas. Patients: In the study period, 293 patients (mean age, 54 years; range, 0-90 years; 112 females) commenced a course of vancomycin or teicoplanin. The 293 patients received 302 courses of glycopeptide antibiotics -- three teicoplanin, three oral vancomycin, and 296 intravenous vancomycin (Box 2). Five of Melbourne's six major metropolitan hospitals participated and administered 209 (69%) of the 302 courses. Twenty hospitals enrolled between one and 11 patients and contributed the remaining 93 courses. Glycopeptide antibiotic use in neonates: Four hospitals enrolled 24 neonates who were prescribed 25 courses of IV vancomycin, with a median duration of 2.3 days (interquartile range, 2.0-4.6 days). One course was for prophylaxis for abdominal surgery; the other 24 courses were for empirical treatment. One treatment course was for respiratory infection and the others were for an unknown site of infection. Flucloxacillin-resistant organisms were isolated for six courses (two MRSA, four coagulase-negative staphylococci). Glycopeptide antibiotic use in adults: Twenty-five hospitals enrolled 269 adults who commenced 277 glycopeptide antibiotic courses; 143 (53%) patients were treated by a medical unit and 126 (47%) by a surgical unit; 73 (27%) of the patients were in an intensive care unit at some stage during the glycopeptide antibiotic course. Of the 269 patients, 235 (87%) were discharged, 30 (11%) died, and 4 (1%) were still in hospital three months after the study. For 94 courses (34%), specialist consultation for the use of vancomycin and teicoplanin was noted in the records. More than 80% of these consultations were with infectious disease/microbiology specialists. There were 263 patients who received 271 courses of IV vancomycin -- 176 (65%) for treatment and 95 for prophylaxis (Box 3). Of the 176 IV vancomycin treatment courses, 120 (68%) were for empirical treatment and 56 (32%) as specific treatment. Empirical courses were shorter than specific courses (P < 0.02). Patients being treated empirically had been in hospital for fewer days before the course commenced than patients receiving specific treatment (P < 0.001). The duration of empirical courses for which a flucloxacillin-resistant organism was subsequently identified was significantly greater than that of the unconfirmed courses (P < 0.05). Of the other six patients, three received a course of oral vancomycin for the treatment of confirmed (two cases) or suspected (one case) Clostridium difficile diarrhoea, and three received IV teicoplanin for treatment of wound infections (2 patients) or cellulitis (1 patient), commenced on the advice of infectious diseases clinicians. Other antibiotic use in adults: In the seven days before IV vancomycin treatment courses, the most frequently prescribed antibiotics were ceftriaxone and cefotaxime (28% of courses), metronidazole (16%), flucloxacillin (15%), and gentamicin (15%). The most frequently prescribed concurrent antibiotics were ceftriaxone and cefotaxime (11% of vancomycin courses), gentamicin (11%), ceftazidime (9%), imipenem (7%), ciprofloxacin (6%) and metronidazole (6%). For 14 treatment courses, vancomycin was continued beyond the close of the study. Immediately following the 162 completed courses (in 162 patients), other antibiotic therapy was commenced for 57 patients (35%), concurrent antibiotic therapy continued for 35 patients (22%), and there was no antibiotic therapy for 50 patients (31%). On-going therapy was not recorded for nine patients (6%), and the remaining 11 patients (7%) died. The antibiotics most frequently commenced immediately after vancomycin were oral flucloxacillin (12 courses), oral fusidic acid and oral rifampicin (12 courses), and oral ciprofloxacin (eight courses). For the 95 IV vancomycin prophylaxis courses, other antibiotics were given concurrently for 46 (48%) courses, most frequently gentamicin (14% of vancomycin courses), ceftriaxone (14%), cephazolin (6%) and ticarcillin/clavulanate (5%). Comparison of five main vancomycin users: The five hospitals that used most vancomycin were major metropolitan university teaching hospitals where use was restricted by protocols and consultations. Use by number of courses was greatest in Hospital 1 but the total quantity used was less than half that used at Hospital 2 (Box 4). Rate of use was significantly lower in Hospital 4 than in the other four hospitals. Surgical use of vancomycin predominated in Hospital 1, while medical use predominated in Hospital 4. Hospitals 2, 3 and 5 had a significantly smaller proportion of single doses for prophylaxis than Hospitals 1 and 4. Discussion We have examined the pattern of use of vancomycin in a large sample of Victorian hospitals. We found that use of teicoplanin and oral vancomycin was low, and that intravenous vancomycin was used predominantly for empirical treatment or prophylaxis. Our study is the first to capture a statewide picture of hospital drug use linked to indication, and we are not aware of any published comparable multihospital pharmacoepidemiological data. Based on the number of inpatient separations for Victorian public hospitals in 1996-97 (about 890 000),10 we reviewed an estimated 82% of public hospital inpatient separations in the two-week study period. We estimated the overall rate of glycopeptide antibiotic use to be 10.3 courses per 1000 inpatient separations, which suggests about 9160 courses are used annually in Victorian public hospitals. The main limitation of our study was that vancomycin courses were not individually compared against explicit criteria to determine the proportion of appropriate use on the basis of indication, dosage and duration. We chose not to compare against criteria because of the variety of prescribing restrictions in participating hospitals. The most frequent indications for empirical IV vancomycin were febrile neutropenia, pneumonia and wound infections. The indications for and duration of empirical therapy could be targets for intervention. For pneumonia, IV vancomycin use may be reasonable for hospital-acquired infections in institutions with a high prevalence of MRSA. For febrile neutropenia, IV vancomycin may be best restricted to patients with suspected associated IV line sepsis. For wound infections, unless there is a high prevalence of MRSA, IV vancomycin treatment should wait until after microbiological confirmation. Oral vancomycin should be restricted to the treatment of antibiotic-associated colitis due to toxigenic C. difficile unresponsive to or relapsing after an adequate course of metronidazole (or bacitracin), or for patients with severe colitis.11 Clinicians should be encouraged to regularly review the need for ongoing drug therapy; however, to improve the current situation, we need effective decision support tools to facilitate timely attention to important test findings.12 Almost half the treatment courses were sanctioned or recommended by infectious diseases/microbiology specialists, who should be familiar with relevant guidelines for vancomycin use. Surgical prophylaxis consumed 35% of IV vancomycin courses, with cardiac and vascular surgery accounting for 75% of prophylactic courses. The duration of vancomycin prophylaxis was generally according to recommendations, with 72% of courses given as single doses and 82% of courses given for less than 24 hours. However, there was considerable interhospital variation in the duration of surgical prophylaxis. The implementation of hospital policies on duration of surgical prophylaxis would be an important target for intervention. Glycopeptide antibiotic use was concentrated in five major metropolitan teaching hospitals. Although these five hospitals all had policies in place, vancomycin use varied substantially. It is of critical importance for patient care and resource management that there is a conscious effort to preserve the utility of vancomycin and teicoplanin. This should be founded on good infection control practice, but there is also a need for all hospitals to implement effective interventional strategies to improve the use of the glycopeptide antibiotics. Acknowledgements Financial support for the employment of the Project Coordinator was provided by the Victorian Drug Usage Advisory Committee and the Victorian Standing Committee on Infection Control. The project was also reliant on the voluntary work of pharmacists at the participating hospitals who undertook all the data collection. We acknowledge the assistance of the other members of the Victorian Drug Usage Evaluation Group in the planning and execution of the study and the preparation of this manuscript: Stephanie J Alvarez, Drug Utilisation Evaluation Pharmacist, Monash Medical Centre; Dr Jo-anne Brien, Senior Lecturer, Department of Pharmacy Practice, Monash University (Parkville Campus); Dr Lisa L Ioannides-Demos, Senior Research Fellow, Department of Epidemiology and Preventative Medicine, Monash University, and Senior Research Officer, Victorian Centre for Ambulatory Care Innovation, Alfred Hospital; Sam Koroneos, Senior Drug Utilisation Pharmacist, Pharmacy Department, Austin and Repatriation Medical Centre; Anne Leversha, Senior Lecturer, Monash University, Faculty of Medicine, and Victorian College of Pharmacy, and Deputy Manager Pharmacy Services, Latrobe Regional Hospital, Traralgon West; Julie A V Lord, Senior Drug Information and Clinical Research Pharmacist, St Vincent's Hospital, Melbourne; Heather J Lyall, Deputy Director of Pharmacy, Geelong Hospital; Roslyn I McKinnon, Executive Officer, Victorian Drug Usage Advisory Committee; Associate Professor R Moulds, Director, Department of Clinical Pharmacology and Therapeutics, Royal Melbourne Hospital; Susan G Poole, Deputy Director, Peter MacCallum Cancer Institute; Dr Gail J Ware, Drug Usage Evaluation Pharmacist, Alfred Hospital. References Ena J, Dick RW, Jones RN, Wenzel RP. The epidemiology of intravenous vancomycin usage in a university hospital: a 10 year study. JAMA 1993; 269: 598-602. Heath CH, Blackmore TK, Gordon DL. Emerging resistance in Enterococcus spp. Med J Aust 1996; 164: 116-120. Reduced susceptibility of Staphylococcus aureus to vancomycin -- Japan, 1996. MMWR Morb Mortal Wkly Rep 1997; 46: 624-626. Quale J, Landman D, Atwood E, et al. Experience with a hospital-wide outbreak of vancomycin-resistant enterococci. Am J Infect Control 1996; 24: 372-379. Witte W. Medical consequences of antibiotic use in agriculture. Science 1998; 279: 996-997. Misan GMH, Martin ED, Smith ER, et al. Drug utilisation review in a teaching hospital: experience with vancomycin. Eur J Clin Pharmacol 1990; 39: 457-461. Radford JM, Whitby RM, Looke DFM, Coombes JA. Vancomycin usage review in the era of vancomycin-resistant enterococci (VRE). Aust J Hosp Pharm 1997; 27: 1410-1413. Guidelines for preventing emergence of vancomycin-resistant enterococci. Melbourne: Victorian Drug Usage Advisory Committee and the Standing Committee on Infection Control in collaboration with the Writing Group for the Therapeutic Guidelines: Antibiotic, 1997. Vernon G, Thomson W, editors. Directory of hospital pharmacy and pharmaceutical organisations. Melbourne: Society of Hospital Pharmacists of Australia, 1996. Department of Human Services Annual Report 1996-97. Melbourne: Department of Human Services, Victoria, 1997. Therapeutic Guidelines: Antibiotic, 10th ed. Melbourne: Therapeutic Guidelines Limited, 1998. Schiff GD, Rucker D. Computerized prescribing. Building the electronic infrastructure for better medication usage. JAMA 1998; 279: 1024-1029. (Received 21 Dec 1998, accepted 17 May 1999) Authors' details Victorian Drug Usage Evaluation Group, Melbourne, VIC. Marion B Robertson, BPharm, MSc, Project Coordinator. Royal Melbourne Hospital, Melbourne, VIC. Jonathan G A Dartnell, BPharm, MPS, Senior Pharmacist, Department of Clinical Pharmacology and Therapeutics. Monash Medical Centre, Melbourne, VIC. Tony M Korman, FRACP, Infectious Diseases Physician. Reprints will not be available from the authors. Correspondence: Mr J G A Dartnell, Department of Clinical Pharmacology and Therapeutics, c/- Post Office, Royal Melbourne Hospital, VIC 3050. Email: Jonathan. DartnellATnwhcn.org.au 1: Definitions Course: The administration to a patient of at least one dose of vancomycin or teicoplanin. If a dose was administered more than 24 hours after a previous dose (and the drug was re-prescribed), this was considered a new course. Patients with renal impairment on regimens with dosing intervals longer than 24 hours were considered to have received a continuous course. Prophylaxis: Antibiotic administration commenced perioperatively to prevent postoperative infection. Empirical treatment: Antibiotic administration commenced before or without identification of flucloxacillin-resistant bacterial pathogens. Specific treatment: Antibiotic administration commenced after identification of flucloxacillin-resistant bacterial pathogens. Duration: Durations of courses were calculated by subtracting the date and time of the first dose from the date and time of the last dose. The duration of a single dose was considered to be 0 hours. Back to text 2: Glycopeptide antibiotic courses commenced in participating hospitals during study period*Hospital locationNumber of courses † (patients)Number of inpatient separationsCourses per 1000 separationsMelbourne52 (51)‡235622.0Melbourne49 (48)245520.0Melbourne38 (37)194319.6Melbourne37 (37)299712.3Melbourne33 (30)§141623.3Regional11 (11)14777.4Melbourne10 (9)53818.6Melbourne10 (10)14776.7Melbourne9 (9)10718.4Melbourne8 (8)10897.3Melbourne8 (7)13575.9Melbourne7 (7)42316.5Regional5 (5)8086.2Melbourne5 (5)10554.7Melbourne3 (3)15002.0Melbourne3 (2)27111.1Regional3 (3)3748.0Regional2 (2)§14613.7Melbourne2 (2)8772.3Melbourne2 (2)4694.3Melbourne1 (1)6681.5Regional1 (1)7251.4Regional1 (1)§2663.8Melbourne1 (1)6361.6Melbourne1 (1)5102.0Overall*302 (293)2944510.3*Another 9 regional and 1 Melbourne hospital accounted for 2785 inpatient separations but did not use glycopeptide antibiotics during the study period. †Intravenous vancomycin except where indicated. ‡Includes 3 courses of teicoplanin. §Includes 1 course of oral vancomycin. Private hospital. Back to text 3: Intravenous vancomycin courses commenced in adultsAll treatment courses 176 treatment courses median duration, 4.7 days (interquartile range, 2.0-8.2 days) indications: wound infections33 (18.8%)pneumonia29 (16.5%)febrile neutropenia21 (11.9%)septicaemia12 (6.8%)intravenous catheter-associated sepsis11 (6.3%)cellulitis9 (5.1%)infected prosthesis9 (5.1%)peritonitis/CAPD8 (4.5%)meningitis3 (1.7%)other16 (9.1%)not recorded25 (14.2%)Gram-positive bacteria, including Staphylococcus, Streptococcus, Enterococcus and Bacillus species isolated for 113 (64%) courses Isolated organism confirmed flucloxacillin-resistant in 78 courses; organism was MRSA in 67 coursesEmpirical treatment courses 120 empirical treatment courses (68% of all treatment courses) median duration, 4.4 days (interquartile range, 1.5-8.0 days) patients in hospital for median 4.0 days (interquartile range, 1-12 days) before course commenced most frequent indications: febrile neutropenia (18%), pneumonia (16%) and wound infections (12%) 32 (26%) of patients had history of beta-lactam antibiotic hypersensitivity or a previous infection with MRSA or MRSE. Two patients had a history of severe hypersensitivity that may have necessitated use of vancomycin rather than beta-lactam antibiotics. flucloxacillin-resistant organism subsequently identified in 24 (20%) empirical courses duration of courses with confirmed resistant organism was 6.9 days (interquartile range, 2.0-13.8 days) compared with 3.9 days (interquartile range, 1.3-6.7 days) for unconfirmed courses (P<0.05) Specific treatment courses 56 specific treatment courses (32% of all treatment courses) median duration, 6.1 days (interquartile range, 3.0-11.6 days) patients in hospital for median 12 days (interquartile range, 4-22 days) before course commenced Surgical prophylaxis courses95 surgical prophylaxis courses 68 (72%) single-dose courses, 78 (82%) less than one day, 12 (12%) one to three days, 5 (5%) more than three days 12 (13%) were for patients with history of beta-lactam hypersensitivity, including four severe cases, and 5 (5%) were for patients with history of MRSA or MRSE infection 51 (54%) used in cardiac surgery; 31 single doses, 12 (24%) lasted more than 36 hours 20 (21%) used in vascular surgery; all were single dosesCAPD=chronic ambulatory peritoneal dialysis. MRSA=methicillin-resistant Staphylococcus aureus. MRSE=methicillin-resistant S. epidermidis. Back to text 4: Comparison of intravenous vancomycin in adults in the major teaching hospitalsHospital 1Hospital 2Hospital 3Number of courses494938Number of patients484837Courses per 1000 separations*20.820.019.6Vancomycin used (g)177371280Median length of stay (days)121816Courses given in intensive care9 (18%)9 (18%) 17 (45%)Courses prescribed by medical unit12 (24%)28 (57%)20 (53%)Indication: prophylaxisNumber of courses (%)28 (57%)15 (31%)15 (39%)Number (%) as single doses †28 (100%)7 (47%)9 (60%)Surgery type (number of courses) cardiac2476 vascular241 other248Indication: treatmentNumber (%) empirical13 (62%)30 (88%) 19 (83%)Median duration of courses (days) empirical3.73.64.8 specific3.04.511.0Indications (number of courses) pneumonia724 wound infection436 febrile neutropenia181 other92112 Hospital 4Hospital 5Number of courses3332Number of patients3229Courses per 1000 separations*12.322.6Vancomycin used (g)299118Median length of stay (days)209Courses given in intensive care6 (18%)9 (28%)Courses prescribed bymedical unit30 (91%)17 (53%)Indication: prophylaxisNumber of courses (%)8 (24%) 16 (50%)Number (%) as single doses †8 (100%)11 (69%)Surgery type (number of courses) cardiac18 vascular63 other15Indication: treatmentNumber (%) empirical18 (72%)10 (62%)Median duration of courses (days) empirical5.51.5 specific3.02.0Indications (number of courses) pneumonia60 wound infection33 febrile neutropenia24 other149* Hospital 4 significantly less than Hospitals 1, 2, 3 and 5 (P<0.02). †Hospitals 2, 3, and 5 significantly less than Hospital 1 (P<0.01) and Hospital 4 (P<0.1). Back to text

Marion B Robertson

MaLAM, a medical lobby for appropriate marketing of pharmaceuticals Peter R Mansfield We can protect scientific medicine from misleading promotion MJA 1997; 167: 590-592 Introduction - How MaLAM began - How MaLAM works - MaLAM and the Third World - MaLAM in Australia - MaLAM in the future? - Acknowledgements - References - Authors' details See also Misleading promotion - - - ©MJA1997 Introduction The Lancet has published 11 pieces about the work of the Medical Lobby for Appropriate Marketing (MaLAM), including three in 1996.1-3 At the international level, MaLAM has become a prominent forum for feedback from health professionals to the pharmaceutical industry regarding the scientific justification of promotional claims.4 More recently, MaLAM has expanded this role in the Australian setting. However, many Australian health professionals know little of this international organisation, based in Adelaide, South Australia.5 Here is the story of how one medical student's idea became an international institution. How MaLAM began In late 1981, I went to Bangladesh to do a medical student elective. There, I saw that, in the context of severe poverty, scientific medicine can achieve great good at little cost (e.g., antibiotics for pneumonia). Consequently, in villages where everyone knows young children who have died, parents will make great sacrifices to buy medicines. I was horrified when I saw that inappropriate pharmaceutical marketing was exploiting these parents' concerns and, at the same time, perverting the objectives of scientific medicine. Examples include the promotion of anabolic steroids and glucose solutions for children with slow growth, tetracycline syrups for children, and breastmilk substitutes. Misleading promotion is an emotional issue. However, it deserves the same calm, rational examination as any other medical issue. David Morley's Paediatric priorities in the developing world suggested that a problem deserves priority if it is common, severe, a cause of community concern and amenable to therapy.6 My personal experience in Bangladesh led me to believe that misleading promotion met the first three criteria. More recently, much good evidence has become available which is relevant to these three criteria (see Box). Interestingly, this evidence comes from the developed world, where the impact of misleading promotion on health is probably less severe than it is in the Third World. However, at the time, the challenge for me was to conceive and then implement a "therapeutic" arm to deal with what had become a personal priority -- the problem of misleading pharmaceutical promotion in the Third World. How MaLAM works During the 1970s and 1980s issues related to pharmaceutical use earned the attention of increasingly sophisticated and effective "consumer critics". However, I perceived a "gap in the market" for an organisation for and of health professionals, representing our interest in protecting quality scientific medical care from misleading promotion. All organisations need feedback to enable them to improve their performance, so pharmaceutical companies need honest feedback from health professionals, as well as from health consumers. Consequently, I designed MaLAM to provide an open participatory forum for dialogue between health professionals and pharmaceutical companies. Having been a member of Amnesty International, I was familiar with that organisation's strategy of coordinated letters: members would be asked to send letters on particular issues to relevant individuals or bodies. I decided to adopt a similar strategy and anticipated that subscribers, via their subscriptions, would cover postage costs. I would provide the "labour" for free, hopefully with volunteer assistance. Before commencing, MaLAM was registered under the South Australian Associations Incorporation Act, which provides a legal basis for good governance and financial accountability for organisations with small or large budgets. MaLAM and the Third World I began publishing our "international" editions in November 1983, with much help from my family and many friends. Most of MaLAM's 53 foundation subscribers were recruited personally or with the assistance of Community Aid Abroad. Health Action International assisted MaLAM to contact health professionals overseas. Some of those contacts later became regional distributors of MaLAM editions to other subscribers in their country or region, thus keeping postage costs at a manageable level. MaLAM editions, produced monthly, usually comprise a newsletter and a letter to a pharmaceutical company about one or more of its promotional claims. Each letter includes a summary of the relevant scientific literature and invites the company to justify or amend its claims. Subscribers also receive a support letter, which they can sign and post to the company so as to request a copy of its reply. Topics are selected from the up to 200 advertisements we receive per month from concerned health professionals. Many MaLAM editions have focused on misleading promotion of drugs, which have an important place when used appropriately but could be dangerous or ineffective if misused. We have also chosen to write to companies when advertising is most seriously at variance with the scientific literature. While it is often difficult to assess how large a role MaLAM played in "causing" improvements, the temporal relationships are usually clear. Our first major success was a letter in 1986 requesting evidence to support the promotion of a mixture of arsenic, strychnine, vitamins and alcohol for stress in Pakistan. The manufacturer announced a withdrawal immediately. In the same year, our editions also became available in French. By 1991, pharmaceutical companies had promised to withdraw 11 drugs after receiving MaLAM letters. The most important of these was a chloramphenicol/streptomycin combination, which had been the top-selling over-the-counter product for diarrhoea in the Philippines. We also published a classification of the quality of "evidence" used by pharmaceutical companies to justify efficacy claims when their advertising was questioned. Some companies provided no justification. Others used the following types of arguments: "endorsement by their own staff", "other companies do the same", "government approval" (without any other evidence), "longstanding use", "endorsement by experts", "animal or in-vitro studies", or "clinical trials" which in fact had major methodological flaws. 18 We believe that pharmaceutical companies are more concerned about their image in "major" markets (i.e., in developed countries) than their relatively small profits from poor countries. Further, because pharmaceutical company executives seem to think in political more often than in scientific terms, it was important for them to know that MaLAM reflects the concerns of large numbers of health professionals rather than a government or fringe agenda. MaLAM's design addresses this by involving large numbers of subscribers in the dialogue as the final quality control step. Subscribers, mostly doctors or pharmacists, now number over 6000, spanning over 30 countries. Accordingly, our impact has increased. MaLAM in Australia In 1992, MaLAM received funding, since increased, but then not renewed, from the federal Department of Health and Human Resources' Pharmaceutical Education Program to enable publication of Australian editions focusing on promotion occurring in this country. This enabled the Secretariat to employ up to one full-time and four part-time staff, although volunteer workers have always been essential. Between June 1993 and August 1996, MaLAM initiated dialogue about the promotion of 17 drugs in Australia. All companies but one have replied. Advertisements for seven drugs that we provided feedback about are no longer used. While the Australian edition appears popular with local subscribers, it is not as effective as the International edition in leading to improvements in marketing pharmaceuticals. The scientific issues are more subtle and the profits involved are greater; companies seem less willing to make improvements. We believe companies have sometimes reacted by interpreting our words in a severe and extreme way, allowing them to criticise easily rather than to respond to our real concerns. Fortunately, some companies seem to understand that listening to "customers" may help them to make more money in the long term. There is an encouraging trend towards a more sophisticated market which will reward quality by favouring drugs that come with reliable information so as to produce the best health outcomes. MaLAM in the future? The quality-use-of-medicine activities,19 the evidence-based medicine movement,20 improving medical education, and the ancient but ever-relevant ideal of doing the best for the patient are all forces supporting better prescribing. MaLAM gains strength from these forces and also tries to assist them. In the future, MaLAM may be able to offer more to health professionals. We would like to increase our contribution to medical education because many subscribers have reported that they find MaLAM a fascinating way to improve their critical-appraisal skills. It is also an interesting way to be up to date on the other side of the story about specific drugs, often at a time of important controversies. For example, our international contacts enable us to draw attention to adverse effects which were well documented in languages other than English before they were listed in the Australian product information. There is also a need for ongoing measurement of the impact of promotion on prescribing, especially the effect of pharmaceutical sales representative visits. If the impact can be measured, then the efficacy of interventions to reduce the harmful consequences of promotion could be tested. While it has been suggested that doctors can learn "to sort the wheat from the chaff",21,22 critical-appraisal skills will not protect against the more subtle methods of influence. Therefore, the best that we can do about pharmaceutical promotion is to try to avoid it or improve it. Personally, I am not in favour of the adversarial approach, and believe that pharmaceutical companies will make improvements if they receive a strong signal from the market. If we work together, then we will be able to protect scientific medicine from Misleading promotion. Acknowledgements I thank Robyn Clothier, Joel Lexchin, and Agnès Vitry for their comments. References Frankel DH. Servier criticised on perindopril campaign. Lancet 1996; 347: 183. Alliot LS. Criticism of Servier re perindopril. Lancet 1996; 347: 837. Vitry A, Mansfield P. Promotion of Coversyl by Servier. Lancet 1996; 347: 1411. Anonymous. MaLAM targets IFPMA. Scrip 1996; 2155: 17. Mansfield P. MaLAM: encouraging trustworthy drug promotion. Essential Drugs Monitor 1994; 17: 6-7. Morley D. Paediatric priorities in the developing world. London: Butterworths, 1973. Wilkes MS, Doblin BH, Shapiro MF. Pharmaceutical advertisements in leading medical journals: Experts' assessments. Ann Intern Med 1992; 116: 912-919. Caradang ED, Moulds RWF. Pharmaceutical advertisements in Australian medical publications: have they improved? Med J Aust 1994; 161: 671-672. Roughead EE. The pharmaceutical representative and medical practitioner encounter: implications for quality use of medicines [master's thesis]. Melbourne: School of Health Systems Sciences, La Trobe University, Aug 1995. Lexchin J, Holbrook A. Methodologic quality and relevance of references in pharmaceutical advertisements in a Canadian medical journal. Can Med Assoc J 1994; 151: 47-54. Shaughnessy AF, Slawson DC, Bennet JH. Separating the wheat from the chaff: identifying fallacies in pharmaceutical promotion. J Gen Intern Med 1994; 9: 563-568. Orlowski JP, Wateska L. The effects of pharmaceutical firm enticements on physician prescribing patterns: there's no such thing as a free lunch. Chest 1992: 102: 270-273. Waud DR. Pharmaceutical promotions. N Engl J Med 1992; 327: 1688. Scott DK, Ferner RE. "The strategy of desire" and rational prescribing. Br J Clin Pharmacol 1994; 37: 217-219. Sutherland M. Advertising and the mind of the consumer: what works, what doesn't and why. Sydney: Allen & Unwin, 1993. Consumers Health Forum Pharmaceuticals Project Final Report. Canberra: Consumers Health Forum, 1995. Denig P, Haaijer-Ruskamp FM. Do physicians take cost into account when making prescribing decisions? Pharmacoeconomics 1995; 8: 282-290. Mansfield PR. Classifying improvements to drug marketing and justifications for claims of efficacy. Int J Risk Safety Med 1991; 2: 171-184. Smith AJ. The quality (of) use of medicines. Med J Aust 1996; 165: 8-9. Ahmed T, Silagy C. The move towards evidence-based medicine. Med J Aust 1995; 163: 60-61. Shaughnessy AF, Slawson DC. Pharmaceutical representatives: effective if used with caution. BMJ 1996; 312: 1494. Black F. Teaching rational prescribing. Aust Fam Physician 1996; 25: 1097-1099. Authors' details Medical Lobby for Appropriate Marketing Inc, Bedford Park, SA. Peter R Mansfield, BM BS, General Practitioner; and Director, Medical Lobby for Appropriate Marketing. Reprints: Dr P R Mansfield, MaLAM, PO Box 172, Daw Park, SA 5041. E-mail: peter.mansfield AT flinders.edu.au - ©MJA 1997 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Peter R Mansfield

Antibiotic use or misuse? The public, as well as prescribers, need education about appropriate antibiotic use MJA 1997; 167: 116-117 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - ©MJA1997 Compared with similar developed countries, Australia has a high rate of antibiotic use. This is made clear in this issue of the Journal by McManus et al.,1 who show that retail sales of oral antibiotics in Australia in 1994 were about 25 defined daily doses (DDDs) per 1000 population/day, compared with 24 in the United States, 16 in the United Kingdom and 11 in West Germany. The reasons for these differences are less clear. Indeed, they seem paradoxical, as Australia has most of the conventional prescribing controls in place -- a strict regulatory process for evaluating new drugs, the tightly controlled Pharmaceutical Benefits Scheme (PBS), and prescription-only availability. Australia also has a strong tradition of promoting appropriate prescribing in medical schools, through publications such as Antibiotic guidelines2 and through education of medical and pharmacy practitioners. The MJA has been an educational leader in this area, publishing articles and editorials on rational drug use,3,4 antibiotic guidelines5 and antibiotic prescribing interventions in both hospitals6,7 and general practice.8 Cynics often blame the high rate of antibiotic use on the pharmaceutical industry and its intensive promotional activities. Yet the industry is also bound by the regulatory environment, its own code of ethics, and the very powerful effects of the PBS on market forces. The PBS has ensured that drugs in Australia are among the cheapest in the Western world. But, has it ensured that we use antibiotics wisely? The climate is now right to educate the public about infections and when antibiotics might not help. Antibiotics are a valuable resource that is easily squandered. They are unique in being specifically designed to have no action on the host. This can make them attractive to both prescriber and patient, as they can be taken "just in case" the infection is bacterial. However, adverse reactions are still a risk. In addition, bacteria have the ability to mutate to or acquire resistance at rates sufficient to reduce or negate antibiotic usefulness within one to two decades.9,10 Unnecessary prescribing adds to the selective pressure for antibiotic resistance. This leads in turn to increased costs to the community because of the need for more expensive, broader-spectrum agents, extra visits to medical practitioners, and further prescriptions or hospitalisations for antibiotic failures. Broader-spectrum agents generate further resistance, leading steadily to multidrug resistance. Eliminating unnecessary antibiotic use cannot stop resistance emerging, but can reduce its frequency and prolong the useful life of the older, cheaper antibiotics. It is widely believed among Australian microbiology and infectious diseases practitioners that their colleagues often misuse antibiotics. This view is reinforced by results presented by McManus et al., from the Therapeutics Resource and Educational Network for Doctors (TREND) project of the Royal Australian College of General Practitioners. These show widespread use of antibiotics for respiratory tract infections, which are mostly caused by viruses. Australians are unlikely to suffer more bacterial infections or superinfections than their counterparts in other developed countries. More likely, the long history of unnecessary prescribing has built up a community belief that antibiotics are needed for most infections. We have also learnt that information about adverse reactions has only a modest impact on prescribers. For example, publicity about serious adverse reactions to trimethoprim- sulfamethoxazole, flucloxacillin and amoxycillin-clavulanic acid, through means such as the Drug reactions advisory committee bulletin, letters to general practitioners and via the PBS, had minimal effects on prescribing volumes. Subsequent regulatory interventions by the Therapeutics Goods Administration and the PBS had variable results. Flucloxacillin use declined about 30% between 1994 and 1995, and adverse hepatic reactions declined by 50%. In contrast, over the same period use of amoxycillin-clavulanic acid rose by about 10%, and adverse hepatic reactions by 15%.11 We have spent the past decade haranguing prescribers without the expected dividends. However, they continue to be handicapped by the lack of rapid diagnostic tests for common infections to determine need for an antibiotic before prescribing. Thus, it may well be time to switch our attention from the supply to the demand side -- patients must be empowered with basic knowledge about infections. Last year saw the first small step, with the introduction of National Medicines Week, focusing on antibiotics. Soon after, the public began to take notice of emerging resistance and the impact of indiscriminate antibiotic use, largely through the "doomsday" and "superbug" scenarios promoted by the media with stories about drug-resistant Streptococcus pneumoniae, multidrug-resistant Mycobacterium tuberculosis, vancomycin-resistant enterococci, and, most recently, vancomycin-resistant Staphylococcus aureus. The climate is now right to educate the public about infections and when antibiotics might not help. This will reduce not only antibiotic misuse, but also the number of patient visits to medical practitioners, with major benefits for both the community and government. We need a measured approach to public education. It should be conducted at many levels, including in secondary schools, during patient visits to health professionals and through specifically targeted local and national programs similar to National Medicines Week. On an optimistic note, as McManus et al. show, oral antibiotic use actually declined slightly between 1989 and 1994. We must capitalise on this trend by intensifying efforts to eliminate unnecessary use. Lessons can be learned from the approach to other major public health issues -- a judicious combination of regulation and education is likely to be most successful. A pro-active approach to the regulation of availability, prescribing and access to antibiotics, rather than one that is reactive to the pressures of cost and adverse reactions, will favour rational use. Education is needed for health professionals, at both undergraduate12 and postgraduate level,8,13 and for consumers. Everyone will benefit from a better understanding of the basics of infectious diseases and their management given that infections are the commonest of human ailments. John Turnidge Director, Microbiology and Infectious Diseases Women's and Children's Hospital, Adelaide, SA McManus P, Hammond L, Whicker SD, et al. MJA 1997; 167: 124-127. Victorian Drug Usage Advisory Committee. Antibiotic Guidelines. 9th edition. Melbourne: Victorian Medical Postgraduate Foundation Therapeutics Committee, 1996. Moulds RFW. From knowledge to action: improving drug prescribing. Med J Aust 1996; 165: 299-300. Moulds RFW. Rational therapeutics: the way ahead. Med J Aust 1992; 156: 823-824. McDonald P. Antibiotic guide-lines: do we know where we are? Med J Aust 1989; 150: 610-611. Harvey KJ, Stewart R, Hemming M, et al. Educational antibiotic prescribing. Med J Aust 1986; 145: 28-32. Landgren FT, Harvey KJ, Mashford ML, et al. Changing antibiotic prescribing by educational marketing. Med J Aust 1988; 149: 595-599. DeSantis G, Harvey KJ, Howard D, et al. Improving the quality of antibiotic prescription patterns in general practice. The role of educational intervention. Med J Aust 1994; 160: 502-505. Turnidge J, Nimmo G, Francis G, and the Australian Group on Antimicrobial Resistance. Evolution of resistance in Staphylococcus aureus in Australian teaching hospitals. Med J Aust 1996; 164: 68-71. Collignon PJ, Bell JM, on behalf of the Australian Group on Antimicrobial Resistance (AGAR). Drug-resistant Streptococcus pneumoniae : the beginning of the end for many antibiotics? Med J Aust 1996; 164: 64-67. Adverse Drug Reactions Advisory Committee. Antibiotics of continuing concern. Aust Adverse Drug React Bull 1996; 15: 6-7. Snell BF on behalf of the organising committee of the ASCEPT/CHF Conference. Rational prescribing: the challenge for medical educators. Med J Aust 1992; 156: 352-354. Eckert GM, Ioannides-Demos LL, McLean AJ. Measuring and modifying hospital drug use. Med J Aust 1991; 154: 587-592. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

John Turnidge

Antibiotic use in the Australian community, 1990-1995 Peter McManus, M Leigh Hammond, Susan D Whicker, John G Primrose, Andrea Mant and Steven R Fairall For editorial comment see Turnidge Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Results - International comparisons of antibiotic usage - Types of antibiotics used in Australia and indications - Discussion - Acknowledgement - References - Authors' details Make a comment - - ©MJA1997 Abstract Objective: To determine the pattern of antibiotic use in the Australian community, 1990-1995, and compare it with the pattern in other developed countries. Design: Survey of data from the national database on drugs dispensed in Australia (1990-1995), an international database on retail drug sales (1985-1994), and Australian prescriber surveys (1994, 1995). Main outcome measures: National and international retail sales of oral antibiotics (defined daily doses [DDDs]/1000 population/day) and antibiotic prescriptions dispensed through community pharmacies by drug type; antibiotic prescribing profiles for common conditions. Results: Antibiotic use in Australia remained steady between 1990 and 1995, with an estimated 24.7 DDDs/1000 population/day dispensed through community pharmacies in 1990 and 24.8 DDDs/1000 population/day in 1995. Amoxycillin, although declining in use, remained the most dispensed antibiotic. Compared with the other countries surveyed, Australia had the highest percentage use of tetracyclines, such as doxycycline, and the lowest percentage use of fluoroquinolones. Use of trimethoprim-sulfamethoxazole and flucloxacillin declined in Australia. In new cases of upper respiratory tract infection or pharyngitis, an antibiotic prescription was recorded for 57% of urban patient encounters and 73% of rural patient encounters. Conclusions: Antibiotic use in Australia is high, as in many other developed countries, but did not increase between 1990 and 1995. The overall profile of antibiotic use in Australia by drug class was similar to that in the United Kingdom. Antibiotics were still commonly prescribed for upper respiratory tract infection (which is usually viral), more commonly by rural than by urban general practitioners. MJA 1997; 167: 124-127 Introduction Patterns of antibiotic prescribing in Australia between 1987 and 1989 were reported previously by the Drug Utilization Sub-Committee (DUSC) of the Pharmaceutical Benefits Advisory Committee, Department of Health and Family Services.1 At the time, the Sub-Committee expressed concern over evidence of "inappropriate and unnecessarily expensive" practice, which was "directed too heavily towards the use of broad spectrum agents and newer more expensive drugs".1 To update these data, DUSC convened a working group in 1995, comprising representatives of DUSC, the Australian Pharmaceutical Manufacturers Association and the Therapeutics Resource and Educational Network for Doctors (TREND) project of the Royal Australian College of General Practitioners. This group reviewed Australian and international data on antibiotic sales and dispensing to determine patterns of antibiotic use in Australia between 1990 and 1995, and to compare these with patterns in similar developed countries. To understand trends in drug use, the group also analysed prescriber surveys of the indications for antibiotic use. Methods Data were derived from four sources: Prescription dispensing data: These were obtained from the database maintained by the DUSC secretariat which monitors dispensing of prescription medicines through community pharmacies in Australia. These data include dispensing to some private hospitals, but not public hospitals. The database contains information on all subsidised prescriptions processed by the Health Insurance Commission, together with an estimate of non-subsidised prescriptions from an ongoing survey of a sample of about 250 community pharmacies.2 Measurement units are either prescription volumes or number of defined daily doses (DDDs)/1000 population/day. The DDD is based on the assumed average daily dose of the drug when used for its main indication by adults. It is the unit approved by the World Health Organization for drug use studies and allows for comparisons independent of differences in price, preparation and quantity per prescription.3 Sales data: Data on sales of oral antibiotics to retail and hospital markets in a number of countries were obtained from Intercontinental Medical Statistics (IMS), Melbourne. This is a commercial market research organisation which collects sales data and surveys general practitioner (GP) prescribing in 33 countries.4 Data were retrieved as unit sales by form and strength and drug class and then converted to DDDs/1000 population/day. Prescriber survey: Diagnoses for which patients were prescribed anti biotics and patient ages were obtained from the Australian Medical Index (AMI), the survey of GP prescribing conducted by IMS. This uses a sample of 420 GPs stratified in line with the total Australian GP population by metropolitan/country location, age, year of graduation, and practice size (patient numbers). These GPs record all patient encounters over seven consecutive days in each quarterly survey period. The data are then projected to obtain quarterly estimates of prescribing patterns by diagnosis and by patient age and sex for the Australian GP population. At the end of a four-quarter cycle, GPs are invited to continue participating. About half agree, and the remainder are replaced by new recruits. As GPs start in various quarters of the year, there is continual turnover; GPs are not usually kept in the survey for more than two years. TREND project: Use of antibiotics for management of upper respiratory tract infection (URTI)/pharyngitis and influenza was examined using the database of 33 203 doctor-patient encounters recorded in August and September 1994 by the TREND project. This project was part of the development of a new practice assessment in therapeutics option within the RACGP Quality Assurance and Continuing Education Program. Participating GPs recorded prospectively their drug and non-drug management, including lifestyle advice, investigations and referrals, for 110 consecutive patient encounters of all types (including surgery and telephone consultations, home, hospital and nursing home visits). The GP sample was drawn from two urban and two rural areas in NSW which were selected randomly from all NSW Divisions of General Practice, after matching within urban (16 Divisions) and rural (11 Divisions) strata. Matching variables were the index of relative socioeconomic disadvantage (from the 1991 Census5 ) and GP-to-population ratios (from the Medicare claims database as at the end of June 1993) (Gordon Calcino, Acting Director, Technical Support Section of the General Practice Branch, Department of Health and Family Services, personal communication). The rural areas included both major and outlying towns, but not remote rural areas. All GPs from the four areas were eligible for the survey, based on a list provided by the General Practice Branch from the Medicare claims database. Of the 783 GPs approached, 303 (38.7%) completed the practice assessment in 1994. Participants had a similar sex distribution to the 1994 NSW GP population, but a somewhat younger average age.6 Results Between 1990 and 1995, there was little change in the level of antibiotics dispensed through Australian community pharmacies, with an estimated 24.7 DDDs/1000 population/day dispensed in 1990 and 24.8 DDDs/1000 population/day in 1995. Pharmaceutical industry sales data of 25.2 DDDs/1000 population/day in 1989 and 24.8 DDDs/ 1000 population/day in 1994 (0.3% fall on compound annual growth rate) confirm this stability in overall use. International comparisons of antibiotic usage Retail sales of oral antibiotics in Australia and seven major developed countries in 1985, 1989 and 1994 are compared in Figure 1. Like most developed countries, Australia had a high use of oral antibiotics. In 1994 retail sales in Australia were second to those in France and followed closely by those in the United States. However, between 1989 and 1994 sales in Australia did not show the compound annual growth seen in all the other countries except Canada -- France (up 2.8%), United States (up 2.3%), Italy (up 2.9%), West Germany (up 4.4%) and the United Kingdom (up 3%). Sales of oral antibiotics to hospitals in 1994 and the percentage this represented of the total market are shown in Box 1 (above). The percentage was similar in Australia, Canada and the UK (7%, 9% and 11%, respectively), lowest in the US (5%) and highest in West Germany (38%). Figure 2 shows the percentage split of the oral antibiotic market by drug class in 1994. Australia had the highest percentage use of tetracyclines (25.5% of total oral antibiotics), but the lowest use of fluoroquinolones (2.2%) and mid range use of penicillins -- both narrow spectrum (7.1%) and broad spectrum (35%). The overall profile of antibiotic use in Australia was similar to that in the UK. Types of antibiotics used in Australia and indications The top 10 antibiotics, on prescription volume, dispensed through Australian community pharmacies in 1990 and 1995 are shown in Box 2. Amoxycillin was the most-dispensed antibiotic in 1990 and, although declining in use, remained in this position in 1995. Dispensing of doxycycline and erythro mycin also declined, while that of amoxycillin-clavulanate increased. Cefaclor and roxithromycin were new additions to the top 10 dispensed antibiotics in 1995. Converting prescription volume to DDDs/1000 population/day altered the relative ranking of some drugs. For example, drugs in the tetracycline group, which have increased maximum quantities available for treatment of severe acne, rose in rank (1990). In contrast, cefaclor, which has a high DDD (1.5g) by Australian standards, fell from third to seventh position (1995). Box 2 also shows antibiotic prescribing profiles for various indications in 1995. For sinusitis, the most prescribed antibiotics were doxycycline (20.7%), amoxycillin-clavulanate (18.1%) and cefaclor (15.1%). For bronchitis, the most prescribed antibiotic was amoxycillin (18.1%), followed closely by roxithromycin (16.5%) and cefaclor (15.2%). In urinary tract infections, trimethoprim-sulfamethoxazole (28.5%) was most commonly prescribed, followed by cephalexin (18.9%) and amoxycillin-clavulanate (17.2%). Antibiotic prescribing for upper respiratory tract infection (URTI)/pharyngitis and influenza was examined in the TREND sample of GPs from the August-September 1994 audit; 11.6% of encounters were for URTI/pharyn gitis and 1.2% for influenza. For new cases of URTI/pharyngitis, an antibiotic prescription was recorded for 57% of urban patient encounters and for 73% of rural patient encounters. Corresponding figures for antibiotic prescribing in new cases of influenza without pneumonia were 30% of urban and 62% of rural patient encounters. The TREND project did not evaluate whether the prescription was to be filled only under certain conditions (e.g., if symptoms had not improved after a certain interval), but some GPs commented that this was their advice to patients. For symptomatic management, the most common choices were decongestants and analgesics. AMI survey data showed that overall antibiotic usage by age broadly followed the proportional representation of particular age groups in the community, with the exception of the 0-19 years age group. This group received 36.9% of antibiotic prescriptions, but made up only 28.7% of the population. However, for specific conditions the age patterns varied. For example, the TREND project showed that an antibiotic was less often prescribed for children aged 0-5 years with URTI (34.1%) than for adults aged 50 years and over (62.5%). Figure 3 shows quarterly fluctuations in dispensing of oral antibiotics compared with oral β-blockers -- a drug type used on an ongoing basis. Antibiotic dispensing was markedly seasonal, with higher levels in the winter quarters (April to June and July to September), while dispensing of oral β-blockers was low at the beginning of the year and high at the end. The second pattern was typical of "safety net" fluctuations.7 These result from Pharmaceutical Benefits Scheme (PBS) provisions that provide drugs free, or at lower cost, to the patient if they are dispensed after the patient has incurred a set expenditure on PBS items in a calendar year (the "safety net" threshold). Consequently, patients tend to fill repeat prescriptions towards the end of the safety net year, after they reach this threshold. Changes to reduce these fluctuations were introduced in November 1994. Discussion This report is a unique attempt by diverse groups to combine their data sources to give a more complete picture of antibiotic use in Australia than has previously been available. The comparison between seven major developed countries showed that community use of antibiotics in Australia between 1985 and 1994 was high -- second only to France, with the US a close third -- but did not increase during the 1990s, as it did in most of the other countries. In 1994, hospitals accounted for only 7% of retail sales of oral antibiotics in Australia, similar to the percentages seen in Canada and the UK. Similarly, a survey of cardiovascular drug use in Australian public hospitals found that hospital use accounted for less than 10% of the total use of all cardiovascular drug groups.8 The highest percentage of antibiotic use in the hospital sector was found in West Germany, where capping of GP prescribing budgets was introduced in 1993. It has been argued that these prescribing budgets for reimbursable drugs have increased hospital budgets.9 Australia had the highest percentage use of tetracyclines among the seven major developed countries, possibly because of its use in managing acne. In contrast, Australia had the lowest percentage use of fluoroquinolones, most likely because of PBS prescribing restrictions ("authority required"). Amoxycillin remains the antibiotic most dispensed through community pharmacies in Australia, but its use declined between 1990 and 1995, undoubtedly because of transfer prescribing to amoxycillin-clavulanate or other antibiotics. Concerns over an increased risk of severe adverse reactions with trimethoprim-sulfamethoxazole in the elderly10 and of hepatotoxicity with flucloxacillin11 were probably respon sible for the marked fall in use of these drugs and the rise in use of cephalexin, a substitute for flucloxacillin in skin and soft-tissue infections pending the availability of dicloxacillin (PBS listed in 1997).12 The winter increase in dispensing of oral antibiotics in Australia contrasted with the "safety net" fluctuations of the oral β-blockers, which are used on an ongoing basis, and probably reflected treatment of respiratory tract infections. In fact, antibiotics were prescribed for 57%-73% of new cases of URTI. This contrasts with peer consensus recommendations on the use of antimicrobial drugs in medical practice. The Antibiotic guidelines13 state that for URTI "the cause is almost invariably viral" and "antibiotics are not indicated". Furthermore, TREND data show that rural GPs are more likely to prescribe antibiotics for URTI than urban GPs. The difference may reflect rural GPs' concern for the greater patient travel and inconvenience in visiting the doctor in the country, with prescriptions being supplied for use if symptoms fail to resolve after a period of time. However, it may also reflect differences in access to continuing education and in industry promotion between rural and urban GPs. The data also provide insight into GPs' perceptions of antibiotic resistance among bacteria. For sinusitis, the most prescribed antibiotics were doxycycline, amoxycillin-clavulanate and cefaclor, which are recommended if resistance to amoxycillin issuspected or proven.13 For bronchitis, amoxycillin was most prescribed, followed closely by roxithro mycin and cefaclor, which are recommended if a b -lactamase producing organism is isolated or if the clinical response is slow. Our results indicate a strong perception among doctors that resistant organisms are a significant clinical problem, at least for sinusitis and bronchitis. Reasons for this are unclear and deserve investigation; they may include previous clinical experience of slow resolution of these infections with standard therapy, or awareness of the prevalence of resistant bacteria in the local community. A corollary to the study of antibiotic use is an examination of the patterns of antibiotic resistance in bacteria, which may be associated with levels of use of particular antibiotics and with total use. This issue is currently being explored in Australia by the Australian Group on Antimicrobial Resistance and by the National Antimicrobial Resistance Surveillance Program and internationally by the Alexander Project. Acknowledgement Members of the Antibiotic Working Group, which helped prepare these data were: Drug Utilization Sub-Committee: Julie Lindner, Peter McManus, John Marley, Andrew Parkes and John Primrose. Australian Pharmaceutical Manufacturers Association and pharmaceutical industry: Lee Ausburn, Roger Fraser, Steven Fairall, Mendel Grobler, Leigh Hammond, Peter Kofler and Jenny Winter. Royal Australian College of General Practitioners Therapeutics Resource and Educational Network for Doctors (TREND): Andrea Mant and Sue Whicker. The TREND project was funded by a grant from the Pharmaceutical Education Program of the Department of Health and Family Services. References Birkett DJ, Mitchell AS, Godeck A, et al. Profiles of antibacterial drug use in Australia and trends from 1987 to 1989. A report from the Drug Utilization Subcommittee of the Pharmaceutical Benefits Advisory Committee. Med J Aust 1991; 155: 410-415. Edmonds DJ, Dumbrell DM, Primrose JG, et al. Development of an Australian drug utilisation database. A report from the Drug Utilization Subcommittee of the Pharmaceutical Benefits Advisory Committee. PharmacoEconomics 1993; 3: 427-432. Nordic Council on Medicines. Nordic Statistics on Medicines 1990-1992. NLN publication number 34. Uppsala, Sweden: NLN, 1993. Hurley SF, McNeil JJ, Berbatis CG. Sources of Australian pharmacoepidemiology data. Community Health Studies 1988; 12: 82-96. Australian Bureau of Statistics. Index of relative socioeconomic disadvantage. Canberra: ABS, 1993. (Catalogue no 1356.0.) Australian Institute of Health and Welfare. Medical labour force 1992-93. National Health Labour Force Bulletin No. 3. Canberra: Australian Institute of Health and Welfare, Jul 1995. McManus P. Drug utilisation [letter]. Med J Aust 1993; 158: 724. Doecke C, Harvey R, Havas L. Cardiovascular drug use in Australian hospitals 1990. Summary report of a survey conducted by the Society of Hospital Pharmacists of Australia and the Australian Institute of Health for the Commonwealth Department of Community Services and Health. Canberra: the Department, Oct 1991. German drug caps boost hospital costs SCRIP 1993; 1877: 4. Adverse Drug Reactions Advisory Committee. Trimethoprim-sulphamethoxazole warning on elderly. Aust Adverse Drug React Bull 1990 Fed. Fairley CK, McNeil JJ, Desmond P, et al. Risk factors for development of flucloxacillin associated jaundice. BMJ 1993; 306: 233-235. Turnidge J. What to use instead of flucloxacillin [editorial]. Aust Prescriber 1995; 18: 54-55. Victorian Medical Postgraduate Foundation. Antibiotic guidelines 1996/97. 9th edition. Melbourne: The Foundation, 1996. (Received 19 Dec 1996, accepted 29 Apr 1997) Authors' details Department of Health and Family Services, Canberra, ACT. Peter McManus, BPharm, MMedSc, Secretariat, Drug Utilization Sub-Committee; John G Primrose, FRACR, Medical Advisor, Health Benefits Division. SmithKline Beecham (Aust), Melbourne, VIC. M Leigh Hammond, FRCPA, Medical Director. Therapeutics Unit, Royal Australian College of General Practitioners, Sydney, NSW. Susan D Whicker, PhD, Scientific Director. Drug and Alcohol Program, Eastern Sydney Area Health Service, Sydney, NSW. Andrea Mant, MD, FRACGP, Clinical Director. GPS Business Unit, Eli Lilly, Sydney, NSW. Steven R Fairall, BScAg, Associate Director. Reprints will not be available from the authors. Correspondence: Mr P McManus, Drug Utilization Sub-Committee, Department of Health and Family Services, GPO Box 9848, Canberra, ACT 2601. E-mail: peter.mcmanus @ health.gov.au Make a comment - - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Peter McManus · John G Primrose · Andrea Mant · Steven R Fairall

Australian trends in opioid prescribing for chronic non-cancer pain, 1986-1996 James R Bell Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - ©MJA1997 Abstract Objective: To identify trends in the use of opioid drugs for chronic non-cancer pain. Design: Review of three sets of official records -- the record of Schedule 8 (S8) opioid drugs used in Australia, 1984-1995, from the national Department of Health, Housing and Community Services; New South Wales Department of Health statistical summaries of the number of authorities to prescribe S8 drugs for cancer pain and non-cancer pain for each June from 1990 to 1996; and NSW Department of Health patient records for a cohort of patients first prescribed S8 drugs in 1991. Main outcome measures: Total quantities of opioids used in Australia; numbers of S8 authorities issued in NSW. Outcome measures for the cohort study were the proportion of patients remaining on opioids long-term, the proportion for whom dose escalated over time, and the diagnoses for which opioids were being prescribed. Results: Between 1986 and 1995, the amount of oral morphine used in Australia rose from 117 to 578 kg. Use of all other oral S8 opioids combined increased from 93 to 149 kg. In NSW, the number of authorities to prescribe for non-cancer pain rose from 3326 in June 1990 to 5743 in June 1996 (73% increase), while cancer pain authorities rose from 2652 to 4831 (82% increase). Sixty-nine of the 102 patients ceased to receive drugs on authority over the five year follow-up. These subjects received opioids for a mean of 19 months. Among the remaining 33 subjects, dose escalation was common. Diagnostic information indicated that many patients had significant psychological and social problems. Conclusions: There has been a dramatic increase in opioid prescribing, a substantial proportion of which is for non-cancer pain. In a sample of patients being treated for non-cancer pain, long term use and dose escalation occurred in one third of cases. MJA 1997; 167: 26-29 Introduction There is evidence that the use of opioids is increasing worldwide,1 and the increasing use of slow release morphine in Queensland has recently been reported.2 In recent years there has been a cautious reappraisal of the role of opioids in chronic non-cancer pain.3,4 A recent survey of members of the Australian Pain Society found that 85% of respondents felt that opioid drugs could be used in patients with chronic pain.5 However, it is well recognised that benefits of opioid use in terms of improved pain control and sense of well-being need to be weighed against the risk of an increase in drug dependence. The aims of this study were to describe trends in opioid prescribing for chronic non-cancer pain, to investigate whether a person who begins taking oral opioids regularly will continue to do so in the long-term, and to assess the extent to which opioid treatment is associated with dose escalation over time. Methods Three data sources were used: Records from the Commonwealth Department of Health, Housing and Community Services. This organisation maintains records of drugs consumed in each State, and officers of the department provided data on national and State consumption of Schedule 8 (S8) opioid drugs for the years 1984-1995. Figures on oral opioid consumption obtained from the Commonwealth give a State by State breakdown on all morphine preparations except morphine mixtures. For the years 1986-1988 use of these morphine mixtures in each State was documented State by State, and NSW accounted for 50%-66% of national consumption; after 1988 only figures for national consumption are available. For the purposes of this study, NSW consumption of morphine mixtures after 1988 was estimated to be 55% of national consumption. By 1995 morphine mixtures accounted for less than 20% of total oral morphine consumption, so inaccuracy in this estimate is unlikely to alter greatly the overall trend in oral morphine use. Monthly summaries of authorities to prescribe S8 drugs from the Pharmaceutical Services Branch (PSB) of the NSW Department of Health. It is a legal requirement in all Australian States that regular prescribing of S8 drugs to any individual patient beyond a certain minimum period requires an authority. The issued authorities specify whether opioids are prescribed for cancer pain or non-cancer pain, and trends in the issuing of authorities provide an indication of whether there has been an increase in prescribing for non-cancer pain. In NSW, the PSB issues these authorities, and since 1990 the department has prepared a monthly summary of all current authorities. Summaries for the month of June each year were used to estimate trends in the point prevalence of authorities to prescribe opioid drugs from 1990 to 1996. Individual patient files held by the PSB. Applications for an authority to prescribe S8 drugs are reviewed by a medical committee, and new applications are usually approved if supported by someone with specialist medical qualifications. Most authorities are issued for 6 or 12 months, at which time a repeat application must be lodged, usually accompanied by a clinical report on the patient's progress. Thus, there is a record of reports and letters which have been submitted supporting applications to prescribe S8 drugs. From these records a cohort of patients was identified for whom a new authority (i.e., not a continuation of a previous authority) was issued in February and March, 1991, to prescribe an opioid drug in non-cancer pain. Records for this cohort were followed up for five years. Files were studied to ascertain in each case whether the patient continued taking S8 drugs for the full five years, whether their daily dose of opioid escalated over time, and to identify their diagnoses and comorbidities. The study was approved by the ethics committee of the South Eastern Sydney Area Health Service. The collection of data from NSW Department of Health files was performed by two medical students. No information identifying patients or prescribing doctors was available to any clinician who could have been involved in the patient's care. Results Opioid consumption The national consumption of opioids for 1986-1995 is displayed in the Figure. This illustrates a dramatic increase in the use of oral morphine, a similar rate of increase in the use of methadone syrup (employed in the treatment of addiction), and a small increase in other S8 opioids (primarily oxycodone and codeine). During the same period, use of injectable opioids also rose, from 4.1 to 7.1 million ampoules per year. The Figure (below) suggests that the advent of slow release morphine in 1990 in Australia has had a marked effect on prescribing patterns, as the rate of increase in morphine prescribing accelerated from that point. However, although some individual opioid drugs have declined in use, the increase in oral morphine has not been accompanied by a decline in the use of other opioid drugs. Figure: Australian consumption of opioids, 1986-1995. Figures for NSW parallel the Australian rise. Between the years 1990 and 1995, total oral morphine use in NSW rose from 87 to 209 kg per year (a 140% increase). In the same interval, the consumption of other S8 drugs rose from 42 to 46 kg per year (10% increase). Injectable S8 drugs rose from 1.2 to 1.3 million ampoules (8% increase). Authorities The number of S8 authorities current each June in NSW rose between 1990 and 1996. In those years, the number of authorities to prescribe for non-malignant pain rose from 3326 to 5743 (73% increase), while cancer pain authorities rose from 2652 to 4831 (82% increase). Follow-up of authority applications There were 102 patients for whom new authorities to prescribe an S8 opioid for non-malignant pain were sought in February and March, 1991: 54 women (mean age, 57; range, 28-91) and 48 men (mean age, 51; range, 23-77) (see Box). Although these were new applications, 30 subjects were already receiving other S8 opioid drugs on authority. The clinical impression is that dose escalation may be more likely in patients taking the potent, short-acting drug dextromoramide, and less likely in those taking low potency codeine or long-acting methadone. Despite the small numbers (see Box), the difference in the proportion of patients taking these different drug types whose opioid dose escalated approached significance (P = 0.053). Thirty-three patients (32.4%; 95% CI, 23.4%-42.3%) were still receiving S8 opioids five years later (although many were receiving a different S8 opioid in 1996). Twenty-six of the 102 patients (25.5%; 95% CI, 17.4%-35.1%) received escalating doses of opioids: 21 of the 33 patients who were still receiving opioids on authority in 1996, and five of the 69 people not receiving opioids on authority in 1996 (chi-squared = 44.69; 1df; P < 0.005). Patients receiving opioids for the full five years were more likely to escalate their dose (odds ratio, 22.4; 95% CI, 7.1-71.0). It is unlikely that escalation was simply a function of patients beginning with a low initial dose of opioid. Converting initial doses to equivalents of oral morphine, the group whose doses did not escalate began with a mean dose of 80 mg of oral morphine per day, while the group whose doses did escalate began with a mean dose of 87 mg per day. The PSB records documented that 14 patients from this cohort died between 1991 and 1996 (7 men, 7 women; mean age, 70; age range, 42-91). Most were elderly, with serious underlying disease. It seems that in many of these patients, prescribing opioids was part of terminal care. Excluding subjects known to have died, 33 of the remaining 88 subjects (38%) were still receiving opioid drugs on authority five years later. The 55 no longer receiving opioids on authority had received opioids for a mean of 19 months. Clinical data from authority applications In 63 applications the primary diagnosis was musculoskeletal pain, specifically back pain in 48 of these. In five cases the diagnosis was simply "chronic pain". Several patients had multiple, unrelated diagnoses -- such as "chronic back pain and gunshot wound", "backache and migraine", or "myalgic encephalomyelitis and migraine". In 27 cases seemingly unrelated diagnoses were recorded. The presence of multiple sources of severe pain probably reflects the prevalence in this population of somatoform disorders (i.e., disorders in which physical complaints are not fully explained by known medical conditions, or in which complaints or impairment are in excess of what would be expected from the patient's medical condition). The comments in the patients' files suggest that in many cases prescribing opioids is a response to difficult and unmanageable problems. There is more than a hint of frustration in many of the comments -- such as the terse letter: The situation is unchanged. His back feels "like a bag of broken china". I am still at a loss to know what to do and I have arranged to see him again in six weeks with further x-ray. Or a general practitioner's bleak summation: This patient has been so adversely affected by her CFS [chronic fatigue syndrome] and migraine she has been rendered completely dysfunctional as a human being and mother. While many of the patients in this study had multiple medical problems and histories of extensive treatment, often there were strong intimations of concurrent psychological and adjustment difficulties. For example, one patient had a history of multiple back operations, with a background of social problems described as "marriage collapsing, alcoholic father living with them, and a history of overdoses on tricyclic antidepressants and on benzodiazepines". While some of the patients had clearly defined diseases, and several were seriously ill, in 62 cases (61%) there were poorly defined medical problems. In 22 cases there was no clinical information other than a diagnosis. Among the other 80 files, the presence of social and emotional problems was noted in 29 cases (36%). The quality and thoroughness of medical information documented in the health department files was very limited. Discussion There has been a dramatic increase in the prescribing of oral morphine over the past decade. To put this rise in perspective, it is useful to compare the increase in prescribed morphine with the increase as a result of government policy in prescribed methadone syrup. Between 1986 and 1995 there was a marked expansion of the methadone program for the treatment of addiction, with the number of patients in treatment Australia-wide rising from around 1000 in 1984 to 13 000 in 1995. However, the increase in morphine consumption, driven by changes in clinical practice rather than policy, has been comparable to the increase in consumption of methadone syrup. Total use of other S8 opioids also increased during this period, suggesting that morphine consumption has not grown through replacing another opioid. The national data on overall opioid use are an accurate measure of the quantity of these drugs being prescribed each year. However, there are limitations on the use of official records in determining how much of this increase was for terminal care, and how much for chronic pain. In this study, the increase in authorities current in NSW was about half as great as the increase in oral morphine use between 1990 and 1995. Given that oral morphine is seldom used in acute pain management, the disparity between authorities and total amount of drug used suggests that many patients receive morphine for prolonged periods without an authority to prescribe having been issued. There is no way of knowing how many doctors prescribe opioids long-term to individual patients without ever seeking authority. Furthermore, it is possible that there is a systematic bias, with doctors prescribing for terminal care being less likely to apply for an authority than when prescribing for chronic non-cancer pain. However, even with these reservations, it seems reasonable to conclude that the increase in authorities in both categories and the increase in overall use of morphine indicate a change in attitudes to opioids, with more liberal use in both terminal care and chronic pain. Might this more liberal approach contribute to a problem with iatrogenic drug dependence? The hallmark of opioid dependence is that it is a chronic, relapsing, long-term problem. Most of the 102 patients who began taking opioid drugs on authority in early 1991 were no longer doing so five years later. However, some of them may have continued to receive opioids without an authority. Patients who move interstate, find a new doctor who does not seek an authority to prescribe or who "doctor shop" to get prescriptions from multiple prescribers may not appear in the health department records even though they continue to receive opioids. Some may have switched to agents such as combined paracetamol-codeine, a drug containing a modest dose of opioid, but for which no authority is required. It is also possible that some patients died without this coming to the attention of the health department. However, even allowing for these possibilities, the figures suggest that fewer than half the surviving patients were still taking opioids regularly five years after first taking them. It is difficult to assess the extent of problems of tolerance and dependence from the incomplete clinical data in official records. Previous studies on selected groups being treated in specialist facilities have reported that opioids can be used safely and effectively,3,4 but these reports give little indication of the extent to which problems are likely to arise in more diverse samples of patients treated in a range of settings. Dose escalation may not be a reliable indication of dependence, but may reflect changes in pathology. However, previous reports indicate that most patients with non-cancer pain do not require escalating doses over time.6 Clinical experience with cancer pain management indicates that during the first weeks of dosing with opioids a degree of tolerance is reached, but this reaches a plateau and thereafter a stable dose can be beneficial for prolonged periods.7 The system of S8 authorities means that patients have usually been receiving opioids for a couple of months before authority application, and by then should usually be receiving a stable and effective dose. Most patients discontinued opioid use after quite prolonged periods without dose escalation. It is likely that among the 25% whose dose escalated there were many patients with problems of dependence. The comments and diagnoses in the files indicate that opioids are often prescribed for patients with social problems, high levels of emotional distress, and unclear medical diagnoses. It is likely that many of these subjects have a mixture of somatoform disorders and diverse medical and psychosocial problems. The benefits and risks of opioid use in this setting are poorly understood. A supportive doctor-patient relationship and attention to psychiatric and medical comorbidity are more important aspects of the management of somatoform disorders.8 The value of psychological treatment has been demonstrated in recent randomised trials.9 The implication for treating chronic pain states where there appear to be contributing psychological or social factors is the need for a comprehensive approach to treatment. Opioid drugs may have a useful role in such a comprehensive approach. The risks of opioid dependence, with escalating pain and drug use and diminished activity, need to be set against the potential benefits in terms of improved pain control and well being. It has been suggested that the risks of dependence can be minimised when the drugs are prescribed by experienced and skilled medical practitioners.3 It is also probable that the current system of requiring doctors to obtain authorities to prescribe opioids long term is a valuable restraint on inappropriate prescribing of these drugs. Acknowledgements Data from the NSW Department of Health files were gathered by two medical students (Amanda Mather and Sarah Baldwin). Mr John Lumby, Pharmaceutical Services Branch, NSW Department of Health, assisted with access to Branch files. Ms Cheryl Regan, Treaties and Monitoring Section, Commonwealth Department of Health and Family Services, assisted by providing summary data on opioid consumption in Australia. The federal and State departments do not necessarily endorse any of the conclusions or opinions drawn from any data. References Hiraga K, Mizuguchi T, Takeda F. The incidence of cancer pain and the improvement in pain management in Japan. Postgrad Med J 1991; 67 Suppl 2: S14-S25. Richards AH. The use of controlled-release morphine sulfate (MS Contin) in Queensland 1990-1993. Med J Aust 1995; 163: 181-182. Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain; report of 38 cases. Pain 1986; 25: 171-186. Zenz M. Morphine myths; sedation, tolerance, addiction. Postgrad Med J 1991; 266: 2392-2397. Australian Pain Society. Newsletter, July 1996. McQuay HJ. Opioids in chronic pain. Br J Anaesth 1989; 63: 213-226. Foley KM. Changing concepts of tolerance to opioids: what the cancer pain patient has taught us. In: Chapman CR, Foley KM, editors. Current and emerging issues in cancer pain; research and practice. New York: Raven Press, 1993: 331-350. Quality Assurance Project. Treatment outlines for the management of the somatoform disorders. Aust N Z J Psychiatr 1985; 19: 397-407. Guthrie E. Psychotherapy of somatization disorders. Curr Opin Psychiatr 1996; 9: 182-187. (Received 11 Oct 1996, accepted 6 Mar 1997) Authors' details Drugs and Alcohol Unit, Prince of Wales Hospital, Sydney, NSW. James R Bell, BA, FRACP, Director. No reprints will be available from the author. Correspondence: Dr J R Bell, Drugs and Alcohol Unit, Prince of Wales Hospital, High Street, Randwick, NSW 2031. E-mail: james.bell @ unsw.edu.au ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

James R Bell

The use of oral opioids in patients with chronic non-cancer pain Management strategies Paul J Graziotti and C Roger Goucke Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Which patients? - Which doctors should prescribe? - Which drug? - Consent - How should these drugs be prescribed? - References - Authors' details - ©MJA1997 Abstract Background: The use of oral opioids in non-cancer pain is increasing, but it is not clear that this is improving outcomes for patients. These management strategies were developed as a consensus view between the two authors, who are both Directors of the Australian Pain Society. The strategies were subsequently reviewed and approved by the other Directors of the Society: four anaesthetists specialising in pain management, a pharmacist, a rheumatologist, two rehabilitation physicians and an occupational therapist. Evidence base: A Medline search of the literature since 1966 produced 163 relevant articles, including two randomised controlled trials of oral opioids in non-cancer pain. Management consensus A small group of patients with chronic non-cancer pain can benefit from the use of oral opioids. Thorough attention to diagnosis and patient history must precede any decision to prescribe opioids. Patients should be psychologically stable. Patient and doctor should agree beforehand on how to assess the outcome of therapy. Only one doctor (the patient's regular primary carer or pain specialist) should prescribe opioids and assess the response. Sustained release morphine preparations are the drug of choice. A trial of therapy, with goals and endpoint agreed between patient and doctor, should precede any decision to prescribe opioids in the long term. MJA 1997; 167: 30-34 Introduction Patients with chronic non-cancer pain present a number of challenges to their treating physicians. One such challenge is whether to use oral opioids in their treatment plan. The combination of poorly defined pathology, significant psychosocial factors, manipulative behaviour, dependence, tolerance and government regulations are formidable influences on management decisions. Because of these concerns, many doctors may decide not to prescribe opioids for patients with chronic non-cancer pain, and certainly current legislation discourages it. Arguments against the use of opioids in these patients have also been published.1,2 Yet, world-wide, there is a growing body of opinion that a small subgroup of patients with chronic non-cancer pain may function better and have less pain if treated with opioids, without requiring rapidly escalating doses or showing addictive behaviour. Data from recent randomised controlled trials3-5 support the finding of benefit in retrospective studies of patients treated with opioids for chronic non-cancer pain.6,7 This evidence suggests that a proportion of patients report an improvement in their level of analgesia and/or level of function.8 The prevalence of drug abuse, dependence and addiction has been estimated to be as low as 3.2%9 or as high as 18.9%,10 depending on definition. Fishbain et al. report that there is little evidence that addictive behaviours are common in the chronic pain population.11 There is evidence, however, that an increasing number of Australian patients are receiving prescribed oral opioids for both malignant and non-malignant pain.12 This may be filling a previously unmet need, but it is not clear if the increased prescribing for non-cancer pain is appropriate, whether there has been any increase in function, reduction of pain, reduction in suffering, or if any of these drugs will enter the illicit market. How then can we ensure the maximum benefit from the prescription of opioids for chronic non-cancer pain? Who are the appropriate patients? Who are the appropriate prescribing doctors? How should the drugs be prescribed? Which drugs should be prescribed? How and when should they be withdrawn? The aim of this article is to explore these issues and provide guidelines to assist practitioners in the appropriate use of oral opioids. Which patients? It is essential that all reasonable attempts be made to achieve a diagnosis for the cause of the pain, including nociceptive, neuropathic and psychological contributions. The demonstration of pathology commensurate with the degree of pain behaviour is desirable. However, patients often have pathology which is difficult to interpret (e.g., degenerative changes on spinal x-rays). Certain conditions result in neuropathic pain, which is usually a clinical diagnosis and may not be reflected in investigations such as radiographs or nerve conduction studies. This should not preclude a trial of opioids in these patients if otherwise appropriate. A thorough history of previous conservative therapy ( Box 1) should be taken before consideration is given to the medium to long term use of opioids. Previous drug therapy should include trials of non-opioid analgesics, tricyclic antidepressants and membrane-stabilising medications (e.g., sodium valproate, carbamazepine, mexiletine). Patients for whom opioids are being considered should be psychologically stable, although it is recognised that this is difficult to define. Patients in chronic pain may develop psychological problems as a result of the pain, and therein lies a dilemma for the physician. Will treating the pain reverse some of the psychological abnormalities? Or are the psychological abnormalities a significant contributor to the overall pain behaviour? Studies would suggest the former in most cases.13 A psychological assessment is essential for patients with poorly defined pathology, younger age, high levels of distress, or previous or ongoing substance abuse. Consideration should be given to managing these patients in a multidisciplinary pain centre ( Box 2). Which doctors should prescribe? The prescribing doctor should have an established therapeutic relationship with the patient. This excludes casualty officers, specialists who see a patient on one occasion only, after-hours locum services and (usually) junior medical staff working in outpatient departments. It is important that only one doctor prescribes the opioids and assesses the response. Patient and doctor must agree on how to assess the outcome of therapy before opioids are prescribed. Failure to reach the predetermined goals is an indication to cease prescribing. All patients who are considered suitable for the long term use of opioids in non-cancer pain should be assessed at some stage in a specialist pain management centre. Shared care between the general practitioner and the pain management centre is ideal. Which drug? Sustained release morphine preparations are the drugs of choice in patients with chronic non-cancer pain, because of their single- or twice-daily dosage and stable blood con centrations as a consequence of their more predictable pharmacokinetics. There is agreement internationally14 and within Australia15 that intramuscular opioids should not be used to treat chronic non-cancer pain. In particular, intramuscular pethidine should be avoided. It has a short half-life, possibly an increased risk of dependence due to its psychomimetic effects, and the potential for excitatory central nervous system effects from accumulated norpethidine concentrations after repeated doses. Codeine phosphate is a short-acting drug and as such has little place in chronic pain management. A controlled release preparation is available overseas and may prove useful. Immediate release morphine as morphine mixture (5-10 mg/mL) may be used for dose finding before beginning the use of sustained release morphine, but is generally unnecessary. It may be useful for breakthrough pain or exacerbations. Transdermal fentanyl patches may, in the future, provide a useful alternative for patients intolerant of morphine. Methadone and oxycodone rectal suppositories are useful alternatives to oral sustained release morphine preparations. Dietary advice should be given to minimise the problem of constipation and consideration should be given to the regular use of laxatives. Consent Patients prescribed opioids for the treatment of chronic non-cancer pain should be fully informed of the potential consequences of this therapy. There is increasing awareness that a written consent form* is a valuable tool, particularly when treating patients who for any reason are difficult to manage.16 Informed consent should include discussion of: Clearly defined specific goals of the treatment program. The likelihood of dependence and the risk of addictive behaviour. All patients will become dependent and are likely to experience withdrawal symptoms if opioid therapy is suddenly stopped. Addictive behaviour occurs in a much smaller proportion of patients and may be minimised by appropriate patient selection. The lack of published data on long term outcome of the effects of medically prescribed opioids. The potential for cognitive impairment, in particular that might affect driving ability. While there are few studies in non-cancer patients assessing cognitive function in the presence of opioids,17 the studies in cancer patients would suggest that cognitive function is actually improved when adequate analgesia is provided.18 The potentiating effect of opioids on the sedative effect of other medication. The possibility (for women) of physical dependence in children born to them if they continue to take opioids in late pregnancy. Indications for the cessation of treatment with opioids. The patient's responsibilities regarding the security of his or her medication. The consequences of aberrant behaviour ( Box 3) should be identified as clearly as possible. Side effects (e.g., constipation, nausea, sedation, dry mouth). How should these drugs be prescribed? Trial of oral opioid Before prescribing opioids on a long term basis, a trial should be undertaken over four to six weeks. Goals for the trial should be identified between doctor and patient, and the endpoint clearly stated. One doctor should institute and monitor the trial. The trial should commence with the equivalent of sustained release morphine 10-50 mg twice a day, with the outcome assessed after one week or less. Depending on response, the dose may be increased or decreased. In general, round-the-clock medication is the accepted regimen, although in patients with fluctuating pain conditions it may be more appropriate to consider a variable dosing regimen with oxycodone or morphine elixir.19 Patients must accept the responsibility of ensuring their supply of medication does not run out after hours. There is controversy regarding the expectation that patients will improve in function. Is it adequate for patients to achieve analgesia only? Is it adequate for patients to state that they feel better only? Certainly patients should reduce their use of other analgesics; ideally, they should show improved function. Perception of improved analgesia should be the minimal requirement, and failure to achieve at least partial analgesia at a moderate dose contraindicates any further long term opioid treatment. Most patients who experience minimal or no analgesic effect will stop taking the drug themselves before the end of the trial. Similarly, many patients who experience adverse side effects, such as severe nausea or constipation, will determine that these outweigh the analgesic benefits and stop taking the drug. Opioid-naive patients whose dose rapidly escalates within a month of starting treatment should generally be considered inappropriate for long term opioid therapy. At the end of the trial period, if the expected outcomes have not been achieved, the drug dose should be tapered over a few days and ceased. Ongoing reviews Patients who are then prescribed opioids on an ongoing basis should be reviewed at first fairly frequently (e.g., weekly), then monthly, by the prescribing doctor. A detailed review by a pain management centre should be undertaken annually. At each review, analgesic efficacy should be assessed, as should any improvement in the level of function. The responsible federal or State health department must be notified. Evidence of aberrant behaviour should be assessed. Aberrant behaviour is variable in its importance and relevance. Box 3 indicates factors which Portenoy20 has considered more or less predictive of the development of addictive behaviour. Patients identified with behaviour in the less predictive category indicate a need to assess the dose of drug, the psychological factors of relevance, the patient's expectations or the type of medication. If patients are identified with features in the more predictive category, the appropriateness of opioid prescription should be seriously reassessed. Often it will be necessary to reduce and then withdraw the opioid over a week. In other cases, a more regulated supply, such as daily or weekly prescriptions, may be appropriate. An initial written consent form indicating those factors for which supply will be withdrawn will make this easier. References Large RG, Schugg SA. Opioids for chronic pain of non malignant origin: caring or crippling. Health Care Anal 1995; 3: 5-11. Butler SH. Opiates for chronic pain: present American controversy. Regul Pept 1994; 52 Suppl 1: S295-S296. Jaddad AR, Carroll D, Glynn CJ, et al. Morphine responsiveness of chronic pain: double blind randomised crossover study with patient controlled analgesia. Lancet 1992; 339: 1367-1371. Arkinstall W, Sandler A, Goughnour B, et al. The efficacy of controlled release codeine in chronic non-malignant pain: a randomised placebo controlled trial. Pain 1995; 62: 169-178. Moulin DE, Iezzi A, Amireh R, et al. Randomised trial of oral morphine for chronic non-cancer pain. Lancet 1996; 347: 143-147. Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain: report of 8 cases. Pain 1986; 25: 171-186. Zenz M, Strumpf M, Tryba M. Long term oral opioid therapy in patients with chronic non-malignant pain. J Pain Symptom Manage 1992; 7: 69-77. Jamison RN. Comprehensive pretreatment and outcome assessment for chronic opioid therapy in non-cancer pain. J Pain Symptom Manage 1996; 11: 231-241. Tanb A. Opioid analgesics in the treatment of chronic intractable pain of non- neoplastic origin. In: Kitahata LM, Collins D, editors. Narcotic analgesics in anethesiology. Baltimore. Williams & Wilkins, 1982: 199-208. Tennant FS, Robinson D, Sagherian A, Seecof R. Chronic opioid treatment of intractable, non-malignant pain. NIDA Res Monagr 1988; 81: 174-180. Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence and addiction in chronic pain patients. Clin J Pain 1992; 8: 77-85. Richards AH. The use of controlled-release morphine sulfate (MS Contin) in Queensland 1990-1993. Med J Aust 1995; 163: 181-182. Waddell G, Pilowski I, Bond MR. Clinical assessment and interpretation of abnormal illness behaviour in low back pain. Pain 1989; 39: 39-41. Hagen N, Flynne P, Hays H, McDonald N. Guidelines for managing chronic non-malignant pain. Canadian Fam Physician 1995; 41: 49-53. Cherry DA, Gourlay GK. Pharmacological management of chronic pain: A clinician's perspective. Agents Actions 1994; 42: 173-174. Burchman SL, Pagel PS. Implementation of a formal treatment agreement for outpatient management of chronic non-cancer pain with opioid analgesics. J Pain Symptom Manage 1995; 10: 556-563. Zacny JP. A review of the effects of opioids on psychomotor and cognitive function in humans. Exper Chem Psychopharm 1995; 3: 432-466. Vainio A, Ollila J, Matikainen E, at al. Driving ability in cancer patients receiving long term morphine analgesia. Lancet 1995; 346: 667-670. Savage SR. Long term opioid therapy: assessment of consequences and risks. J Pain Symptom Manage 1996; 11: 274-286. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 1996; 11: 203-217. Authors' details Department of Pain Management, Sir Charles Gairdner Hospital, Perth, WA. Paul J Graziotti, FANZCA, FFARCS, Visiting Specialist; West Australian Director, Australian Pain Society. C Roger Goucke, FANZCA, Head; Secretary, Australian Pain Society. No reprints will be available from the author. Correspondence: Dr C R Goucke, Department of Pain Management, Sir Charles Gairdner Hospital, Perth, WA 6009. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Paul J Graziotti

Movement disorders with selective serotonin reuptake inhibitors Adverse Drug Reactions Advisory Committee MJA 1997; 166: 259 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Orolingual dyskinesia - Cases - Akathisia - Case - Comment - References - - ©MJA1997 The selective serotonin reuptake inhibitors (SSRIs) are being prescribed increasingly for major depression. The Adverse Drug Reactions Advisory Committee (ADRAC) has received more than 1800 postmarketing reports of adverse reactions to the SSRIs (fluoxetine, paroxetine and sertraline), with the most common reactions reported being rashes, headache, anorexia, nausea, vomiting, diarrhoea, dizziness, agitation, tremor and increased sweating. Reports describing the movement disorders of orolingual dyskinesia and akathisia are reviewed here. Orolingual dyskinesia Marchioni et al. described orolingual movements (intermittent facial movements, initially involving the tongue and lips) in a 74-year-old woman who had taken fluoxetine for seven months. 1 ADRAC has received nine reports of orolingual dyskinesia (after excluding reports describing tardive dyskinesia or orolingual movements as part of a generalised dyskinesia) where an SSRI was the only suspected drug since 18 January 1993. Fluoxetine was the suspected drug in four reports, sertraline in three and paroxetine in two. The nine reports described seven women and two men aged 22-89 years (median, 51 years). These dyskinesias were variously described as abnormal involuntary orolingual-buccal movements, persistent repetitive jaw movements, involuntary chewing movements and involuntary facial movements. In eight of the nine patients, they started within one month of starting to take the SSRI; in the remaining patient the movements started five months after starting to take the SSRI. Six of the nine patients had recovered at the time of reporting. Cases A 29-year-old woman taking no other medications was prescribed paroxetine 20 mg daily for depression. Four hours after taking only one paroxetine tablet she developed persistent repetitive jaw movements with chattering of her teeth. The movements and chattering occurred markedly for two days, and continued to occur with cold or fatigue over the next two weeks before gradually settling. She took no tablets after the first one. In another case, a 22-year-old man taking no other medications was prescribed a 20 mg paroxetine tablet daily for depression. After taking paroxetine for four weeks he experienced involuntary facial movements, accompanied by disturbed speech and agitation. He immediately stopped taking the paroxetine and quickly and fully recovered. Akathisia Olivera described a 40-year-old woman who developed akathisia (a form of restlessness in which there is the inability to sit still, an urge to move about constantly and a feeling of muscular quivering) after three days of taking paroxetine 20 mg daily. 2 ADRAC has received nine reports of akathisia where an SSRI was the only suspected drug since 17 February 1993. Fluoxetine was the suspected drug in six reports, paroxetine in two and sertraline in one. These nine reports described seven women and two men aged 29-86 years (median, 54 years). The akathisia started within 33 days of commencing the SSRI in seven patients, and the onset was within two days of commencing the SSRI in two of these seven. However, in the remaining two patients, the akathisia started five and eight months after commencing the SSRI. Eight of the nine patients had recovered at the time of reporting. Case An 86-year-old woman was prescribed 20 mg paroxetine daily for depression. Her only other medication was 5 mg felodipine daily, which she had started taking 12 months previously. She developed akathisia after taking paroxetine for five months -- she was unable to keep still, with restless legs and a constant need to pace. After she stopped taking the paroxetine only, she recovered fully. Comment Although acute dystonia is well recognised as an early adverse reaction to SSRIs, orolingual dyskinesia might be mistakenly thought to only occur later as tardive dyskinesia. It is important for prescribers to be aware that movement disorders such as orolingual dyskinesia and akathisia can occur in patients of any age, and that their onset may vary considerably from immediately on starting treatment to after many months of treatment. Adverse Drug Reactions Advisory Committee, PO Box 100, Woden, ACT 2606. References Marchioni E, Perucca E, Soragna D, et al. Choreiform syndrome associated with fluoxetine treatment in a patient with deficient CYP2D6 activity. Neurology 1996; 46: 853. Olivera AA. A case of paroxetine-induced akathisia. Biol Psychiatry 1996; 39: 910. - - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Oral retinoids and pregnancy Annabelle Chan, Marshall Hanna, Malcolm Abbott and Rosemary J Keane MJA1996; 165: 164-167 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - Adverse reactions - Teratogenicity - Prescribing guidelines - Compliance - Pregnancy prevention programs - Recommendations - Conclusions - Acknowledgements - References - Authors' details Register to be notified of new articles by email - - ©MJA 1996 The oral retinoids isotretinoin and etretinate are uniquely effective in the treatment of severe cystic acne and keratinisation disorders. Because of their known teratogenicity, there are strict prescription guidelines, but exposure during pregnancy still occurs. A dedicated effort by women and their clinicians is required, involving patient selection, education and informed consent, detailed contraceptive counselling, and careful monitoring and management, including pregnancy testing before commencement of therapy. (MJA 1996; 165: 164-167) Introduction T he Australian Drug Evaluation Committee lists only five drugs in Medicines in pregnancy 1 as Category X -- drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. The oral retinoids isotretinoin (Roaccutane, Roche) and etretinate (Tigason, Roche) are two of the five listed. The newly released acitretin (Neotigason, Roche) should also be included. These synthetic retinoids closely resemble naturally occurring vitamin A, essential for the maintenance of visual and reproductive function and for proliferation and differentiation of epithelial tissues. 2 They were released in the United States and Europe in 1982 and in Australia towards the end of 1985. Acitretin was released in Australia in late 1995 to replace etretinate, as it is more rapidly eliminated from the body. Isotretinoin is uniquely effective in severe cystic acne, and etretinate and acitretin in severe psoriasis and other keratinisation disorders which have proved recalcitrant to all other therapies. This accounts for their availability on prescription despite their teratogenicity . Adverse reactions The commonly reported adverse reactions (which are largely dose-related, of early onset and reversible on discontinuation) include dryness of the lips, mouth and eyes, hair loss and pruritus. 3 Less common but more severe, probably idiosyncratic, reactions (which may occur after weeks or months of therapy) include altered vision, headache, joint and muscle pain, abnormally raised serum transaminase levels, serum lipid changes, as well as increases in serum triglyceride and chol esterol levels and an increase in low density : high density lipoprotein ratio. Rare reactions include mental depression, severe hepatitis, diffuse hyperostosis of the spine and benign intracranial hypertension. Teratogenicity The most serious side effect, teratogenicity, was foreshadowed by animal studies, so that, at the time the drugs were released, strong warnings against exposure during pregnancy were given. The retinoids are believed to interfere with the activity and migration of cranial neural crest cells during development and thus cause craniofacial, thymic, conotrun cal heart and central nervous system malformations 4,5 (Box 1). Intellectual deficits in more than half the children exposed in utero have also been reported in follow-up studies to five years of age. 6 Isotretinoin Any fetal exposure during the first trimester within the therapeutic dose range of isotretinoin may be teratogenic. 7 Isotretinoin has a short elimination half-life of about 20 hours and the recommended contraception period after cessation of therapy is one month. Estimates from prospectively reported (i.e., before outcome was known) exposed pregnancies place the risk of teratogenicity for isotretinoin for first trimester exposure at around 28%, 7 reducing to around 4% for pregnancies occurring within one month of cessation of treatment 8 (Box 2). Etretinate Birth defects associated with etretinate include meningomyelocele, craniofacial and skeletal abnormalities and brain defects. 4,5 Etretinate is readily taken up into adipose tissue and slowly released from it. Thus, it has a long elimination half-life (120 days or more 2 ) and the recommended contraception period after therapy is two years. The best estimate from the literature of the risk of teratogenicity for exposure to etretinate during pregnancy is about 26%, 9 but the risk is likely to be less, as the pregnancies considered probably include retrospectively reported ones (in which there is a tendency to under-report normal outcomes). The risk for pregnancies occurring within two years of cessation of treatment appears to be considerably less, about 2%. All estimates are based on relatively few pregnancies (Box 2). Acitretin In spite of a shorter elimination half-life of 50 hours, a two-year contraception period after therapy has also been recommended for acitretin, as in some women there is conversion of acitretin to etretinate during therapy. 2,3,9 Up to 1994, there had been no exposures to acitretin during pregnancy reported prospectively to the manufacturer (Roche) with known outcomes; of three reported retrospectively, one aborted fetus had characteristic defects, one baby had high frequency hearing loss and a third was normal. None of the 32 prospectively reported pregnancies conceived in the two-year period after therapy has resulted in an infant with a birth defect (S Weber, Roche Products Medical Information Department, personal communication). Prescribing guidelines In Australia, authority to prescribe oral retinoids for specified conditions needs to be obtained under the Pharmaceutical Benefits Scheme, and they can only be prescribed by dermatologists (except in regions where there is no derm atologist available and a specialist physician may have authority to prescribe under State law). However, in the United States and Canada, 10 general practitioners and physicians may also prescribe these drugs. Roche recommends that: The possibility of pregnancy must be ruled out by a pregnancy test within two weeks before commencing treatment. Treatment should be commenced on the second or third day of the next normal menstrual period. An effective form of contraception should be used for at least one month before treatment, during treatment and for at least one month after cessation of treatment with isotretinoin, and for two years after treatment with etretinate and acitretin. Women should be effectively counselled about the risks to a fetus, and if pregnancy does occur they should immediately stop taking the drug and seek medical advice. To increase understanding of the implications of treatment, a specially designed consent form should be signed by the patient before commencing treatment. Breastfeeding should not occur while a woman is taking oral retinoids. The drugs should not be given to others, and should be kept out of reach of children. The manufacturer has also made available to dermatologists patient information pamphlets (also in several languages other than English), contraceptive guidelines and a special consent form for treatment. A warning that the product causes birth defects is carried on the drug package as well as the dispensed product. The Australasian College of Der matologists has provided comprehensive guidelines for prescription, focusing on signed informed consent for treatment, the performance of tests for pregnancy, liver function and lipid levels before treatment, and the importance of regular review. Compliance Despite these measures, exposure to the drugs during pregnancy has occurred both in Australia 11,12 and in other countries. While most women have been advised of the teratogenicity of the drugs, there has been less strict compliance with pregnancy tests and signed consent before initiation of treatment, with 4% of dermatologists in the Netherlands, 13 73% in the United States 14 and 80% in Australia 11 undertaking pregnancy tests, and 59% in the United States 14 obtaining signed consent for therapy. About a third of the women in the United States and Canada with exposure during pregnancy were already pregnant at the time therapy was commenced; 4,7 33% in one study 4 and 40% in the other 7 were not using contraception, while 26% were using less reliable methods and 65% of those taking oral contraception reported using contraception irregularly. 7 Women under 25 years showed the poorest compliance (50%) with contraceptive use. 7 Use of oral retinoids for other than the specified indications has been reported, 13,14 as well as prescription by unauthorised doctors, 12 and use of drugs left over from previous prescriptions or obtained from friends or relatives. 7 Pregnancy prevention programs Pregnancy prevention programs 15,16 instituted in 1988 by the manufacturer and the US Food and Drug Administration included additional features such as a check list of selection criteria for suitable patients, a self-evaluation test for patients, drug packages with drawings of associated birth defects and "avoid pregnancy" icons, a contraception referral program with reimbursement for the first visit by the manufacturer, a recommendation to use two forms of contraception simultaneously, 16 and periodic communications with prescribers and pharmacists. Encouraging outcomes were achieved among participants, such as a low pregnancy rate of 3.4 per 1000 courses of treatment with isotretinoin, 15 and a trend towards more appropriate use of contraception among women who were counselled with the entire program. 16 Even so, compliance with the guidelines, such as pregnancy testing (64% 15 ), waiting until the next menstrual period before commencing therapy (70% 15 ) and use of effective contraception, was still incomplete. Recommendations While the search continues for safer drugs, how can we reduce the risk of pregnancy in women taking oral retinoids while achieving maximum benefits from this unique group of drugs? (see Box 3). Conclusions A recent study 20 has provided further support for the teratogenicity of preformed vitamin A in dosages of 10 000 IU or more daily in the form of supplements. The recommended daily amount of vitamin A for women in Australia is 2500 IU and supplements exceeding this or heavy consumption of liver and liver products 2 should be avoided, particularly during therapy with oral retinoids, as well as during pregnancy. The successful implementation of a pregnancy prevention program during oral retinoid therapy could be viewed as a pregnancy rate no greater than the failure rate of the recommended contraceptive method. If this is taken as 0.3 per 100 woman-years for the combined oral contraceptive pill 18 (with the potential to be less with the simultaneous use of another method), then the pregnancy rate during therapy with isotretinoin, with an average contraception period of six months per woman per course (four months for treatment 11 and one month before and after therapy), ideally should not exceed 1.5 per 1000 courses of treatment. The estimated rates of 3.1 terminations per 1000 courses of treatment with isotretinoin 12 and 3.4 pregnancies per 1000 courses of treatment 15 recently reported are relatively low but can be reduced further. This requires the wholehearted commitment of women and their clinicians. Acknowledgements We are grateful to the staff of the South Australian Health Commission Library for helping us to obtain the references and many others not listed, and to Roche Products Medical Information Department for additional references and statistics on exposed pregnancies. References Australian Drug Evaluation Committee. Medicines in pregnancy. An Australian categorisation of risk of drug use in pregnancy. 2nd ed. Canberra: AGPS, 1992. Chalmers RJG. Retinoid therapy -- a real hazard for the developing embryo. Br J Obstet Gynaecol 1992; 99: 276-278. Saurat J-H. Side effects of systemic retinoids and their clinical management. J Am Acad Dermatol 1992; 27: S23-S28. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837-841. Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986; 33: 355-364. Teratology Society: recommendations for isotretinoin use in women of childbearing potential. Teratology 1991; 44: 1-6. Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992; 26: 599-606. Dai WS, Hsu M-A, Itri LM. Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 1989; 125: 362-365. Geiger J-M, Baudin M, Saurat J-H. Teratogenic risk with etretinate and acitretin treatment. Dermatology 1994; 189: 109-116. Hogan DJ, Strand LM, Lane PR. Isotretinoin therapy for acne: a population-based study. Can Med Assoc J 1988; 138: 47-50. Lee M, Cooper A. Survey of Australian isotretinoin prescribing. Australas J Dermatol 1991; 32: 13-16. Chan A, Keane RJ, Hanna M, Abbott M. Terminations of pregnancy for exposure to oral retinoids in South Australia, 1985-1993. Aust N Z J Obstet Gynaecol 1995; 35: 422-426. Eurocat. Surveillance of the retinoic acid embryopathy: a pharmacy based study. Eurocat Newsletter December 1992; 6(4). Doering PL, Araujo OE, Frohnapple DJ, et al. Patterns of prescribing isotretinoin: focus on women of childbearing potential. Am Pharmacother 1992; 26: 155-161. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 1995; 333: 101-106. Pastuszak A, Koren G, Rieder MJ. Use of the retinoid pregnancy prevention program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol 1994; 8: 63-68. Kovacs G. Oral contraceptives -- can we make them more effective? Med J Aust 1993; 159: 224-225. Ceyrac DL, Serfaty D, Lefrancg H. Retinoids and contraception. Dermatology 1992; 184: 161-170. Sturkenboom MCJM, de Jong-van den Berg LTW, van Voorst-Vader PC, et al. Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment. Br J Clin Pharmacol 1994; 38: 229-235. Rothman K, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995; 333: 1369-1373. Authors' details South Australian Health Commission, Public and Environmental Health Service, Adelaide, SA. Annabelle Chan, FAFPHM, Senior Medical Consultant, Pregnancy Outcome Unit; and South Australian Birth Defects Register, Women's and Children's Hospital, North Adelaide, SA. Malcolm Abbott, AUA, FSHP, Pharmacist, Therapeutic Goods Section; currently Rural Pharmacist, Territory Health Services, Katherine District, NT. Rosemary J Keane, RN, RM, Midwife, Pregnancy Outcome Unit. Flinders Medical Centre, Adelaide, SA. Marshall Hanna, FRACP, FACD, Senior Visiting Dermatologist, Department of Dermatology. Reprints and Correspondence: Dr A Chan, South Australian Health Commission, Public and Environmental Health Service, PO Box 6, Rundle Mall, Adelaide, SA 5000. To top of article ©MJA 1996 < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Annabelle Chan · Marshall Hanna · Malcolm Abbott · Rosemary J Keane

Drug-resistant Streptococcus pneumoniae: the beginning of the end for many antibiotics? Peter J Collignon and Jan M Bell, on behalf of the Australian Group on Antimicrobial Resistance (AGAR)* Abstract - Introduction - Methods - Antibiotic sensitivity testing - Statistical analysis - Results - Discussion - Acknowledgements - References - Authors' details - ©MJA1997 Abstract Objective: To determine the levels of antibiotic resistance in Streptococcus pneumoniae in Australia. Design: Prospective, Australia-wide, laboratory-based survey. Setting: 27 hospital and private laboratories around Australia, from January 1994 to August 1995. Subjects: First 100 patients with clinically significant isolates of S. pneumoniae at each laboratory. Outcome measures: Resistance to penicillin (determined from penicillin minimum inhibitory concentration [MIC] measured by the Etest), erythromycin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, cefotaxime and ceftriaxone. Results: A total of 2396 isolates were tested (including 537 invasive isolates and 740 from children). Penicillin resistance was seen in 161 isolates (6.7%), including 17 with high level resistance. Penicillin resistance rates were significantly lower in invasive than in non-invasive strains (3.7% versus 7.6%; odds ratio [OR], 0.47; 95% confidence interval [CI], 0.28-0.77; P = 0.001). There was no significant difference in penicillin resistance rates between children ( < 15 years) and adults (7.3% versus 6.5%; OR, 1.14; 95% CI, 0.80-1.63; P = 0.47). Resistance rates were higher for most other antibiotics than for penicillin (chloramphenicol, 6%; erythromycin, 11%; tetracycline, 15%; and trimethoprim-sulfamethoxazole, 42%). No high level resistance was seen to third generation cephalosporins, but 17 of 109 penicillin-resistant isolates tested (16%) displayed intermediate resistance to cefotaxime. Rates of antibiotic resistance varied between States, with the lowest rates in Tasmania. Conclusions: Antibiotic resistance levels in S. pneumoniae are increasing in Australia and high level penicillin resistance is being encountered for the first time (including in invasive strains). This will lead to an increasing number of therapeutic dilemmas and possible therapeutic failures, especially important in meningitis. MJA 1996; 164: 64 Introduction The pneumococcus (Streptococcus pneumoniae) continues to be a common cause of serious and life-threatening infections, including pneumonia, bacteraemia and meningitis. It is also a frequent cause of respiratory tract infections, such as otitis media and sinusitis.1-4 A major advance was made in the treatment of these infections with the introduction of penicillin 50 years ago. Until relatively recently, pneumococci were considered so uniformly sensitive to penicillin (with minimum inhibitory concentrations [MICs] < 0.02 mg/L) that sensitivity tests were usually not performed. It was from Australia in 1967 that the first clinically significant isolate of a penicillin-resistant pneumococcus was reported.5 However, penicillin resistance was not a major clinical problem in this country, although it caused major problems elsewhere, particularly in Papua New Guinea and South Africa.1-3 In the late 1970s and the 1980s, rates of resistance (including multiple resistance) increased in Western countries, particularly in Spain (with resistance levels of 50%).1,2,3 A recent United States study found 25% of invasive S. pneumoniae isolates were penicillin-resistant.6 Resistance rates are usually higher in children, and the distribution of resistance varies within countries and population groups.1,2,3,6 In an Australia-wide study of over 1800 isolates of S. pneumoniae in 1989, we found that only 1% were penicillin-resistant,7 a lower rate than in most other Western countries. However, some communities (especially Australian Aboriginals) have relatively high rates of resistance.8 Because of the worldwide increase in resistance to many antibiotics and the implications of penicillin resistance in S. pneumoniae for treatment of life-threatening conditions (particularly meningitis), we undertook a further study of resistance to penicillin and other commonly used antibiotics in clinically significant S. pneumoniae isolates from both the community and hospitals. Methods Twenty-seven hospital and private laboratories from around Australia parti cipated. From January 1994, each laboratory tested the first 100 consecutive clinically significant isolates. The rate of collection varied from 5 to 20 months, with all laboratories filling their quota in August 1995. Patients' sex, age, specimen site and inpatient or outpatient status were recorded prospectively. Clinically significant isolates were defined as those isolated either from normally sterile sites (e.g., cerebrospinal fluid and blood [invasive isolates]) or from specimens that made contact with mucosal surfaces (e.g., sputum) if they were associated with an increased white cell count on gram staining and would normally have been reported as clinically significant. Throat or surveillance swabs were excluded, as were duplicates of clinically significant isolates. S. pneumoniae was identified by colonial morphology, a -haemolysis on blood agar plates, susceptibility to optochin and/or bile solubility. Antibiotic sensitivity testing Isolates were tested for susceptibility to penicillin, erythromycin, trimethoprim-sulfamethoxazole, tetracycline and chloramphenicol by the standardised routine method of each laboratory. Methods included disc diffusion with either National Committee for Clinical Laboratory Standards (NCCLS)9 (14 laboratories) or Calibrated Dichotomous Sensitivity (CDS)10,11 (7 laboratories); agar dilution12 with either Isosensitest agar (Oxoid) (2 labora tories) or Mueller-Hinton agar (3 lab oratories); and the ATB system (BioMerieux sa , Marcy-l'Etoile, France) (1 laboratory). The MIC of penicillin was also determined for each isolate by the Etest on Mueller-Hinton agar supplemented with 5% blood;13,14 plates were incubated at 35¡C in 5% CO 2 for 20-24 hours. 14 The interpretive criteria of the NCCLS15 were used for susceptibility categorisation of Etest values (susceptible, MIC < 0.06 mg/L; intermediate resistance, MIC = 0.125-1 mg/L; and high level resistance, MIC > > 2 mg/L). For the study, antibiotic resistance was defined as decreased susceptibility (both intermediate and high level resistance),6,12 and multidrug resistance as decreased susceptibility to two or more of the antibiotic agents tested. Isolates from normally sterile sites and those that appeared resistant to penicillin or chloramphenicol by routine susceptibility testing or had penicillin MICs > > 0.047 mg/L were forwarded to Monash Medical Centre for further susceptibility testing: Etest strips were used to determine cefotaxime and ceftriaxone MICs. Statistical analysis Fisher's two-tailed exact test was used to calculate P values. Calculations were performed with True Epistat software.16 Results A total of 2396 isolates from different patients were tested. The average age of the patients was 41.6 years (range, < 1 day to 98 years); 32% were children ( < 15 years) and 60% were male. The percentage of penicillin-resistant isolates from each specimen site is shown in Box 1; the overall rate of penicillin resistance was 6.7%, with rates in individual laboratories ranging from 0 to 13%. High level resistance was seen in 17 isolates, including two from normally sterile sites. The rate of penicillin resistance was significantly lower among invasive isolates than among non-invasive isolates (3.7% versus 7.6%; odds ratio [OR], 0.47; 95% confidence interval [CI], 0.28-0.77; P = 0.001) (Box 2). The rate of penicillin resistance was slightly higher among children ( < 15 years) than among adults, but the difference was not statistically significant (7.3% versus 6.5%; OR, 1.14; 95% CI, 0.8-1.63; P = 0.47). Resistance to antibiotics other than penicillin was common (Boxes 2 and 3). Rates varied around Australia, with the lowest rates for nearly all antibiotics in Tasmania and the highest in the eastern States, particularly Queensland and New South Wales. The rate of penicillin resistance was highest in South Australia. Very high levels of resistance were seen for trimethoprim-sulfamethoxazole (29%-52%). All five antibiotics were tested on 1895 isolates; 267 (14%) were multi resistant, with 159 (8%) resistant to three or more antibiotics and 31 (1.6%) to all five (Box 3). Of 124 penicillin-resistant isolates tested, 72 (58%) were resistant to three or more non--lactam agents; 40% were resistant to chloramphenicol; 52% to erythromycin; 64% to tetracycline; and 78% to trimethoprim-sulfamethoxazole. Of the 1771 pencillin-susceptible isolates, 101 (6%) were resistant to three or more non--lactam agents; 3% to chloramphenicol; 8% to erythromycin; 12% to tetracycline; and 39% to trimethoprim- sulfamethoxazole . Of 109 penicillin-resistant isolates tested with cefotaxime, 17 (16%) had intermediate resistance (MIC, 1 mg/L). These comprised 12 of 13 isolates with high-level penicillin resistance and 5 of 96 with intermediate penicillin resistance. Only three of the 109 isolates had intermediate resistance to ceftriaxone (all with high-level penicillin resistance). Discussion We found that the level of penicillin resistance among S. pneumoniae isolates was six times higher than that found in 1989 in the only other large multicentre Australian study,7 but fortunately it was still lower than in most other countries. Penicillin resistance rates are very high in Third World countries, and in some areas of Western Europe and the USA.1-3 However, the rate of rise in resistance in Australia appears very similar to that seen in the early 1980s in countries such as Spain1-3 and in the early 1990s in the United States;6 there, only 0.02% of isolates nationally were penicillin-resistant in the early 1980s and still only 1.3% in 1992,6 but a recent study found a rate of 25%, with much higher rates in some subgroups (e.g., 40% in white children). Of equal concern was that 3% of isolates had high level resistance to both penicillin and third generation cephalosporins.6 Over the next few years, we are likely to see similar rates of resistance developing in Australia. The finding of high level penicillin resistance among S. pneumoniae isolates in Australia is of particular concern; in meningitis caused by organisms with any level of penicillin resistance, penicillin treatment is likely to fail.1-3,17,18 Penicillin resistance has consequences for other related drugs, as in S. pneumoniae it is not due to -lactamase production (as in Staphylococcus aureus ), but to changes in the target for penicillin (the penicillin-binding proteins).1,2,19 This change increases the MICs for all -lactams, including the third generation cephalosporins.1,2,19 However, the levels of third generation cephalosporins achieved in cerebrospinal fluid are still high enough to eradicate organisms with intermediate penicillin resistance.1-3,18 Alternative regimens include combination therapy with vancomycin, third generation cephalosporins and rifampicin, as well as newer agents such as meropenem, teicoplanin and quinolones (under investigation),1 but none has been adequately evaluated. Of even greater concern are the implications of the rapid rise in resistance to third generation cephalosporins noted in the United States. Primary resistance to these drugs is less frequent than to penicillin, but requires less genetic change.1,19 In some areas up to 27% of penicillin-resistant pneumococci have high level resistance to cefotaxime.1 This leads to therapeutic failure of these agents, yet they are the main treatment for the increasingly common intermediate penicillin-resistant strains. No high level cefotaxime-resistant strains were seen in our study or have been reported in Australia, to our knowledge. However, given the worldwide spread of resistant pneumococci in the recent past, they will inevitably be seen soon in Australia and leave us with major therapeutic dilemmas in the treatment of meningitis. In life-threatening situations other than meningitis (e.g., bacteraemia), high dose intravenous penicillin appears sufficient to eradicate organisms with intermediate resistance, as drug levels achievable in serum are still much higher than the MIC.1,2,3 There is, however, controversy, and many recommend use of either cefotaxime or ceftriaxone.1,3 For organisms with high level resistance, the most appropriate agent is unclear. However, we would favour vancomycin. In non-life-threatening infections with penicillin-resistant pneumococci, the most appropriate antibiotics are less clear. In otitis media, amoxycillin still appears the best choice,20,21 as drug levels achieved in the middle ear can still exceed the MICs of strains with intermediate resistance (although higher doses may be needed). Other oral agents available in Australia for use in children (cefaclor, trimethoprim, erythromycin and cefpodoxime) do not reach adequate levels to eradicate resistant isolates.20,21 Third generation cephalosporins, such as ceftriaxone, are active, but their parenteral route is likely to preclude their use. Combining clavulanic acid with amoxycillin is no advantage, as the resistance is not due to -lactamase. For high level penicillin-resistant isolates there does not appear to be a satisfactory oral agent. The reasons for the increasing resistance in S. pneumoniae worldwide are not completely understood, although antibiotic pressure appears to be a major factor.1 A few resistant clones were shown to have spread from one continent to others (e.g., from Spain to the United States and Iceland) and then through the local population, undergoing minor genetic changes in the process.1,3,19 The pneumococcus can acquire DNA molecules from other bacteria that probably include viridans group streptococci (e.g., Streptococcus mitis), which form part of the normal flora of the nasopharynx.1,19 While it would probably be impossible to eradicate carriage of these resistant organisms from the population, it may be possible to reduce the rate of increase in resistance by minimising the prescription of unnecessary antibiotics. Other strategies, such as vaccination, may be necessary. Unfortunately, the currently available vaccine is a polysaccharide and therefore a poor immunogen, especially in young children. Studies are under way to assess a conjugated pneumococcal vaccine (i.e., a carbohydrate with protein carrier), but vaccine development is difficult as there are over 80 serotypes of pneumococci (compared with only one commonly invasive serotype of Haemophilus influenzae -- type b). However, at present most of the resistant organisms belong to relatively few serotypes.1,2,3 A vaccine containing most of these might not only decrease life-threatening disease, but might also decrease carriage of the organisms, as was found for the H. influenzae type b (Hib) vaccine.1 However, as the pneumococcus can acquire DNA from other organisms,1,19 the number of resistant serotypes is likely to increase. Our study was one of the largest in the world where all organisms were clinically significant and all were assessed for MIC for penicillin. It is valuable not only for showing the rate of resistance (both intermediate and high level), but also for providing a baseline to assess future changes in resistance and to differentiate subtle shifts in resistance in the whole population of pneumococci from the introduction of resistant clones. In the past, determining MICs was time-consuming, laborious and not routine. The recent development of the Etest (which consists of a strip of paper impregnated with increasing concentrations of antibiotic from one end to the other) has simplified the procedure. This technological advance, along with the willingness of so many laboratories around Australia to participate in the project, has allowed us to obtain information essential for guiding us in making appropriate antibiotic choices and designing empiric therapy for these emerging threats. Acknowledgements We wish to thank the many doctors, scientists and technicians at the participating laboratories who donated their time and resources to carry out this project. The penicillin Etest strips were supplied by Australian Laboratory Services Pty Ltd at cost price. Eli Lilly provided funding for many of the participants to meet at the twice-yearly AGAR meeting. Cefotaxime and ceftriaxone Etest strips were donated by AB Biodisk (Sweden). References Lister PD. Multiply-resistant pneumococcus: therapeutic problems in the management of serious infection. Eur J Clin Microbiol Infect Dis 1995; 14 Supp 1: 18-25. Klugman K. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 171-196. Schreiber J, Jacobs M. Antibiotic-resistant pneumococci. Pediatr Clin North Am 1995; 42: 519-537. Collignon P. Penicillin-resistant pneumococci: will the recent Olympics bring back to Australia more than gold? Med J Aust 1992; 157: 655-657. Hansman D, Bullen M. A resistant pneumococcus. Lancet 1967; 2: 264-265. Hofmann J, Cetron M, Farley M, et al. The prevalence of drug resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995; 333: 481-486. Collignon P, Bell J, on behalf of AGAR. Streptococcus pneumoniae : how common is penicillin resistance in Australia? Aust N Z J Med 1992; 22: 473-476. Hansman D, Morris S, Gregory M, McDonald B. Pneumococcal carriage amongst Australian aborigines in Alice Springs, Northern Territory. J Hyg (Camb) 1985; 95: 677-684. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. 5th ed. Approved standard. Document M2-A5. Villanova, Pa: NCCLS, 1993. Bell SM, Gatus BJ, Pham JN, et al. CDS users group newsletter No. 6. Sydney: The Prince of Wales Hospital, 1993. Bell SM. Additions and modifications to the range of antibiotics tested by the CDS method of antibiotic sensitivity testing. Pathology 1988; 20: 303-304. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 3rd ed. Approved standard. Document M7-A3. Villanova, Pa: NCCLS, 1993. Jorgensen JH, Ferraro MJ, McElmeel ML, et al. Detection of penicillin and extended spectrum cephalosporin resistance among Streptococcus pneumoniae clinical isolates by use of the Etest. J Clin Microbiol 1994; 32: 159-163. AB Biodisk . Etest Technical Guide 5B. Solna, Sweden: AB Biodisk , 1995. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. 5th informational supplement. Document M100-S5. Villanova, Pa: NCCLS, 1994. True Epistat [computer program]. Version 5.0. Richardson, TX: Epistat Services, 1994. Collignon P, Bell J, Hufton I, Mitchell D. Meningitis caused by a penicillin- and chloramphenicol-resistant Streptococcus pneumoniae . Med J Aust 1988; 149: 497-498. Friedland I, McCracken G. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae . N Engl J Med 1994; 331: 377-382. Tomasz A. The pneumococcus at the gates. N Engl J Med 1995; 333: 514-515. Barnett E, Klein J. The problem of resistant bacteria for the management of acute otitis media. Pediatr Clin North Am 1995; 42: 509-517. Nelson C, Mason E, Kaplan S. Activity of oral antibiotics in middle ear and sinus infections caused by penicillin-resistant Streptococcus pneumoniae : implications for treatment. Pediatr Infect Dis J 1994; 13: 585-589. (Accepted 30 Nov 1995) Authors' details Infectious Diseases Unit, Woden Valley Hospital, Canberra, ACT. Peter J Collignon, FRACP, FRCPA, Head of Unit, Microbiologist and Infectious Diseases Physician. Department of Microbiology and Infectious Diseases, Monash Medical Centre, Melbourne, VIC. Jan M Bell, BSc(Hons), BA, Scientist. * Australian Group on Antimicrobial Resistance (AGAR). For this study AGAR consisted of the microbiology laboratories at: ACT: Woden Valley Hospital (Peter Collignon, Linda Halliday). NSW: Concord Hospital (Joan Yap, Tom Gottlieb, Glenn Funnell); Illawarra Regional Hospital (Keith Wise, Rodney Jones); Liverpool Hospital (Denise Daley, Rosemary Munro); Prince of Wales Hospital (Jeanette Pham, Barrie Gatus, Sydney Bell); Royal North Shore Hospital (Clarence Fernandes); Royal Prince Alfred Hospital (Richard Benn, Barbara Yan, Alison Vickery). QLD: Mater Misericordiae Hospital, Brisbane (Martyn Tilse, Janet Montgomery); Princess Alexandra Hospital (Graeme Nimmo, Jacqueline Schooneveldt); Royal Brisbane Hospital (Narelle George, Joan Faoagali); Sullivan, Nicolaides and Partners (Jenny Robson, Sylvia van der Valk); Toowoomba Base Hospital (David Farrell). SA: Flinders Medical Centre (Hendrik Pruul); Institute of Medical and Veterinary Science (Irene Lim, Richard Lumb); Queen Elizabeth Hospital (Peter Lawson, David Grove). TAS: Diagnostic Pathology (which includes Hobart Pathology and Launceston Pathology) (Barbara Henderson, Danny McColl, Gary Fenton); Launceston General Hospital (Erika Cox, Veronica Lyons); Royal Hobart Hospital (Keith Ott, Rob Peterson). VIC: Alfred Hospital (John Spicer, J Clare Franklin); Dorevitch Pathology (Liz Snashall); Heidelberg Repatriation Hospital (Barrie Mayall, Angie Chan, Vicki Moritz); Melbourne Pathology (Christine Hargreaves); Monash Medical Centre (Dianne Olden, Jan Bell, John Turnidge); Royal Children's Hospital and Microbiological Diagnostic Unit (Geoff Hogg, Marion Easton, Janet Strachan). WA: Fremantle Hospital (David McGechie, Neil Stingemore, Graham Francis); Royal Perth Hospital (Keryn Christiansen, Claire Khinsoe, Geoff Coombs). Reprints: Dr P J Collignon, Infectious Diseases Unit, Woden Valley Hospital, PO Box 11, Woden, ACT 2606. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Peter J Collignon · Jan M Bell · the AGAR