Infectious diseases

The use of biological agents as weapons of war is not new. In the 14th-century siege of Kaffa, on the Black Sea, the attacking Tartars catapulted bodies of plague victims at the defending Genoese, who contracted the disease and abandoned the city. Over the past century, many countries have developed the capacity to use biological agents to produce casualties in humans and domestic animals and to damage crops and environmental systems. Some biowarfare programs are known to have continued despite the adoption by 144 countries of the 1972 Biological Weapons Convention, which prohibited development or acquisition of such weapons. Early recognition of unusual clinical illness by physicians is an integral part of the public health response to a biological attack. We review the features of four biological agents of greatest concern. In this article, we discuss smallpox, a disease not seen in the world for the past two decades, and botulism. A subsequent article will discuss anthrax and plague. SmallpoxEpidemiologyIn a world declared free of smallpox in May 1980,1 this disease has characteristics that make it particularly suitable for biological warfare. It can be spread person-to-person. With the cessation of vaccination programs over 20 years ago, immunity has waned among those who have been vaccinated, while those born since 1980 are unvaccinated. The virus spreads by the respiratory route (primarily by droplet nuclei or aerosols expelled from the nasopharynx of infected people) or by direct contact (being released from ulcers on the oral mucosa from the time lesions appear on the skin and two to three days after onset of fever). It has also been transmitted by soiled clothing and blankets used by patients. Smallpox spreads rapidly between close family contacts2 and within hospitals when no special precautions are taken.3 Smallpox as a weaponOther features of smallpox that contribute to its suitability as a weapon are the stability of the virus in aerosol form and the likely small infective dose.4 Smallpox virus was added to the biowarfare program of the Soviet Union in 1980. Successful methods of stockpiling large amounts of this virus and delivering it from aircraft or ballistic missiles have been developed.5 With the discontinuation of the Soviet civilian biowarfare program in 1992, hundreds of experienced scientists became available to sell their services and take smallpox virus to other countries.5 The Indian strain of smallpox virus, used in the Soviet biowarfare program, causes a mortality of about 30% in unvaccinated people. Clinical features and diagnosisThe incubation period of 10–14 days ends with sudden onset of fever, headache and backache, usually severe enough to confine the patient to bed. Fever usually continues as the rash develops, with pain associated with pustule growth. Scabs develop and gradually separate, leaving pitted scars. The rash is the most important feature allowing early recognition of smallpox (Box 1). Most cases have been "ordinary type" smallpox, which has pustular lesions, but variant forms ("flat" and "haemorrhagic type" smallpox) occurred rarely and were almost always fatal. Modified smallpox occurred in people with waning immunity after vaccination and those who were vaccinated very early in the incubation period, and comprised a few skin lesions, which evolved more rapidly than those in unvaccinated people. Clinical diagnosis can be confirmed by electron microscopy of vesicular or pustular fluid or scabs, which should be collected and processed under maximum containment conditions. Management and preventionThe only proven effective treatment for smallpox is vaccination before or within three days of exposure, which may abort or modify the severity of an attack. Other treatment is supportive only, plus antibiotic therapy if secondary bacterial infection develops. Strict quarantine with respiratory isolation for 17 days is required of all cases and direct contacts of index cases. Vaccination with vaccinia virus is effective in preventing smallpox for at least five years and may prevent or modify infection for a much longer period, but this varies greatly from person to person. However, very few doses of vaccine are available worldwide at present. Furthermore, smallpox vaccination is associated with more severe adverse effects than any other type of vaccination: for example, encephalitis occurs at a rate of one per 300 000 primary vaccine doses and a quarter of cases are fatal, with some survivors having permanent neurological deficits.4 Therefore, both the World Health Organization and the United States Centers for Disease Control and Prevention have recommended that it should be used only to contain suspected cases and not for mass vaccination.6 BotulismEpidemiologyBotulism is extremely rare in Australia, with no reported foodborne cases since 1991.7 The causative organism, Clostridium botulinum, is an anaerobic, spore-forming, gram-positive rod found in soil (Box 2). It produces a potent neurotoxin that causes paralysis of skeletal and smooth muscle by interfering with acetylcholine release at the neuromuscular junction. Botulism as a weaponBotulinum toxin was first developed as a biological weapon over 60 years ago; it can be aerosolised, or used to contaminate food,8 and the estimated lethal oral dose is 70 µg. The Aum Shinrikyo cult released aerosolised toxin in Japan in the 1990s, but fortunately no cases of botulism resulted. The Soviet Union and Iraq have produced large amounts of botulinum toxin, and Iraq loaded toxin into missiles and bombs.8 Clinical featuresTwo forms of botulism could arise from deliberate release of botulinum toxin — foodborne and inhalational botulism. In contrast, gastrointestinal (infant) and wound botulism arise from infection with C. botulinum, rather than ingestion or inhalation of toxin, and are unlikely to occur in a biological attack. Foodborne botulism, the most common natural form of the disease, results from ingestion of preformed toxin that is produced when food contaminated with C. botulinum has been stored under anaerobic conditions. Cases are mostly associated with improperly home-bottled or preserved foods, but could potentially result from intentional addition of toxin to food. Botulism after inhalation of aerosolised toxin is an unnatural, man-made form of the disease, and would be the intended result of toxin delivery by missiles, bombs or aerosolisation devices. Only one instance of inhalational botulism has been reported, involving accidental exposure of three veterinary personnel to toxin re-aerosolised from animal fur.8 The incubation period for gastrointestinal botulism and probably also inhalational botulism (based on animal studies) is usually 12 to 72 hours. All forms of botulism have identical clinical features, with the exception that foodborne botulism may be preceded by gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal cramps).8 The pattern of illness is characteristic: onset with cranial nerve palsies of bulbar distribution, followed by descending motor weakness (from head and chest muscles to upper, then lower, limbs) in a patient with a normal conscious state and no fever.9 Absence of sensory changes is another important negative feature. Reflexes are preserved early, but may be lost with time. Dilated pupils, blurred vision, dry mouth and constipation indicate parasympathetic involvement. Severity of the weakness and its rate of progression vary, depending on the amount of toxin ingested. With modern medical therapy, mortality of foodborne botulism is less than 10%. DiagnosisDiagnosis is initially clinical. The principal differential diagnoses are the Miller–Fisher variant of Guillain–Barré syndrome (a demyelinating condition causing cranial nerve palsies and absent deep tendon reflexes) and disorders of the neuromuscular junction, such as myasthenia gravis. These and other conditions can be differentiated from botulism on the basis of clinical signs (eg, impaired consciousness in brainstem stroke or infection), analysis of the cerebrospinal fluid (infection and Guillain–Barré syndrome), neuroimaging (stroke) and electromyography (myasthenia gravis). Laboratory testing for botulism is complicated and time consuming and is available only through selected public health laboratories. To detect toxin, mice are inoculated with serum, faeces or vomitus; the organism, if present, can also be cultured from these specimens. Results are not available soon enough to assist initial diagnosis or management. Management and preventionPrompt administration of botulinum antitoxin, available in the US but not Australia, lessens disease severity. As the toxin is an equine preparation, serum-sickness-like reactions may occur in some recipients, but anaphylaxis is rare. Otherwise, treatment is supportive. Close respiratory monitoring is essential, and patients should be admitted to an intensive care or high-dependency unit. In one foodborne outbreak, 20% of patients required mechanical ventilation. An investigational toxoid vaccine has been given to laboratory and military personnel in the United States but is not available for more widespread use. 1: Smallpox lesions in an unvaccinated child Evolution of smallpox lesions from papules (top left; three days after onset of fever) to vesicles and pustules (bottom right; nine days after onset of fever). For the first two to three days, the rash of smallpox resembles that of chickenpox, but the two can be differentiated by the following: Smallpox lesions appear after two to three days of prominent prodromal symptoms (fever, headache and backache) and develop slowly (over nine to 10 days). Chickenpox lesions develop rapidly after a one- to two-day prodrome (fever and malaise). All smallpox lesions develop at the same pace and, on any part of the body, appear identical. Chickenpox lesions are much more superficial and develop in crops over a two- to four-day period, with scabs, vesicles and pustules seen simultaneously on adjacent areas of skin. Smallpox lesions are most concentrated on the face, arms and legs, and may occur on the palms or soles. Chickenpox lesions are most dense over the trunk and almost never found on the palms or soles. 2: Clostridium botulinum Gram-positive rods with characteristic subterminal spores (Gram stain; original magnification x 1000). (Picture courtesy Microbiological Diagnostic Unit, Public Health Laboratory, University of Melbourne, VIC.)

Michael Whitby FRACP, FRCPA · Alan C Street FRACP · Tilman A Ruff FRACP · Frank Fenner MD, FRS

A growing range of infections can be safely and effectively treated with parenteral antimicrobial therapy at home, including cellulitis, pyelonephritis, pneumonia, endocarditis, osteomyelitis, septic arthritis and deep abscesses. Patients may be admitted to HITH directly from the emergency department or after a period of in-hospital care; they must be thoroughly assessed for suitability, including clinical stability and social circumstances, and both patient and carer consent must be obtained. Patients should be medically reviewed weekly at the hospital to monitor progress of therapy and check for possible complications, including adverse drug reactions. Antibiotic selection should be based on appropriate prescribing principles rather than purely dosing convenience. Innovative dosing regimens, including once-daily aminoglycosides, continuous-infusion β-lactams (eg, flucloxacillin), once- or twice-daily cephalosporins (eg, cephazolin) and oral fluoroquinolones (eg, ciprofloxacin) provide effective therapy for a wide range of infections that would have previously required in-hospital care. Appropriate use of HITH leads to improved patient and carer satisfaction, efficient in-hospital bed use and possibly some financial efficiencies.

Series Editors:

To the Editor: Donovan and colleagues bring attention to the restrictions placed by the Health Insurance Commission via the Medicare system on clinicians investigating patients for sexually transmitted infections (STIs).1 In their study of Sydney general practitioners, they suggested that reform was required to the three-test pathology testing rule to improve gonorrhoea screening in high-risk individuals living in a region of epidemic gonorrhoea. In the Kimberley region of Western Australia, where we practise, syphilis, gonorrhoea and chlamydia continue to be endemic. Best-practice guidelines for primary healthcare providers in WA state that investigation for other possible STIs is essential to the care of patients with STIs or HIV infection.2 Health policy should be based on best-practice standards. For patients with confirmed or suspected STIs, this means that Medicare funding should meet the full costs of all tests for suspected STIs (as indicated by clinical need and best-practice guidelines) to enable and facilitate effective control of these infections at the population health level. An Australian legal precedent exists for medical practitioners regarding testing for STIs. In the New South Wales Supreme Court case of BT v Oei, it was found that a doctor has a duty of care to offer testing for other STIs to a patient with one STI or a suspected STI.3 In that case, a sexual partner of an HIV-positive patient brought successful legal action against her partner's doctor for failing to diagnose HIV infection in her partner. The doctor was found negligent in failing to offer an HIV test to a patient with ongoing symptoms who had been found to be infected with hepatitis B virus and whose only risk factor for this infection was unprotected sex. The doctor's duty of care was found to extend to the patient's sexual partner, who became infected with HIV after unprotected sex with her partner. Given that best-practice guidelines and a legal precedent exist which confirm that a medical practitioner should offer testing for other STIs to a patient with one STI or a suspected STI, what are the medicolegal implications of the Health Insurance Commission's three-test rule? Comment: The Journal sought a comment from the Commonwealth Department of Health and Ageing, but after three months had yet to receive a response.

Graeme H Johnson MB BS (Hons), BMedSci(Hons) · Donna B Mak FAFPHM, FACRRM

To the Editor: The experience described by Jones on books as carriers of disease in a recent issue of the Journal,1 following Ferson's article in the Christmas issue,2 reminded me of my experience in about 1933 at the Coast Hospital (now Prince Henry Hospital) at Little Bay, Sydney. My mother was a medical resident at the Coast, which was the infectious diseases hospital for NSW. She developed acute diphtheria and was admitted. I (aged five) and my sister had been immunised and were not sick. However, we were throat swabbed, and the swabs were positive for Corynebacterium diphtheriae. We spent three weeks in the hospital with no treatment until we returned negative throat swabs. While waiting to be admitted to the "blocks", we saw children with shaven heads through glass doors, and I've always assumed they were the ones with scarlet fever, as did Jones.1 I was given The Anzac book, on Gallipoli, to browse through. This is now a collector's item and very valuable. Then, much to my chagrin, I was not allowed to take it home. Later, in 1953, I was to return to my old ward as a resident medical officer, although I was never to find out what happened to all those books!

John V Roche MB BS, FRACGP, D(Obs), RCOG, DRACOG

Acute meningitis and encephalitis are medical emergencies that require prompt assessment (usually by cerebral imaging and lumbar puncture) and treatment; specialist consultation is recommended.

Miles H Beaman FRACP, FRCPA · Steven L Wesselingh FRACP, PhD

Community-acquired pneumonia is caused by a range of organisms, most commonly Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae and respiratory viruses. Chest x-ray is required for diagnosis. A risk score based on patient age, coexisting illness, physical signs and results of investigations can aid management decisions. Patients at low risk can usually be managed with oral antibiotics at home, while those at higher risk should be further assessed, and may need admission to hospital and intravenous therapy. For S. pneumoniae infection, amoxycillin is the recommended oral drug, while benzylpenicillin is recommended for intravenous use; all patients should also receive a tetracycline (eg, doxycycline) or macrolide (eg, roxithromycin) as part of initial therapy. Flucloxacillin or dicloxacillin should be added if staphylococcal pneumonia is suspected, and gentamicin or other specific therapy if gram-negative pneumonia is suspected; a third-generation cephalosporin plus intravenous erythromycin is recommended as initial therapy for severe cases. Infections that require special therapy should be considered (eg, tuberculosis, melioidosis, Legionella, Acinetobacter baumanii and Pneumocystis carinii infection).

Paul D R Johnson PhD, FRACP · Lou B Irving FRACP, FRACGP · John D Turnidge FRACP, FRCPA

How real is the threat, and how prepared are we? The world changed on September 11, 2001, and again on October 4, when the first case of inhalational anthrax in the United States raised worldwide fears of bioterrorism. Although the threat of bioterrorism in Australia has been assessed as low,1 defence and civil authorities had upgraded preparations before the 2000 Olympics.2 Those plans, coordinated by Emergency Management Australia, provided a basis for responses by state emergency services, health services and postal services to the numerous false alarms, "white powder" incidents and hoaxes that followed the US events. No anthrax spores or human anthrax cases associated with these incidents have been detected in Australia, but understandably they have caused considerable public anxiety. In retrospect, it now appears that the anthrax-containing letters in the US were probably of domestic origin, with no targets outside that country.3 After the US incidents, health departments were swamped with calls from the public asking what had been done to protect them. They wanted to know how to protect themselves, and whether they needed antibiotics, vaccines for anthrax or smallpox, or gas masks. Health authorities emphasised communication to reassure those who were worried, as well as to provide authoritative information and planning advice about anthrax and other conceivable threats. Should a biological incident ever occur in Australia, communication would be even more important, not only in managing the emergency, but also in minimising community alarm, which could cause more damage than the biological agent itself. In any incident, healthcare agencies would play a key role in recognising resulting illnesses and managing the health consequences. The anthrax threat has highlighted the importance of multidisciplinary approaches to biological emergencies. Security intelligence must be wedded to health intelligence, and the lessons learned from past disaster management appropriately applied. As an editorial in the Lancet recently said, "Appropriate reaction to such deliberate attacks, but also to any other emerging epidemic, by a well-organised and well-functioning public health system requires preparedness at all times on all levels".4 Australia's federal system requires close collaboration between the Commonwealth, States and Territories. Emergency service responses are coordinated by Emergency Management Australia. Public health agencies work with emergency services in the States and collaborate through the Communicable Diseases Network Australia and the Public Health Laboratory Network to coordinate national reporting, surveillance, laboratory diagnosis and public health responses for communicable disease outbreaks. Biosecurity planning in Australia has built on these existing disease and disaster surveillance systems.2 Recently, these networks have collaborated to revise training schedules and case definitions to support the earliest possible recognition of any event resulting from deliberate release of a biological agent. Health authorities, through the Communicable Diseases and Public Health Laboratory networks and the network of Chief Health Officers of the States, have also strengthened their linkages with Emergency Management Australia, the federal department of Defence and other government agencies. Anthrax: The review of Australia's policies has adapted advice from the US Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and United Kingdom Public Health Laboratory Service for local needs. Guidelines for anthrax treatment and post-exposure prophylaxis have been developed by public health physicians, microbiologists and infectious disease specialists, and endorsed by Australia's Chief Health Officers and directors of public health services. It has been agreed that primary care providers should not prescribe chemoprophylaxis in the event of suspected anthrax. Instead, they should immediately contact their local public health unit for advice about referral for diagnosis and further management (contact details for State and Territory health authorities are available on Fact sheet — anthrax <http://www.health.gov.au/pubhlth/strateg/communic/factsheets/anthrax_fact.htm>). To minimise inappropriate antibiotic use, general practitioners should not provide individuals with a contingency supply of antibiotics for prophylaxis. State and Territory health authorities are ensuring that there are adequate supplies of appropriate antibiotics in case of an emergency, and the Commonwealth Government is working with pharmaceutical companies to ensure continuity of supply. Anthrax vaccine is not currently registered for use in Australia and is not recommended as a first-line response to an anthrax incident. Smallpox: The US government's intention to procure 250–300 million doses of smallpox vaccine for mass vaccination appears to have been modified after expert advice. Existing vaccine is effective but has significant adverse effects. The calf-lymph-derived live smallpox vaccine used in the WHO smallpox eradication program is associated with a post-vaccinal encephalitis rate of 3–4 per million primary vaccine doses.5 Forty per cent of encephalitis cases are fatal, and some survivors have permanent neurological deficits. Progressive vaccinia occurs among those who are immunocompromised. WHO guidance is that, given the substantial risk of adverse events after vaccination, mass vaccination of populations is not recommended when there is little or no real risk of exposure. Despite the stated intention of the US to develop a new vaccine supply against a possible bioterrorism incident, no country is planning to give smallpox vaccine routinely to its citizens. Smallpox is not transmissible until the onset of rash, when the individual becomes ill and is likely to be confined to bed. This provides the rationale for measures to contain any outbreak: after the first cases are identified and isolated, contacts are vaccinated; vaccination prevents or ameliorates disease, even when it is undertaken after exposure to the virus.5 Thus, both WHO and CDC recommend an approach which involves early case detection and post-exposure vaccination with a view to "ring fencing" any outbreak.5-7 Australia has no smallpox vaccine available at present. As a precautionary measure, the Commonwealth Government has arranged with international agencies to secure access to vaccine in the unlikely event of a smallpox incident; arrangements have also been made to secure supplies of vaccine to be held in Australia. If smallpox were introduced into Australia, we would then be in a position to implement a strategy of surveillance, quarantine and vaccination. WHO has pledged support to any country in which an incident occurs, as this would constitute an international emergency. WHO will help countries pool resources to contain any outbreak as rapidly as possible. Conclusions: Although the risk to Australia is regarded as low, we need to be prepared for a bioterrorism incident. Australia's strong public health infrastructure forms the basis for an effective response to any such incident. While much of the initial planning has focused on anthrax and smallpox, progress has been made on public health and clinical protocols for other potential bioterrorism agents. No public health or security system can guarantee complete safety from bioterrorism attack, but Australia's public health expertise will ensure that harm to the community is minimised. For the assistance of doctors, a comprehensive guide for dealing with patient inquiries is available on the website of the Commonwealth Department of Health and Ageing (<http://www.health.gov.au/pubhlth/strateg/bio/index.htm>). This also contains a list of contacts for public health authorities around Australia. Relevant information can also be accessed through the WHO and CDC sites (<http://www.who.int/emc/deliberate_epi.html> and <http://www.cdc.gov>, respectively).

Richard A Smallwood · Angela Merianos · John D Mathews

About 6% of patients acquire an infection in hospital, and the incidence of hospital-acquired infections may be increasing. Common hospital-acquired infections are respiratory and urinary tract infections, surgical wound infections and infections associated with intravascular cannulas. The common hospital pathogens are methicillin-resistant Staphylococcus aureus, antibiotic-resistant gram-negative bacilli and, more recently, vancomycin-resistant enterococci. Surveillance is the cornerstone of effective infection control and prevention of hospital-acquired infections. Strategies to prevent both development of antibiotic resistance and spread of resistant organisms are necessary. Preventive strategies include prudent antimicrobial use, timely handwashing, aseptic technique, short hospital stays, minimal use and early removal of invasive devices, adequate staffing and an active infection control program. Sound infection control practice and prudent antibiotic use will reduce antimicrobial-resistant organisms and hospital-acquired infections

Series Editors:

Few areas of medicine have undergone greater change during the past 50 years than infectious diseases. The optimism and clinical confidence associated with the development of antimicrobial agents from the 1940s onwards has been tempered by the emergence of new diseases, such as AIDS and infections associated with transplantation and cancer therapy, and by the widespread development of antibiotic resistance. Despite many advances, infectious diseases continue to account for about a quarter of all deaths worldwide1 (Box 1). Furthermore, a security dimension has emerged. A recent report on The global infectious disease threat and its implications for the United States from the US Central Intelligence Agency (CIA) analysed this "non-traditional threat": The dramatic increase in drug-resistant microbes, combined with the lag in development of new antibiotics, the rise of megacities with severe health care deficiencies, environmental degradation, and the growing ease and frequency of cross-border movements of people and produce have greatly facilitated the spread of infectious diseases.2 Clinicians today require more knowledge of infectious diseases than ever before. In this issue of the Journal (page 229), we begin MJA Practice Essentials — Infectious Diseases. This series cannot hope to cover all new aspects of infectious disease. Instead, we aim to discuss clinically important areas where recent advances have occurred in diagnosis or treatment, new diseases have been identified, or healthcare changes have necessitated new clinical approaches to "old" diseases (eg, endocarditis and cellulitis) (Box 2). Some important topics, such as HIV infection and bioterrorism, are beyond the scope of this series. Wherever possible, recommendations are evidence-based, with the evidence graded according to the system of the National Health and Medical Research Council3 (Box 3). As with much of medicine, management of infectious diseases is affected by the competing needs for prompt empirical treatment and for a definite diagnosis to allow focused therapy. Advances in diagnostic technology have enhanced the possibilities for rapid, accurate diagnosis of conditions such as sexually transmitted diseases, deep-seated infections such as endocarditis and osteomyelitis, and common viral infections.4 However, identification of bacterial pathogens and their antibiotic susceptibilities still requires careful specimen collection and slow, generally labour-intensive, microbiological culture methods. Furthermore, many rapid diagnostic tests are sufficiently expensive that initial empirical "shot-gun" therapy without investigation can seem attractive. As effective antiviral agents become ever more readily available, many of the issues faced with antibiotics, such as rapid diagnosis, susceptibility testing and dosage monitoring, must also be considered. Current administrative pressure for shorter hospital stays and fewer outpatient or general practitioner consultations appears to encourage use of broad-spectrum empirical antibiotic and antiviral therapy, rather than careful investigation, review and directed therapy. Combined with the community's apparent ready acceptance or expectation of antibiotic therapy, this may explain Australia's ranking as the world's second-largest per-capita consumer of antibiotics (after France).5-7 Similarly, in the US and Canada, it is estimated that about 50% of all outpatient prescriptions for antibiotics are unnecessary.7,8 Antibiotic resistance is now emerging as a key challenge to many healthcare programs. Indeed, developments such as multidrug-resistant tuberculosis and resistance among common pathogens in developing countries (eg, Salmonella and Shigella spp. and malaria) threaten to totally undermine many current healthcare gains.7 It is therefore essential that all Australian clinicians accept the responsibility that goes with the privilege of prescribing antimicrobial agents. In both developed and developing regions, hospital-acquired infections are increasingly recognised as a major contributor to healthcare morbidity and costs.7 For this reason, good hospital infection control practices are no longer simply a concern for microbiologists and infection control committees, but must be understood by all staff, including hospital administrators — even if the latter consider them merely as "risk management". Few health issues attract more media attention than nosocomial infection. Current training about infectious diseases appears relatively limited among some medical personnel. A recent review of the general training curricula of the 12 Australian medical colleges found that five (Anaesthetists, Ophthalmologists, Medical Administrators, Radiologists and Psychiatrists) did not mention antibiotics at all.6 Similarly, among the 19 subspecialty groups in the Royal Australasian College of Physicians, only two specify the need for training in antibiotics (Thoracic Medicine and Infectious Diseases).6 The challenge for Australian clinicians in the current era of "information overload" is to improve the appropriateness of investigations and treatment of infectious diseases to avoid unnecessary antimicrobial therapy.6,7,9,10 Thus, MJA Practice Essentials — Infectious Diseases focuses on practical clinical problems that are either common or are sufficiently acute or severe that early recognition is important to limit morbidity or restrict disease spread. Whenever possible, recommendations are evidence-based. 1: Causes of death worldwide in 1998 (% of all deaths)* * Adapted from World Health Organization leading causes of death for 1998 (total of 53.9 million deaths from all causes worldwide).1 † Cancers, cardiovascular, respiratory and digestive deaths can also be caused by infections, further raising the percentage of deaths caused by infectious diseases. 2: Infectious diseases series contents Infections in pregnancy Hospital-acquired infections Community-acquired pneumonia Acute community-acquired meningitis and encephalitis Hospital-in-the-home Emerging viral infections in Australia Sexually transmitted infections Soft tissue, bone and joint infections Infections in the returned traveller Herpes simplex and varicella Antibiotic resistance 3: Levels of evidence Throughout the series, evidence is graded using the system of the National Health and Medical Research Council:3 E1 Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2: Evidence obtained from comparative studies (including systematic reviews of such studies), with concurrent controls and allocation not randomised, cohort studies, case–control studies, or interrupted time series with a control group. E33 Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV: Evidence obtained from case series, either post-test or pre-test/post-test.

M Lindsay Grayson MD, FRACP, FAFPHM · Steven Wesselingh PhD, FRACP

Some infections are more serious in pregnant than non-pregnant women because of the potential for vertical transmission to the fetus or infant (eg, varicella, rubella, cytomegalovirus infection, toxoplasmosis and listeriosis). Pre-pregnancy or routine antenatal screening for presence of, or susceptibility to, some of these infections and appropriate management can prevent adverse fetal or perinatal outcomes; screening should include rubella IgG, hepatitis B surface antigen, serological tests for syphilis and HIV antibody. If certain other vertically transmissible infections are suspected because of a positive antenatal test result, confirmatory tests for maternal and, if indicated, fetal infection are essential before intervention is considered (eg, cytomegalovirus infection). For some vertically transmissible infections that are not readily preventable, appropriate management of maternal infection can reduce fetal damage (eg, toxoplasmosis).

Series Editors:

To the Editor: A 27-year-old hospital medical officer received a penetrating needlestick injury to her left hand, drawing blood, after using a 22-gauge needle to deroof a vesicle for diagnosis in a two-year-old patient with orolabial herpes simplex virus type 1 (HSV-1). The medical officer had no significant medical history, took no regular medication, and had no previous history of oral or genital herpes. On Day 4, a vesicle appeared at the site of inoculation, with surrounding erythema. The medical officer first presented on Day 6, by which time the vesicle was crusting over, with several satellite lesions (see Figure). She described mild pain in her left axilla, but no fevers or sweats. A 10-day course of oral famciclovir (250 mg, three times daily) was prescribed and she was restricted from work until the lesions had completely healed (Day 16). During 12 months of follow-up there has been no clinical recurrence. Specimens from the two-year-old child were positive for HSV-1 by direct immunofluorescence, and HSV-1 DNA was detected by polymerase chain reaction (PCR). Specimens from the medical officer on Day 6 were negative for HSV-1 by direct immunofluorescence, but positive by PCR. There was no evidence of HSV-2 or varicella zoster virus in either specimen. To our knowledge this is the first reported transmission of HSV-1 after needlestick injury. Herpetic whitlow (HSV of the hands), a well-recognised occupational hazard for dentists and anaesthetists, is frequently misdiagnosed, resulting in unnecessary surgical procedures and delayed healing. In healthcare workers, pain and also work restrictions to limit cross-infection reduce productivity. Horizontal transmission can occur in the absence of clinical lesions, but latex gloves are an effective barrier.1 There are few guidelines available for postexposure prophylaxis for HSV-1, and no controlled clinical trials in humans. The short incubation period and early establishment of latency in HSV infection remain obstacles for effective delivery of postexposure prophylaxis. HSV can establish latent infection of neurones in the absence of peripheral replication.2 In an animal model, postexposure treatment with famciclovir or valaciclovir inhibited peripheral replication of HSV, reducing latent infection but not preventing it altogether.2 In one case report, a patient who started taking famciclovir within one hour of a needlestick injury did not develop whitlow and remained seronegative for HSV.4 Famciclovir and valaciclovir have high oral bioavailability, minimal toxicity and proven efficacy in treating HSV. Available data suggest that treatment with these drugs after documented exposure to HSV reduces the severity of acute disease, limits the number of neurones infected and may reduce the frequency of subsequent recurrences. If started early enough, postexposure prophylaxis may prevent latent infection altogether.

Mark W Douglas FRACP, BScMed(Hons) · Jane L Walters MB BS(Hons), MSc, DTM · Bart J Currie FRACP

To the Editor: We report the appearance of erythromycin and inducible clindamycin resistance in the south-west Pacific strain of non-multiresistant methicillin-resistant Staphylococcus aureus, which has recently appeared in eastern Australia. Infections occur predominantly in Polynesian people and are usually community-acquired. Most strains belong to Western Samoan phage patterns (WSPP1 or WSPP2) and pulsotype A when typed by pulsed-field gel electrophoresis.1,2 These strains are resistant to all β-lactams, but are usually susceptible to erythromycin, clindamycin, gentamicin, tetracycline, trimethoprim–sulfamethoxazole and ciprofloxacin. Although most of these antibiotics would not be recommended for therapy,3 clindamycin has been recommended for non-parenteral treatment of soft-tissue and bone infections, as it is efficacious in treating similar infections caused by methicillin-susceptible S. aureus.4 Twenty isolates of community-acquired, non-multiresistant pulsotype A MRSA were collected from patients from southern Brisbane and Logan in 1997 and 1998.2 A further 16 isolates were obtained from Ipswich patients between December 1998 and February 2001. We found that all 36 isolates were susceptible in vitro to gentamicin, tetracycline, trimethoprim–sulfamethoxazole, ciprofloxacin, rifampicin, fusidic acid and vancomycin. However, two of the Ipswich isolates had erythromycin and inducible clindamycin resistance. When susceptibility testing was performed using standard disc methods, both isolates appeared resistant to erythromycin but susceptible to clindamycin. However, on testing for inducible macrolide resistance (MLSB phenotype) using a disc-approximation method, both showed inducible clindamycin resistance.5 These isolates were from superficial abscesses in Polynesian people with community-acquired infection. They were indistinguishable by pulsed-field gel electrophoresis, but there were no epidemiological links. As yet, we have found no community-acquired pulsotype A strains of MRSA with erythromycin resistance and constitutive (ie, non-inducible) clindamycin resistance. Two other recent Australian studies found erythromycin resistance in 13 of 153 and three of 29 isolates of non-multiresistant MRSA, respectively.3,6 These studies did not report clindamycin susceptibilities, and it was not clear what proportion of the isolates belonged to phage patterns WSPP1 or WSPP2, or were community-acquired. As clindamycin has been recommended as a therapeutic option for soft-tissue and bone infections caused by non-multiresistant MRSA, this finding of inducible clindamycin resistance has important implications. Microbiology laboratories should screen for inducible clindamycin resistance in erythromycin-resistant strains, and, if found, an alternative antibiotic should be used for treatment.7 Alternatively, rather than assessing inducible clindamycin resistance with a disc-approximation test, some laboratories may prefer to report all erythromycin-resistant strains as clindamycin-resistant. Also, given the increasing incidence of community-acquired MRSA infection in Australia, all suspected staphylococcal infections that are not responding to empiric therapy with β-lactam antibiotics should be swabbed for culture.

Wendy J Munckhof MB BS, FRACP FRCPA, PhD · Jacqueline Harper BSci (Hons), PhD · Jacqueline Schooneveldt BAppSci, MAppSci, GCM · Graeme R Nimmo MB BS, MSc MPH, FRCPA

Should Australia follow the US decision to base prophylaxis on results of maternal screening? Ever since group B streptococcus (GBS) emerged as the commonest cause of perinatal sepsis in the late 1970s, there has been controversy about prevention strategies. A few hospitals in Australia were among the first in the world to introduce routine antenatal screening for GBS carriage and intrapartum antibiotic prophylaxis for carriers.1 This approach was later vindicated by randomised controlled trials in selected carriers2 and the demonstration of lower rates of sepsis after intrapartum prophylaxis compared with historical rates.3 However, problems remain. Group B streptococcus is a normal vaginal commensal in healthy women, but colonisation is often intermittent, and rates of colonisation can vary from 18% to 27%, depending on the detection method.4 Moreover, vaginal carriage is a very crude predictor of perinatal sepsis, with fewer than 1% of the infants of carriers affected (1–2/1000 overall) without intervention.1,5 In 1996, the Centers for Disease Control and Prevention (CDC) in the United States published consensus guidelines for selecting women for intrapartum antibiotic prophylaxis using either of two alternative strategies. One strategy was based on maternal GBS carriage, and the other on clinical risk factors — preterm labour (< 37 weeks' gestation), prolonged rupture of membranes (> 18 hours) or intrapartum fever (> 38oC).6 The rationale for the latter strategy was that, before widespread use of intrapartum antibiotics, one or more of these risk factors was found in up to 80% of mothers of infants with GBS sepsis.1,7 Gradual implementation of these consensus guidelines in the US was associated with a fall in the incidence of perinatal GBS sepsis from 1.7/1000 in 1992 to 0.5/1000 in 1999.8 In Australia, there was also a decrease in the incidence of perinatal GBS sepsis, from 1.2/1000 in 1991–1993, when three of nine neonatal units surveyed had prevention strategies in place, to 0.5/1000 in 1995–1997, when all 11 units surveyed had prevention strategies.5 A recent review concluded that there is evidence, albeit from relatively poor-quality trials, that intrapartum prophylaxis reduces the incidence of neonatal sepsis, but not deaths.9 Despite this evidence, concern continues about excessive use of intrapartum antibiotics. There have been several reports that their increasing use is associated with an increased proportion of cases of neonatal sepsis caused by penicillin-resistant bacteria.10,11 Although it is sometimes difficult to prove, there is considerable empirical evidence that increased antibiotic use generally leads to increasing bacterial resistance. It is plausible that exposure to antibiotics in utero might delay colonisation of the infant gut with penicillin-sensitive anaerobes and allow penicillin-resistant facultative bacteria — many of which are potential pathogens — to become established. Recently, the CDC published revised guidelines, recommending a single strategy for prevention based on universal prenatal screening for vaginal or rectal GBS colonisation.12 The recommendation was based on a retrospective cohort study, which showed that perinatal GBS sepsis was significantly less frequent in infants of women given intrapartum antibiotics on the basis of documented GBS screening results (0.33/1000 births) than in infants of women managed on the basis of risk factors (0.59/1000 births; relative risk, 0.48; 95% CI, 0.37–0.63).13 This result is not surprising. A risk factor-based protocol cannot, by definition, prevent sepsis in infants whose mothers have no risk factors. On the other hand, the proportion of cases prevented by a protocol based on GBS colonisation depends on the sensitivity of the screening method, effectiveness of prophylaxis and compliance with the protocol.4,14 What was surprising in the CDC study was that the anticipated overall rate of intrapartum antibiotic use was similar for both prevention strategies (31% and 29%).13 In contrast, we showed that in Australia a strategy based on risk factors would lead to significantly less use of intrapartum antibiotics (18%–20% of women) than a strategy based on antenatal screening at 35–37 weeks' gestation (35%).4 This difference is apparently due to a higher incidence of risk factors in the US compared with Australia, and failure to account for women given intrapartum antibiotics during preterm labour before results of screening are available. They suggest that obstetricians in Australia should not immediately discard the option of a risk-based strategy. Neither strategy is ideal, but either, if properly implemented, can reduce the incidence of perinatal GBS sepsis. The GBS screening strategy results in at least a third of healthy young women (and their infants) being given intravenous antibiotics during labour, at significant cost and with some risks, but can achieve a lower rate of perinatal GBS sepsis.13 In Australia, with a risk-based strategy, significantly fewer women and infants would receive intravenous antibiotics. Whichever strategy is chosen, the most important determinant of its effectiveness will be compliance.

Gwendolyn L Gilbert MD, FRACP, FRCPA

Mycobacterium ulcerans is an environmental bacterium causing skin ulcers. An endemic area of M. ulcerans disease in temperate south-east Victoria, where the disease is known as "Bairnsdale ulcer", has been extensively studied, and continues to involve new geographic areas.1 A less well known endemic area exists in tropical far north Queensland between Mossman and the Daintree River (Douglas Shire) (Box 1), where it is called "Daintree ulcer".2 Our patient presented with diffuse limb swelling of acute onset without ulceration and associated with systemic symptoms, which is unusual for M. ulcerans disease in Australia; only two previous cases from far north Queensland have presented in this way.2 Most patients in Australia initially note a papular lesion, which subsequently ulcerates after weeks to months without associated systemic symptoms.3 The classic ulcer is painless, with a sharp, undermined edge and surrounding induration, indicating the extent of necrotic subcutaneous tissue. Histopathological examination of excised tissue from patients with M. ulcerans disease shows large numbers of extracellular mycobacteria, a poorly developed immune response and widespread necrosis of subcutaneous tissue,4 which may be mediated by a recently described lipid toxin (mycolactone) produced by M. ulcerans.5 The accepted treatment of M. ulcerans disease remains complete surgical excision of all necrotic tissue, often extending well beyond the visible margins of the ulcer, with primary closure of small lesions and immediate or delayed skin grafting to larger lesions. Antimycobacterial therapy appears ineffective,2 despite in-vitro sensitivity of the organisms to several antimycobacterial agents, possibly because of clustering of the organisms in necrotic fat, where penetration of antimicrobials is likely to be poor. We have used adjunctive therapy in addition to surgical excision in patients with locally extensive or disseminated disease, and/or incomplete surgical excision. In these situations, relapse and residual functional impairment are more common. The combination of rifampicin, ethambutol and clarithromycin, although not established in the treatment of M. ulcerans infection, has shown good activity against other non-tuberculous mycobacteria, and M. ulcerans is sensitive in vivo to rifampicin6 and in vitro to clarithromycin.7 Early diagnosis can reduce the extent of surgical excision required, and therefore the residual scarring and deformity, and may also minimise the risk of relapse. Increased awareness of the disease in endemic areas is important in early diagnosis. A diagnostic polymerase chain reaction (PCR) test,8 developed at the Royal Children's Hospital (Melbourne), has 96% sensitivity and 100% specificity for M. ulcerans and is available from the Victorian Infectious Diseases Reference Laboratory, Melbourne. It can be performed within one day from a dry swab of the ulcer, and allows clinicians to make a rapid decision about whether or not surgical excision is required. Laboratory culture confirmation remains important and provides isolates for further analysis, but it may take more than six weeks. Microscopy for acid-fast bacilli from ulcer swabs, although sensitive, is non-specific — it cannot distinguish M. ulcerans from other non-tuberculous mycobacteria. The high specificity of the diagnostic PCR is important, as, in contrast to M. ulcerans infection, other non-tuberculous mycobacteria usually respond to antimycobacterial therapy. Clinical record A 45-year-old farmer from near Mossman, Queensland, presented with fevers and severe pain, swelling and redness of the left forearm. He recalled striking his forearm on a tree branch two weeks previously, with resulting bruising and soreness, but had not noticed any skin break. Treatment with oral cephalexin for presumed cellulitis was commenced five days before admission, with no improvement. Examination showed an erythematous, tender swelling of his whole left forearm, with pitting oedema and indistinct margins from 10 cm above the elbow to 5 cm above the wrist (Box 2). M. ulcerans infection was considered in the differential diagnosis because of an awareness of the disease among healthcare workers in this area. Microscopic examination of Ziehl–Neelsen-stained skin biopsies revealed acid-fast bacilli, and a swab taken from the base of a punch biopsy site was positive for M. ulcerans by polymerase chain reaction (PCR), confirming the diagnosis of oedematous M. ulcerans disease. M. ulcerans was subsequently cultured from the skin biopsy. Excision of skin and necrotic tissue was performed to the approximate margin of the lesion and split-skin grafts were applied. Histological examination showed typical changes of M. ulcerans disease, with extensive necrosis of the deep dermis and subcutis undermining intact epidermis. Numerous acid-fast bacilli were seen to the margins of the excised tissue. Because the disease was present to the excision margins, antimycobacterial therapy with rifampicin 600 mg daily, ethambutol 1200 mg daily and clarithromycin 500 mg twice a day was commenced. Three weeks after surgery, recurrent redness, swelling and pain developed at the proximal and distal margins of the wound. Re-excision of these necrotic areas at the wrist and upper arm was performed and further split-skin grafts applied. Histopathological examination of these specimens showed no acid-fast bacilli and cultures were negative. Antimycobacterial therapy was continued for two months after surgery. There has been no evidence of subsequent recurrence of disease and the patient has regained normal function in the affected arm. 1 : Mycobacterium ulcerans-endemic area The location of the M. ulcerans-endemic area, Douglas Shire, far north Queensland, Australia. 2 : Mycobacterium ulcerans disease The patient's left arm before operation, showing extensive oedema and erythema. Lessons from practice Increased awareness of Mycobacterium ulcerans infection in the endemic areas (south-east Victoria and far north Queensland) is important in early diagnosis. The disease may present with an acute onset and oedema, without ulceration. Early diagnosis can reduce the extent of surgical excision and minimise the risk of relapse. A diagnostic polymerase chain reaction (PCR) test with 96% sensitivity and 100% specificity for M. ulcerans is available from the Victorian Infectious Diseases Reference Laboratory (Melbourne).

Grant A Jenkin FRACP · May Smith MSc, BA · Mark Fairley FRACGP · Paul D R Johnson PhD, FRACP

To the Editor: We wish to report the identification of a novel virus causing lower respiratory tract disease in Australian children. The presence of this virus was recently described in Dutch children and tentatively called human metapneumovirus (hMPV).1 Clinical symptoms of infection are reported to resemble those of human respiratory syncytial virus (hRSV) infection. We therefore investigated whether the virus was present in Australian children. Three isolates were identified from a random selection of 200 nasopharyngeal aspirate (NPA) specimens collected throughout 2001 from children presenting to the Royal Children's Hospital, Brisbane, or the Logan Hospital, a public hospital to the south of Brisbane, with clinical respiratory tract disease. All NPA specimens were initially negative for hRSV, influenza A and B, parainfluenza 1, 2 and 3 and adenovirus by direct fluorescent antigen testing and subsequent viral culture. These negative NPA specimens were then screened by polymerase chain reaction (PCR) for hMPV, based on the known sequence of the virus.2 Sequencing of the PCR product in all three positive samples was 100% homologous with the known hMPV sequence. Viral growth was subsequently detected in culture from two of these samples, and confirmed as hMPV, using the method of van den Hoogen et al.1 Co-existent infection with coronavirus, rhinovirus, Bordetella pertussis, Chlamydia pneumoniae and Mycoplasma pneumoniae was excluded by PCR screening of the three hMPV isolates using validated in-house methods based on established protocols. Clinical features of the infected children are summarised in the Box. This is the first report of the presence of hMPV infection in Australian children and describes a new viral respiratory syndrome. It also adds to the clinical spectrum and understanding of respiratory viruses causing acute bronchiolitis in children. Only 25%–33% of NPA specimens collected from our population with suspected respiratory tract disease yield a positive result for a known viral or bacterial pathogen. Clinical features in this small cohort are difficult to separate retrospectively from hRSV. Based on the findings of this limited preliminary study of children presenting to hospital with respiratory tract symptoms, we would predict that hMPV is also relatively common in the Australian community. We are currently undertaking further characterisation of the hMPV isolates, a more detailed study of the epidemiology of hMPV disease, as well as developing improved diagnostic assays to rapidly identify clinical cases and assess seroprevalence of immunity to hMPV. Clinical features of human metapneumovirus in three Australian children Case 1 (Girl, 12 months) Case 2 (Boy, 5 years 11 months) Case 3 (Boy, 20 months) Date of nasopharyngeal aspirate collection 17/2/01 21/3/01 11/5/01 Presenting symptoms Rhinorrhoea, cough, tachypnoea, wheeze, vomiting Rhinorrhoea, cough, pharyngitis, conjunctivitis Rhinorrhoea, cough, fever Symptom duration before presentation (days) 4 3 4 Clinical signs Respiratory distress with hypoxia, rhinorrhoea, pharyngitis, chest wheeze with crackles Pharyngitis, chest wheeze Rhinorrhoea, pharyngitis, chest wheeze, cervical lymphadenopathy Chest X-ray Not performed Bilateral parahilar pneumonic infiltrates Bilateral parahilar pneumonic infiltrates Clinical diagnosis Bronchiolitis Viral lower respiratory tract infection Viral lower respiratory tract infection Outcome Admitted for oxygen therapy and nasal suctioning for three days Symptomatic treatment at home Symptomatic treatment at home

Michael D Nissen · Ian M Mackay · Stephen J Withers · David J Siebert · Theo P Sloots

To the Editor: I write to offer a re-analysis of the data presented by Whitby and colleagues.1 They reported a meta-analysis of crude estimates and relative risk of death derived from nine published studies for Staphylococcus aureus bacteraemia. They concluded that bacteraemia caused by methicillin-resistant S. aureus (MRSA) is associated with a "real increase in risk of death" compared with bacteraemia caused by methicillin-sensitive S. aureus (MSSA), with a relative risk of 2.12. However, they failed to explore fully the possible confounding effect of the patients' underlying diseases and treatment in their analysis. With this in mind, I offer a re-analysis of their data using regression analysis. Mortality rates versus median length of stay in hospital before bacteraemia (LOS) are shown in the Box (next page) for the five studies for which these data were presented by Whitby et al (in Boxes 1 and 2). The four studies without LOS data were combined, using the median LOS from the other five studies in the figure and the regression model. The regression analysis was performed with and without the weights provided by Whitby et al (Box 2), and also with and without the four studies for which LOS data were not available. Regression analysis revealed a significant association between mortality rate and LOS (P < 0.005). However, the addition of group status (MRSA or MSSA) failed to achieve significance in any iteration of the regression, while LOS remained a significant predictor of mortality risk. This suggests that, with S. aureus bacteraemia, mortality rate increases with length of time in hospital before the bacteraemia. The likely explanation is that patients residing in hospital for longer periods are sicker. Moreover, they are more likely to have been exposed to antibiotics, leading to increased risk of acquiring an S. aureus strain that is methicillin-resistant. The mortality risk is no different for MRSA versus MSSA bacteraemia if LOS, a surrogate marker for severity of patient illness, is taken into account. The difference that Whitby et al observed between the groups of patients with MRSA and MSSA bacteraemia could be accounted for by the difference in LOS between these groups. Mortality rate versus hospital length of stay before bacteraemia (LOS) in patients with MRSA or MSSA bacteraemia

James C Hurley MB BS, PhD, FRACP

In Reply: We thank Hurley for his comments on our meta-analysis.1 However, we strongly dispute that our analytical technique is flawed, and argue that we have been extremely cautious in drawing our conclusions. Hurley's contention is that hospital length of stay before bacteraemia (LOS) is a surrogate for severity of underlying disease and risk for colonisation with methicillin-resistant Staphylococcus aureus (MRSA), and that these factors explain the higher mortality in patients with MRSA. We agree that LOS may be a confounder. It may be an effect modifier, whereby patients in hospital for longer may be more ill, and therefore more susceptible to infection with and death from MRSA. Both are intuitive and biologically plausible conclusions. In fact, we referred to these possibilities in our Discussion, writing that "patients who ultimately become infected with MRSA are more seriously ill than those who become infected with MSSA [methicillin-sensitive S. aureus]" and "separating the effect of the bacteraemia per se from the effects of patients' underlying disease and treatment is a major problem when comparing outcomes". We also cautioned readers that available published data on mortality made it impossible for us to adjust for numerous potential confounders, including LOS, as the information given did not link these potential confounders with the outcome in individual patients. Hurley has not, as he suggests, undertaken an analysis that would allow him to control correctly for the potential confounder, LOS. He, like us, used "group-as-a-unit" data, but, although the groups are homogeneous for MRSA or MSSA, they are heterogeneous for LOS. Adequate examination of and control for potential confounders requires either individual patient data or data from homogeneous groups. Hurley has attempted to use analysis normally reserved for individual data.4 His analysis was analogous to treating the data as though from an ecological study, a design in which control of confounding is difficult,5 and thus does not permit him to draw his conclusions. Our analysis (not presented in our original article) of only those studies where the authors attributed mortality to bacteraemia6-8 found that the magnitude of effect remained (fixed-effect relative risk, 2.27; 95% CI, 1.75–2.96; P < 0.001; test for heterogeneity, χ2 = 6.14, df = 4, P = 0.19). As MRSA bacteraemia is a rare event and published studies are small, the statistical ability to control for confounding and effect modification is limited. Until sufficient suitable data for individual patients are available for analysis, we have remained restrained in our assessment. Mindful that MRSA bacteraemia is associated with increased mortality, regardless of the cause, we hold with our original conclusion that "our findings justify ongoing surveillance and proactive management of MRSA in healthcare facilities".

Michael Whitby · Mary-Louise McLaws · Geoffrey Berry

To the Editor: With respect to the article by Ferson in the Christmas issue of the Journal, a personal experience of an unwanted side effect which occurred in 1927 may be of interest. I was a boarder at school, and four weeks before sitting for the Leaving Certificate examination I contracted a violent sore throat associated with a bodywide erythema similar to sunburn, but without any associated burning sensation. The doctor had no hesitation in diagnosing scarlet fever, and I was transferred to the Coast (now Prince Henry) Hospital, which was the infectious diseases hospital for leprosy, scarlet fever, diphtheria and the like. I had asked if I could take my textbooks to the hospital, but was told that if I did they would be destroyed when I was discharged. I left the books at school, spent four weeks in isolation and returned to school with one weekend to prepare for the examinations — the results were quite disappointing!

Sir Keith Jones

In a recent issue of the Journal, Blake and colleagues described a cluster of three cases of measles from western Sydney.1 The index patient acquired measles overseas, while the other two patients acquired the infection during a hospital visit and probably in the waiting room of a general practice, respectively. Measles is highly contagious and can spread with relative ease in healthcare settings, especially if there is a failure to diagnose the infection, to isolate the infectious patient or to notify the case so that other infection control measures can be implemented. Other recent Australian outbreaks of measles have also been associated with virus importation from overseas and subsequent nosocomial transmission.2-4 Measles was imported in nine separate incidents investigated in Western Australia between March 1999 and October 2000, and subsequently transmitted among hospital patients, visitors and healthcare workers on two separate occasions. Victoria has experienced two outbreaks in the past three years,3,4 and a third is evolving (Dr Sean Tobin, Medical Officer, Communicable Diseases Section, Department of Human Services, Victoria, personal communication). In two of the three outbreaks, the index patient had returned from overseas during the incubation period, and genotyping provided strong evidence that the viruses were imported. All three outbreaks involved predominantly young adults. Healthcare staff aged in their 20s or early 30s accounted for six of the 75 cases in the 1999 Victorian outbreak (a doctor, three nurses, a social worker and a medical student3), and for two of the 51 cases in the first of the 2001 Victorian outbreaks (a medical student [the index case] and a nurse who remained unvaccinated despite being identified as susceptible in the previous outbreak5). In the latter outbreak, an unvaccinated 11-year-old child also became infected after attending an emergency department at the same time as an infectious patient. In the current outbreak, one case was in a 36-year-old hospital orderly, and another in a 30-year-old pharmacy assistant, both almost certainly infected while at work (Dr Sean Tobin, personal communication). The hospital orderly, born in 1965, might have been expected to be immune to measles, having grown up when measles virus was circulating in the community and measles epidemics occurred every two years.6 However, people born between about 1968 (when measles vaccine was first licensed in Australia) and 1981 (when a measles–mumps combination vaccine was introduced to the Australian childhood schedule) grew up when exposure to wild measles virus was decreasing. Because of initial poor vaccine coverage, there was inadequate compensation for the subsequent decline in natural immunity in the population, leaving a proportion of this age group, now aged 20–33 years, at risk of measles infection.7 These cases of measles transmission in healthcare settings in Victoria, Western Australia and New South Wales illustrate failure to implement the published guidelines for measles control.8 These involve four key components: isolate the patient, confirm the diagnosis, identify other cases and identify and protect all susceptible persons. However, the failures may be caused by a general lack of awareness of the guidelines rather than an unwillingness to follow their recommendations. In particular, the guidelines are not useful if measles has not been diagnosed. Measles is now relatively uncommon and more likely to affect young adults than children.2 A high index of suspicion is needed, and measles should always be considered in the differential diagnosis of fever and rash in an unwell adult, especially if the person was born between 1968 and 1981. Had the four key components of outbreak control been implemented in some or all of the reported measles outbreaks, some or all of the infections in these outbreaks may have been prevented. As recommended in the guidelines for measles control,8 vaccination of some or all of the young adults involved in these outbreaks may also have prevented further cases. Australia has recently spent more than $30 million on a highly successful mass-vaccination campaign that has effectively protected school-aged children against measles.9 It seems extraordinary that measles transmission can still occur in hospitals or general practice surgeries. Case reports are very unlikely to reveal the extent of the problem. It might be said that transmission of measles — or any other vaccine-preventable disease — in a healthcare setting is a sentinel sign of system failure. Offering susceptible healthcare workers measles–mumps–rubella vaccine has been made a quality standard for all healthcare workers in the United States,10 and a similar approach may be warranted in Australia. Healthcare providers in hospitals and the wider community should record which staff members are susceptible to vaccine-preventable diseases that may be occupationally transmitted, and should provide facilities for vaccination of all those who wish to protect themselves and their patients. As recommended in the Australian guidelines for measles control, young adults intending to travel to measles-endemic countries should be advised to check and update their measles vaccination status. At a time when measles transmission has probably been interrupted in several Australian States,2,11 it is important to suspect the diagnosis of measles in young adults with rash and fever, especially those with a history of international travel, and to take pro-active infection control measures to prevent measles transmission in healthcare settings.

Heath A Kelly · Michaela A Riddell · Ross M Andrews

Throughout the world until the mid-1990s, HIV infection was invariably fatal, with a median survival of one to two years after diagnosis of AIDS. Symptomatic HIV disease and AIDS imposed significant burdens on healthcare budgets, in addition to the often immeasurable societal costs. Now, for some, the availability of more effective antiretroviral therapies has transformed the HIV/AIDS epidemic. Mortality and AIDS diagnoses have fallen precipitously since widespread introduction of these treatments.1,2 Evidence to date suggests that the effectiveness of antiretroviral therapy has persisted.3 Mother-to-child HIV transmission can be effectively controlled, so that in the developed world paediatric HIV infection is rare. In developed countries, antiretroviral therapy is one of the most cost-effective interventions for treatment of a chronic disease.4 These unequivocal improvements are largely unprecedented for an infectious disease only 20 years old. However, HIV/AIDS continues to represent a significant global public health crisis. The United States identified HIV/AIDS as a threat to national security, and a special session of the United Nations General Assembly was convened in 2001 to address the epidemic. In the past five years, a clear paradox has emerged. On the one hand is the challenge of sustaining the improved longevity and quality of life for people who have access to effective treatments and care. On the other is the challenge of securing equivalent outcomes in the estimated 95% of HIV-infected people who live in countries that cannot afford antiretroviral therapy. For these 34 million or so people, HIV infection remains a death sentence. HIV/AIDS in developed countries. Combination antiretroviral therapy is not curative. The intent of treatment is to reduce the rate of virus replication, thus forestalling further damage to the immune system and, in most people, facilitating recovery and reducing the risk of life-threatening opportunistic infections or neoplasia. However, effective drug regimens are complex, and adherence is difficult. Ongoing virus replication increases the risk of selecting viruses that are resistant to treatment. As all 15 currently available antiretroviral drugs inhibit only one of two enzymes (HIV reverse transcriptase or protease), the selection of viruses resistant to one drug often carries the additional penalty of cross-resistance to other drugs. This limits the options available for future treatment. Each antiretroviral therapy has well described acute and chronic toxicities. More recently, clinical observations from Australian researchers implicate these agents in development of a syndrome termed lipodystrophy.5 Characteristically, patients present with abnormalities in body fat; many have insulin resistance, and some develop type 2 diabetes mellitus. The increased risk of cardiovascular disease arising from the glycaemic abnormalities may be compounded by hyperlipidaemia of an atherogenic profile. As all HIV-infected patients will need lifelong treatment with antiretroviral agents, these newly described toxicities could be a significant impediment to continued successful clinical outcomes. There is an urgent need for new therapies that inhibit HIV replication at new sites (such as HIV integrase and virus–cell fusion), that do not select for cross-resistance to other antiretrovirals, and that are not associated with metabolic toxicities. The potential role of immunotherapies (eg, interleukin 2 and therapeutic vaccines) warrants continued investigation, as they may be unaffected by cross-resistance to antiretrovirals and may have less long term toxicity. HIV/AIDS in developing countries. The scale of the HIV/AIDS problem in the developing world is alarming. Life expectancy in some countries will be reduced, in the absence of HIV treatment, by as much as 50%. This effectively negates all gains achieved through public health programs in these countries over recent decades. Addressing the inequities of healthcare around the world will take more than biomedical solutions — not only do drugs need to be made available more cheaply, but healthcare professionals need training, education, support and resources. In addition, treatment must be seen in the context of a comprehensive prevention and care framework. We need to revisit how medical research might contribute to resolving this enormous crisis. As part of such an approach, evaluations are being planned of simplified methods for clinical monitoring of HIV disease, deferred treatment strategies and abbreviated therapy regimens. We can be optimistic that research will deliver at least a partially effective prophylactic vaccine, but even optimistic estimates suggest this will take seven to 10 years. Every day about 15 000 people are infected with HIV, of whom 95% are in developing countries. In the seven to 10 years that a vaccine may take to develop, some 35 million people will be facing a reduced lifespan unless there is substantial change in their access to proven treatments. For the remaining 5% of HIV-infected individuals, the challenge is to develop new treatments.

Sean Emery BSc(Hons), PhD · David A Cooper MD, DSc, FRACP, FRCPA, FRCP

Recent years have seen the continuing emergence of new infectious diseases and the re-emergence of old ones. However, there have also been major advances in diagnosis and treatment of infectious diseases, as well as in our understanding of their pathogenesis. Future control of these diseases will require attention to the behavioural, environmental and healthcare factors that drive microbial evolution. For example, the "epidemic" of injecting drug use promotes HIV spread; Legionnaires' disease is "opportunistic" on air-conditioning and water-treatment systems; and immunosuppressive therapies and medical instruments that are difficult to sterilise (eg, endoscopes and phaco-emulsification handpieces) create opportunities for new infections. HIV and hepatitis C. HIV epidemics are emerging in Papua New Guinea and South-East Asia. Australia successfully combated the first wave of HIV infection in the late 1980s and is in a position to support control programs in these areas. The most important development in HIV control is the concept that treatment is an essential component of prevention, promulgated at the recent United Nations General Assembly Special Session on HIV/AIDS.1 In Australia, where antiretroviral resistance is now common, the emerging approach to management is immunotherapy (boosting the immune response with agents such as interleukin 2 and vaccines). Hepatitis C virus has been revealed as more common than expected in Australia, with over 200 000 people estimated to be infected.2 It rarely presents as an acute symptomatic infection, but emerges insidiously with symptoms of chronic fatigue, and in some people progresses to cirrhosis and (rarely) hepatocellular carcinoma. Progression to chronic liver disease appears more likely if infection is acquired through transfusion or at an older age.3 For infection acquired through injecting drug use, rate of progression to cirrhosis is 5%–10% after 20 years. Endoscopy is a recognised route of transmission that requires attention. Creutzfeldt–Jakob disease. The emergence of variant Creutzfeldt–Jakob disease (vCJD) has prompted changes to transfusion services in Australia and review of food and therapeutic products and infection control measures. In routine medical practice, there is a need to identify people at risk of CJD before neurosurgery, ophthalmic surgery and diagnostic procedures that contact infected tissue, and to implement measures to contain healthcare-associated transmission of classic CJD. However, the necessary standards of infection control are neither widely agreed nor practised. As no cases of vCJD have yet been reported in Australia, the cost–benefit of implementing infection control measures for vCJD is uncertain and is currently being actively considered by the Special Expert Committee on Transmissible Spongiform Encephalopathies of the National Health and Medical Research Council. Emergence of vCJD in Australia will dramatically alter infection control practices, not least because vCJD manifests in a wider range of tissues than classic CJD (eg, in the tonsils). Infection control procedures will be needed for procedures involving lymphatic tissues as well as brain. Vaccines. Haemophilus influenzae type b (Hib) vaccine has substantially eradicated Haemophilus meningitis and pneumonia from the Australian community, and the new conjugated pneumococcal vaccines have similar potential to prevent invasive pneumococcal disease. A raft of other new vaccines are in advanced stages of development, including vaccines that stimulate cell-mediated responses against many viruses, Chlamydia spp. and even cancers. Vaccines for varicella are currently marketed, and clinical trials are under way on vaccines for herpes simplex virus, human papilloma virus, HIV, malaria and tuberculosis. Key factors in vaccine use are access, funding and long term safety. The role of routine vaccination for pneumococcus, varicella virus and meningococcus in Australia has yet to be debated, but these vaccines will have impacts on routine practice. Antiviral agents. There are now effective antiviral agents for the herpes viruses, HIV, hepatitis B and C viruses and influenza virus. The range of antiviral compounds is expanding, and their role in treatment and prevention is a current challenge for clinical research. Diagnostic methods. Molecular diagnostic methods are now established for infectious diseases and are being tailored for easy use in standard laboratories, and even as point-of-care kits for the consulting room. A prion diagnostic kit should be available within two years. Concepts in pathogenesis. Infection is now recognised to have a role in conditions as diverse as cancer of the cervix (human papilloma virus), preterm birth (bacterial vaginosis) and cerebral palsy (chorio-amnionitis). In contemplating the future, the bad news is that infectious diseases evolve continuously and will continue to present in new guises. The good news is that molecular biology has provided new tools for diagnosis and control. However, advances have mostly comprised new strategies to control emerging disease agents. The challenge is to modify the environmental, social and behavioural factors that promote the emergence of new infections.

Peter J McDonald AM

Hazards and help in communications Books as carriers of disease In the early years of bacteriology, librarians, microbiologists and public health physicians were much exercised by the question of whether books could transmit infectious diseases. Mark J Ferson MJA 2001; 175: 663-664 Surveys and experiments on transmission - Attempts to sterilise books - Public health responses - Australian responses - Acknowledgements - References - Authors' details - - More articles on Public and environmental health Given the current concern about transmission of anthrax spores via the mail, it may be instructive to revisit early research on whether books can transmit other infectious diseases. As the theory of spontaneous generation gave way to ground-breaking discoveries in the new science of bacteriology by Pasteur, Lister, Koch and others,1 it was perhaps not surprising that this question was posed at an 1879 meeting of librarians in Chicago.2 Although there was no evidence that bibliophiles had ever expressed a "fear of books as vehicles of pestilence",3 the question seemed to exercise greatly the minds of librarians, microbiologists and public health physicians, and numerous articles were published on the subject in medical and library journals over the succeeding 60 years. These articles sought to determine whether books could transmit infectious diseases and how library books could best be sterilised without damage. Surveys and experiments on transmission An early survey of United States boards of health elicited some notable and bizarre cases of infectious diseases acquired from books.4 These included scarlet fever transmitted by a book in which a young sufferer had inserted strips of his peeling skin as bookmarks, diphtheria in two children acquired through handling school books from a farmhouse where six cases of the disease had occurred 42 years previously, and smallpox in a man who borrowed books from a circulating library in a neighbouring town affected by a smallpox epidemic.4An 1896 issue of The Lancet drew attention to a French study demonstrating isolation of streptococci, pneumococci and Corynebacterium diphtheriae, but not Salmonella typhi or Mycobacterium tuberculosis, from books soiled with the secretions of infected patients.5,6 However, the obviously cynical author felt that fear of contagion would be insufficient to drive readers to buy rather than borrow books.5 A later study found that washings from library books which had been borrowed by people with tuberculosis failed to transmit infection when inoculated into the peritoneal cavity of guinea pigs.7 Attempts to sterilise books A 1911 report sought alternatives to gaseous methods of disinfection, which are unable to penetrate closed books, and to steam, which damages books. Immersing books for 20 minutes in petrol containing 2% carbolic acid sterilised all inoculated cultures of C. diphtheriae, S. typhi, Escherichia coli and Staphylococcus aureus, but did not reliably destroy the infectivity of books contaminated with sputum containing M. tuberculosis.8 Thankfully, the author provided a recipe for a mixture of essential oils to hide the strong odours of petrol and carbolic acid and, perhaps rather obviously, exhorted the reader "to keep . . . the book until dry away from the fire". The following year, an evidence-based review was published, drawing on references in English, German, Italian and French.9 On balance, formalin vapour was concluded to be ineffective, as the gas cannot penetrate the pages of a closed book. The author was unable to replicate the results of the previous study on petrol and carbolic acid, but supported earlier studies showing that the application of hot, moist air (78º-80ºC and 30%-40% humidity) to closed books for 32 hours destroys non-sporing bacteria and mycobacteria without injuring the books. For those not requiring immediate results, several studies found that storing books for a month in a warm, dry room minimised risk of transmission of tuberculosis,7,10 streptococci11,12 and staphylococci.12 Finally, there was concern about the lack of knowledge of virus survival, with a clear statement that books used by a smallpox sufferer should be burned.13 Public health responses In Britain, the government introduced specific provisions into public health legislation through the Public Health Act Amendment Act 1907. This required that a library book borrowed by a member of a household with a notifiable disease be returned to the local authority for disinfection or destruction, with failure to do so attracting a fine of up to £2. These provisions were continued in later versions of the Public Health Act and remain in force today. As the local authority was required to compensate the library for destroyed books, there was some incentive to disinfect them. However, well after introduction of the legislation, discussion continued among members of the Society of Medical Officers of Health as to whether books could transmit infectious diseases,14,15 with much difference of opinion. Australian responses In Australia, public health legislation does not specifically refer to libraries but does mention books. Regulations in the Victorian Health Act 1890 for preventing spread of contagious diseases require that "The room occupied by the patient . . . in all cases, whenever possible, all hangings . . . shall be removed, together with books . . . and sunshine and fresh air in current allowed full play."16 On the other hand, 1896 guidelines provided by the New South Wales Department of Public Health for householders concerned about diphtheria or scarlet fever stated that the "only articles which must always be burnt are books, papers and toys; they cannot be safely disinfected".17,18 Public health laws of the other States made no reference to books. This lack of official guidance did not prevent libraries making their own rules about the handling of books borrowed by individuals with infectious diseases. The clearest manifestation of this concern was the fashion for private lending libraries, particularly in Melbourne, to promote themselves as "hygienic" (Box) because of their practice of placing books in cabinets with formalin vapour (Dr Richard Travers, Rheumatologist, Royal Melbourne Hospital, VIC, personal communication, Sep 2001). This was despite the fact that formalin vapour had already been shown to be an ineffective disinfectant of books. By the 1950s and 1960s, the proliferation of public libraries had largely killed off private lending libraries, and the declining risk of infectious diseases and consequent public interest meant that the concept of books as transmitters of disease was no longer worthy of serious consideration. Acknowledgements I wish to thank Brenda Heagney and Donna Mendrawi of the History of Medicine Library of the Royal Australasian College of Physicians, Sydney, for assistance in obtaining historical references. References Lechevalier HA, Solotorovsky M. Three centuries of microbiology. New York: Dover, 1974. McClary A. Beware the deadly books: a forgotten episode in library history. J Library History 1985; 20: 427-433. Winterich JT. A primer of book-collecting. Revised edition. New York: Greenberg, 1935: 114-120. Reinick WR. Books as a source of disease. Am J Pharm 1914; 86: 13-25. Books as disseminators of disease. Lancet 1896; 1: 180. From our own correspondent. Paris. Lancet 1896; 1: 388. Kenwood H, Dove EL. The risks from tuberculous infection retained in books. Lancet 1915; 2: 66-68. Beebe WL. Carbo gasoline method for the disinfection of books. J Am Public Health Assoc 1911; 1: 54-60. Nice LB. The disinfection of books. Bull Med Library Assoc 1912; 1: 61-66. Smith CR. Survival of tubercle bacilli in books. Am Rev Tuberculosis 1942; 46: 549-559. Balmain AR. Recovery of Streptococcus scarlatinae from experimentally infected books. Lancet 1927; 2: 1128. Smiley HE. Books — shall they be sterilized? Rhode Island Med J 1933; 16: 5-6. McCartney JE. Infection by books. Lancet 1925; 2: 212. Society of Medical Officers of Health. Home Counties Branch. Public Health 1923-24; 37: 265-266. Society of Medical Officers of Health. North Western Branch. Public Health 1923-24; 37: 295-296. Cole HS, Morris H. The Health Act, The Infant Life Protection Act, The Margarine Act, with regulations, notes of English cases and index. Melbourne: Charles F Maxwell, 1894. Department of Public Health, New South Wales. Suggestions to householders for the prevention of scarlet fever (or scarlatina), on the domestic isolation and disinfection, and on the law on infectious diseases. (Public Health Act, 1896, part III.). Sydney: WA Gullick, Government Printer, 1898. Department of Public Health, New South Wales. Suggestions to householders for the prevention of diphtheria, on the law on infectious diseases, and on isolation and disinfection. (Public Health Act, 1896, part III.) Sydney: WA Gullick, Government Printer, 1898.(Received 23 Oct, accepted 29 Oct, 2001) Authors' details South Eastern Sydney Public Health Unit, Sydney, NSW. Mark J Ferson, MD, FRACP, FAFPHM, Director, and Conjoint Associate Professor, School of Public Health and Community Medicine, University of New South Wales, Sydney, NSW. Reprints will not be available from the author. Correspondence: Dr M J Ferson, South Eastern Sydney Public Health Unit, Locked Bag 88, Randwick, NSW 2031. fersonmATsesahs.nsw.gov.au Make a comment Bookplate for Stinton's Hygienic Library, Moonee Ponds, Melbourne, VIC, circa 1940s. Back to text

Mark J Ferson

We report the first instance in Australia of treatment failure due to a strain of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin — heteroresistant vancomycin-intermediate S. aureus (hVISA). The infection occurred in a 41-year-old man with multiple risk factors. No transmission of the organism to other patients or the environment was detected. This case may herald the beginning of a new phase of staphylococcal resistance in Australia. Peter B Ward, Paul D R Johnson, Elizabeth A Grabsch, Barrie C Mayall and M Lindsay Grayson MJA 2001; 175: 480-483 Clinical record - Assessment of patient isolates - Results - Discussion - Competing interests - Acknowledgements - References - Author's details - - - More articles on Infectious diseases and parasitology The glycopeptides, vancomycin and, to a lesser extent, teicoplanin, are the mainstay of therapy for infections caused by methicillin-resistant Staphylococcus aureus (MRSA),1,2 and currently up to half of all S. aureus strains isolated in hospitals in Australia are MRSA.3,4 Despite substantial glycopeptide use over many years, the emergence of MRSA strains with reduced susceptibility to vancomycin and teicoplanin has been reported only recently.5-7 Subsequently, MRSA strains have been reported that contain limited subpopulations with intermediate resistance to glycopeptides, while most of the population remains glycopeptide-susceptible.8-14 These are termed heteroresistant vancomycin-intermediate S. aureus (hVISA) (see glossary in Box 1). We report here the first Australian case of infection due to hVISA. Clinical record A 41-year-old male smoker with long-standing type 1 diabetes, haemodialysis-dependent end-stage renal failure, hepatitis C and peripheral vascular disease was admitted to hospital in late August 2000 with bilateral lower-limb ischaemia refractory to prostacyclin therapy. Despite hyperbaric oxygen and multiple courses of antibiotics (including cephalexin, flucloxacillin, gentamicin and clindamycin), the patient developed increasing lower-limb gangrene, necessitating a right below-knee amputation on Day 41 of hospital admission. On Day 47, ulcers on his left foot were found to be infected with MRSA and Enterobacter spp. Therapy with vancomycin (1 g) and meropenem (500 mg) postdialysis (ie, three times a week) was commenced. Intravenous teicoplanin (400 mg every third day) was later substituted for vancomycin, as the patient developed a rash after the initial dose of vancomycin. However, his condition worsened, necessitating a left below-knee amputation on Day 50. Therapy was continued with teicoplanin, intravenous gentamicin (160 mg daily) and metronidazole (500 mg twice daily), but both amputation wounds broke down and repeated cultures grew MRSA and E. coli, finally necessitating a left above-knee amputation on Day 105. Despite therapeutic serum levels of teicoplanin (troughs of 6.5-15.9 mg/L, measured on 10 occasions over eight weeks), both amputation sites remained actively infected with MRSA and E. coli. On Day 120 (after 73 days' glycopeptide therapy), teicoplanin was ceased, and a new oxazolidinone, linezolid (600 mg intravenously, twice daily), was commenced in combination with oral ciprofloxacin and metronidazole. Over the next five days, dramatic improvement was noted in all infected wounds. After 11 days, intravenous linezolid was changed to oral linezolid (600 mg twice daily). MRSA was isolated from the amputation sites nine days after linezolid was begun, but was not detected again in any subsequent cultures. The patient continued to receive oral linezolid for 81 days. His condition improved steadily, and he was transferred to a rehabilitation unit on Day 179. Over the subsequent six months, he remained reasonably well, with no evidence of MRSA infection. Assessment of patient isolates After attending a presentation during which new laboratory methods for the accurate identification of VISA and hVISA were presented (Annual Conference of the Australian Society for Antimicrobials, Melbourne, April, 2001), we decided to further investigate stored MRSA isolates from the patient. Two MRSA strains obtained from the right below-knee amputation stump were retrieved from storage at -70ºC. These strains (AR1 and AR2) were isolated on hospital Day 104 (after 57 days of teicoplanin therapy) and Day 129 (nine days after changing from teicoplanin to linezolid therapy), respectively. The two strains were assessed for in-vitro antibiotic susceptibility using routine methods (agar dilution and broth microdilution).15 They were also assessed for glycopeptide-resistant subpopulations using methods described previously.5-7 These comprised: Colony morphology: Each isolate was examined macroscopically for the heterogeneous colony morphology typical of hVISA; pure cultures have been reported to produce a mix of both large and small colonies when cultured on Columbia agar with 5% horse blood (Oxoid, Basingstoke, UK) and other media.6,7 Colonies suspected of glycopeptide resistance were further assessed for vancomycin and teicoplanin resistance. Vancomycin gradient plates: Vancomycin resistance was assessed using vancomycin gradient plates prepared as described previously.6 Thirty mL of brain-heart infusion (BHI) agar (Oxoid, Basingstoke, UK) containing vancomycin (4 mg/L) was poured into a 10 cm square petri dish raised on one edge by 6 mm. After setting, the resultant wedge was overlaid with a 30 mL layer of BHI agar without antibiotic and allowed to set horizontally. Plates were stored for 24 hours at 4ºC to allow diffusion of vancomycin into the upper agar layer. Twenty-four-hour cultures of organisms in brain-heart infusion (BHI) broth were adjusted to a 0.5 McFarland standard, and 20 µL aliquots were spread on the gradient plates in an even line along the increasing antibiotic gradient. Plates were assessed after 48 hours' aerobic incubation at 37ºC.6 E test minimum inhibitory concentration: Both vancomycin and teicoplanin resistance was assessed by E test (AB Biodisk, Solna, Sweden), using methods and interpretations recommended in the United States7 and Europe.11 US methods use Mueller-Hinton agar (Oxoid, Basingstoke, UK) and an inoculum equivalent to the 0.5 McFarland standard, and define intermediate vancomycin resistance as MIC, 8-16 mg/L. European methods use BHI agar and a heavier inoculum (2 McFarland standard) and define intermediate vancomycin resistance as MIC ≥8 mg/L. Teicoplanin intermediate resistance is defined as MIC > 8 mg/L (US) or > 6 mg/L (Europe). Inoculated media were incubated aerobically for 24 hours at 37ºC.7,11 Population analysis profile: The proportion of cells in the population of each isolate that was resistant to a range of vancomycin and teicoplanin concentrations was assessed, using methods described previously.6,9 Assessment of nosocomial transmission As the presence of hVISA was first recognised five months after the patient's infection was cured empirically, screening was undertaken to ascertain whether hVISA had been transmitted nosocomially: Nose, groin, hand and wound specimens from the index patient were cultured to assess current MRSA and hVISA infection or colonisation. Nose and groin specimens were collected from all patients attending the in-centre haemodialysis units also attended by the index patient. These were assessed, along with multiple environmental samples from the units, for the presence of MRSA and hVISA. All patients in the Nephrology Department who had been diagnosed with MRSA infection or colonisation between October 2000 and May 2001 were identified from the hospital's microbiology database. Their clinical course was reviewed to identify those whose condition did not respond to vancomycin. Stored MRSA isolates from these patients were assessed for glycopeptide resistance, as described above. All MRSA isolates obtained at our institution since May 2001 were assessed prospectively for hVISA using a screening plate of BHI agar with vancomycin (4 mg/L).12 Results Antibiotic susceptibility of index isolate Routine antibiotic sensitivity testing: The two patient isolates, AR1 and AR2, were confirmed to be MRSA and to have identical susceptibility profiles. Both tested resistant to penicillin, methicillin, erythromycin, trimethoprim, cotrimoxazole, clindamycin and ciprofloxacin, but susceptible to tetracycline, chloramphenicol, mupirocin, fusidic acid, vancomycin (MIC, 2 mg/L) and teicoplanin (MIC, ≤ 8 mg/L) using agar dilution methods,15 and to linezolid (MIC, 1.5 mg/L) using the E test.15 Glycopeptide-resistant subpopulations: Both AR1 and AR2 displayed small and large colony variants, consistent with previous reports of hVISA, VISA and VRSA.6,7 By E test, both isolates had a vancomycin MIC of 6-8 mg/L (US method) and 8 mg/L (European method), and a teicoplanin MIC of 24 mg/L (US method) and 16-24 mg/L (European method). Repeated analysis of AR2 using vancomycin gradient plates demonstrated growth across the entire 4 mg/L vancomycin gradient, confirming the MIC to be > 4 mg/L, and the isolate to be hVISA. Population analysis profiles were also consistent with both isolates' being hVISA. In particular, detailed analyses of AR2 demonstrated that colony subpopulations were able to grow on 3 mg/L and 4-6 mg/L vancomycin plates at frequencies of 1 in 10 and 1 in 105-106, respectively (Box 2). In comparison, control organisms generated resistant colonies at a rate of < 1 in 108 at these concentrations. Similarly, population analysis of AR2 using 8 mg/L and 16 mg/L teicoplanin demonstrated presence of resistant subpopulations at frequencies of 1 in 103 and 1 in 105-106, respectively (Box 2). These findings are consistent with those for hVISA reported by Hiramatsu.5,6,9 Nosocomial transmission of hVISA MRSA, hVISA and VISA were not detected in cultures obtained from the index patient after completion of linezolid therapy. Similarly, hVISA was not detected from nose or groin cultures of 85 patients who were either current renal ward inpatients or undergoing in-centre haemodialysis. Also, hVISA was not detected in cultures of 28 environmental sites in the ward and haemodialysis units, suggesting that routine cleaning was effective in limiting significant hVISA colonisation and contamination. Twenty-six renal patients were identified from the microbiology database with MRSA infection during the eight months between October 2000 and May 2001. Six of these patients were considered by the Nephrology Department to have had a slow clinical response to anti-MRSA treatment. MRSA isolates were retrieved from frozen storage for all six patients, and the most recently obtained MRSA isolate was assessed for all (except one patient in whom the second most recent isolate was assessed). None of these MRSA strains were hVISA. Prospective screening of all MRSA isolates at our institution for hVISA began in July 2001. Of 315 isolates obtained from 128 patients, none were hVISA. Discussion This is the first report of clinical treatment failure caused by MRSA with reduced susceptibility to glycopeptides in Australia. Similar cases have been described in Europe, North America and South-East Asia,7,16 and a single strain of vancomycin-resistant S. aureus has been reported in Japan.17Slow clinical response, and even treatment failures, associated with glycopeptide therapy for MRSA infections have been described previously.1,18-20 This has generally been attributed to the characteristics of glycopeptides: their penetration into sites of established sepsis, which is generally inferior to that of other agents, such as β-lactams, and their slow bactericidal activity.20-22 Empirically, we attributed the clinical failure of teicoplanin in our patient to multiple factors, including his advanced vascular disease, and poor drug delivery (despite adequate serum teicoplanin levels), as well as the inherent characteristics of the drug.2 However, the patient's very rapid clinical improvement and the ultimate clearance of MRSA soon after commencement of linezolid is consistent with our later identification of the infecting strain as hVISA. Our detailed search did not detect hVISA contamination of the haemodialyis environment, or colonisation or infection of other haemodialysis patients, or any subsequent patients with MRSA at our hospital. Thus, we believe that hVISA is not widespread in our hospital, and that our case is unusual. Now that the microbiological methods to identify hVISA have been clearly described,6,7,14 it is likely that strains will be identified in Australia. However, it is a challenge to establish a laboratory screening protocol for hVISA and to determine what resources should be allocated to screening for hVISA. The Centers for Disease Control and Prevention in Atlanta recommend that routine screening of all MRSA isolates for vancomycin resistance is currently unnecessary and probably wasteful. Instead, attention should be focused on patients in whom glycopeptide therapy is failing, or those at increased risk of MRSA carriage and infection, such as patients undergoing haemodialysis or chronic ambulatory peritoneal dialysis.7,12 Our identification of hVISA may be the beginning of a new phase in the emergence of antibiotic resistance in Australia, when the glycopeptides vancomycin and teicoplanin will no longer be effective in some cases of MRSA infection.18-20,23 This raises challenges for clinical management, laboratory detection and infection control. Furthermore, while two recently available agents, linezolid and quinupristin-dalfopristin, appear active against hVISA, VISA, MRSA and vancomycin-resistant enterococci, resistance to linezolid has already been reported among strains of both MRSA and Enterococcus faecium.21,22,24 Thus, we may be approaching an era when there are no effective therapies for some strains of MRSA. Competing interests None declared. Acknowledgements We wish to acknowledge the invaluable assistance of the infection control practitioners and staff of the Microbiology and Nephrology departments. References Kucers A. Vancomycin. In: Kucers A, Crowe S, Grayson ML, Hoy J. The use of antibiotics. 5th ed. Oxford: Butterworth Heinemann, 1997: 763-790. Fekety R. Vancomycin, teicoplanin, and the streptogramins: quinupristin and dalfopristin. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000: 382-392. Turnidge JD, Bell JM. Methicillin-resistant Staphylococcus aureus evolution in Australia over 35 years. Microb Drug Resist 2000; 6: 223-229. Gottlieb T, Mitchell D. The independent evolution of resistance to ciprofloxacin, rifampicin and fusidic acid in methicillin-resistant Staphylococcus aureus in Australian teaching hospitals (1990-1995). Australian Group for Antimicrobial Resistance (AGAR). J Antimicrob Chemother 1998; 42: 67-73. Hiramatsu K, Hanaki H, Ino T, et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997; 40: 135-136. Hiramatsu K. The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan. Am J Med 1998; 104 Suppl 5A: 7S-10S. Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to vancomycin and other glycopeptides in Staphylococcus aureus. Emerg Infect Dis 2001; 7: 327-332. Howe RA, Wootton M, Walsh TR, et al. Heterogeneous resistance to vancomycin in Staphylococcus aureus. J Antimicrob Chemother 2000; l45: 130-132. Trakulsomboon S, Danchaivijitr S, Rongrungruang Y, et al. First report of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin in Thailand. J Clin Microbiol 2001; 39: 591-595. Wong SS, Ho PL, Woo PC, Yuen KY. Bacteremia caused by staphylococci with inducible vancomycin heteroresistance. Clin Infect Dis 1999; 29: 760-767. Walsh TR, Bolmstrom A, Qwarnstrom A, et al. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol 2001; 39: 2439-2444. Fridkin SK. Vancomycin-intermediate and -resistant Staphylococcus aureus: what the infectious disease specialist needs to know. Clin Infect Dis 2001; 32: 108-115. Wootton M, Howe RA, Hillman R, et al. A modified population analysis profile (PAP) method to detect hetero-resistance to vancomycin in Staphylococcus aureus in a UK hospital. J Antimicrob Chemother 2001; 47: 399-403. Centers for Disease Control and Prevention. Staphylococcus aureus with reduced susceptibility to vancomycin-Illinois, 1999. MMWR Morb Mortal Wkly Rep 2000; 48: 1165-1167. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. Supplement M100 S11. Wayne, Pa: The Committee, 2001. Geisel R, Schmitz FJ, Thomas L, et al. Emergence of heterogeneous intermediate vancomycin resistance in Staphylococcus aureus isolates in the Dusseldorf area. J Antimicrob Chemother 1999; 43: 846-848. Hiramatsu K, Aritaka N, Hanaki H, et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 1997; 350: 1670-1673. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115: 674-680. Wood CA, Wisniewski RM. Beta-lactams versus glycopeptides in treatment of subcutaneous abscesses infected with Staphylococcus aureus. Antimicrob Agents Chemother 1994; 38: 1023-1026. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34: 1227-1231. Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46: 775-784. Prystowsky J, Siddiqui F, Chosay J, et al. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother 2001; 45: 2154-2156. Hanaki H, Kuwahara-Arai K, Boyle-Vavra S, et al. Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant Staphylococcus aureus clinical strains Mu3 and Mu50. J Antimicrob Chemother 1998; 42: 199-209. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001; 358: 207-208. (Received 10 Sep, accepted 26 Sep, 2001) Authors' details Austin and Repatriation Medical Centre, Melbourne, VIC. Peter B Ward, BAppSc, PhD, Senior Scientist, Microbiology Department; Paul D R Johnson, FRACP, PhD, Deputy Director, Infectious Diseases Department, and Associate Professor, Department of Medicine, University of Melbourne, VIC; Elizabeth A Grabsch, BSc, MPH, Infection Control Scientist, Microbiology Department; Barrie C Mayall, FRACP, FRCPA, Medical Microbiologist, Microbiology Department; M Lindsay Grayson, FRACP, FAFPHM, MD, Director, and Professor, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, and Department of Medicine, University of Melbourne, Melbourne, VIC. Reprints: Dr P B Ward, Microbiology Department, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, VIC 3084. Peter. WardATarmc.org.au Make a comment 1: Glossary (adapted from references 7 and 12) MRSA: Methicillin-resistant Staphylococcus aureus. An isolate of S. aureus, resistant to methicillin, with minimum inhibitory concentration (MIC) to vancomcyin ≤2mg/L. MRSA does not produce vancomycin-resistant subpopulations during routine laboratory susceptibility tests. hVISA: Heteroresistant vancomycin-intermediate S. aureus. An isolate of MRSA which produces subpopulations with vancomycin MICs ≥4mg/L, typically at a rate of 1:105 to 1:106 resistant:sensitive colonies. Antibiotic-resistance detection methods that use large inocula, such as E test, are needed to screen for hVISA. VISA: Vancomycin-intermediate S. aureus. An isolate of MRSA which produces colonies with vancomycin MICs of 8-16mg/L at high frequency, and is detectable as "intermediate resistant" using standard low-inocula susceptibility tests. VRSA: Vancomycin-resistant S. aureus. An isolate of MRSA which produces populations of colonies with vancomycin MICs >32mg/L at high frequency. Back to text 2: Number of colonies resistant to defined concentrations of vancomycin and teicoplanin among subpopulations of a Staphylococcus aureus strain, AR2, isolated from the index patient. A range of inocula (103-109) were used to measure viable subpopulations at each antibiotic concentration. Back to text

Peter B Ward · Elizabeth A Grabsch · Barrie C Mayall

Research Mega-dose vitamin C in treatment of the common cold: a randomised controlled trial Carmen Audera, Roger V Patulny, Beate H Sander and Robert M Douglas MJA 2001; 175: 359-362 Abstract - Methods - Results - Discussion - Acknowledgements - Competing interests - Reference - Authors' details - - - More articles on Infectious diseases and parasitology Abstract Objective: To determine the effect of large doses of vitamin C in the treatment of the common cold. Study design: Double-blind, randomised clinical trial with four intervention arms: vitamin C at daily doses of 0.03 g ("placebo"), 1 g, 3 g, or 3 g with additives ("Bio-C") taken at onset of a cold and for the following two days. Participants and setting: 400 healthy volunteers were recruited from staff and students of the Australian National University, Canberra, ACT, between May 1998 and November 1999. The trial continued for 18 months. Interventions: Participants were instructed to commence medication when they had experienced early symptoms of a cold for four hours, and to record daily their symptoms, severity, doctor visits and use of other medications. Main outcome measures: Duration of symptoms and cold episodes; cumulative symptom severity scores after 7, 14 and 28 days; doctor visits; and whether participants guessed which medication they were taking. Results: 149 participants returned records for 184 cold episodes. No significant differences were observed in any measure of cold duration or severity between the four medication groups. Although differences were not significant, the placebo group had the shortest duration of nasal, systemic and overall symptoms, and the lowest mean severity score at 14 days, and the second lowest at 7 and 28 days. Conclusions: Doses of vitamin C in excess of 1g daily taken shortly after onset of a cold did not reduce the duration or severity of cold symptoms in healthy adult volunteers when compared with a vitamin C dose less than the minimum recommended daily intake. A recent Cochrane systematic review of the effects of vitamin C on the common cold concluded that large maintenance doses of vitamin C do not lower the incidence of colds in well-nourished subjects in Western countries.1 Nevertheless, the meta-analysis of 17 trials found that prophylactic doses of at least 1g per day were associated with a statistically significant weighted mean reduction in symptom days of about 0.45 days per cold (9% of symptom days).1 However, the authors of the Cochrane review could not draw conclusions about the therapeutic effects of vitamin C (ie, effects when taken at onset of a cold).1 Findings of four well-conducted trials of the effects of treating colds with a loading dose of vitamin C were inconclusive2-5(Box 1). This prompted us to design a study to answer the question "Would vitamin C, when used exclusively as a therapeutic agent in doses that greatly exceed the required daily intake, reduce the duration or severity of symptoms of the common cold in healthy Australian adults?". Methods Our study was a double-blind, randomised trial comparing the effects of different doses and formulations of vitamin C. We chose as "placebo" a dose of 0.03g per day of vitamin C (about half the recommended minimum daily intake), recognising that all participants would have some nutritional vitamin C intake. Ethics approval was obtained from the Human Ethics Committee of the Australian National University, Canberra. Participants Staff and students of the Australian National University, Canberra, ACT, were recruited between May 1998 and November 1999 through personal letters and emails, announcements at student gatherings and direct approach in university common areas. Volunteers were eligible for the study if they were aged over 18 years, not pregnant or planning to become pregnant, in good general health, and did not take vitamin supplements regularly or take vitamin C, echinacea, zinc or Chinese herbal preparations regularly at the onset of a cold. Volunteers were clearly informed about the objectives of the study and signed an informed consent form. They also completed a questionnaire about their current health and medication status, including respiratory infections in the previous year. An information letter was provided for their general practitioners. Participants who returned information on one respiratory event were eligible to re-enrol in the study. Interventions Participants were randomised to receive one of four interventions: vitamin C in a daily dose of 0.03 g, 1 g or 3 g, or "Bio-C" (containing vitamin C [3 g daily] plus bioflavenoids [75 mg], rutin [150 mg], hisperidin [150 mg], rose hip extract [750 mg] and acerola [150 mg]). They were to take the medication at onset of cold symptoms and on the following two days. The medications were prepared by Blackmores Ltd (Sydney, NSW) as compressed tablets with identical appearance and packaging. Dosage was confirmed by chemical analysis of unused tablets at the end of the study. A random number table was constructed to order the medications sequentially so that each sequence of four numbers comprised all four types of medication. The medications were issued to investigators in 400 sequentially numbered sets of three bottles, each bottle containing the daily dose in three tablets. As volunteers joined the study they were given a set of three bottles and a correspondingly numbered "respiratory event card" to record outcome. The code was retained by the manufacturer until we were ready to analyse the results. Participants were instructed that they must have at least two of the following symptoms for a minimum of four hours before commencing medication: sore or scratchy throat, nasal congestion or discharge, headache or stinging eyes, muscle aches, fever, or "four hours of certainty that a cold is coming on". On the first day of illness, they were to take the contents of one bottle (three tablets) as soon as possible. For the next two days, they were to take three tablets a day at intervals of at least four hours. Outcome measures The respiratory event card was designed to be carried in a wallet or purse. When a cold began, participants were instructed to score symptoms daily, noting presence and severity (1, mild; 2, moderate; or 3, severe) of cough, nasal, throat, and systemic symptoms, including fever, headache, aches, feeling unwell and "other symptoms". Recording was to cease either when all symptoms disappeared or 28 days after onset of the cold. Participants were also instructed to record hours between onset of symptoms and first dose of medication, use of other medication and whether they sought medical attention. They were also invited to guess to which medication group they had been assigned. Duration of the cold was measured from day of symptom onset to the last day of any symptom. Cold severity scores were the sum of daily individual symptom scores throughout the duration of the cold. Symptom days and severity scores for cough, nasal, throat and systemic symptoms were considered separately, and cumulative scores were considered at 7, 14, and 28 days. For any one day of symptoms, the maximum severity score was 12. Participants who did not return a respiratory event card were sent reminder letters after nine months and 15 months. The initial 12-month study period was extended by six months in an effort to increase the response rate. Statistical analysis We aimed to study 75 individuals in each intervention arm, in the expectation that the study would have an 80% power to detect a 30% difference between groups in duration or severity, which we considered clinically significant. Desired sample size was calculated assuming a mean duration of seven days and a standard deviation of four days. Statistical comparisons were carried out using the software package SPSS.6 Distribution, mean and median of duration and severity scores for each symptom were compared between the four groups by t-tests, analysis of variance and box plots. Results Study population Four hundred sets of medication were distributed to 323 volunteers. By November 1999, when the study was terminated, 149 people had returned completed respiratory event cards for 184 cold episodes. These 149 were significantly older than those who did not return cards (45.1 versus 40.9 years; P < 0.05), but the two groups did not differ significantly in sex distribution or previous cold history. Personal characteristics and previous cold history of those who returned cards are shown in Box 2, along with time from symptom onset to beginning medication. Participants in the four medication groups were comparable in sex distribution and time to beginning medication, but those who took Bio C were significantly older and had fewer colds in the previous year than those in the other three groups (P < 0.05). Cold duration and severity Duration and severity of symptoms are compared between the four medication groups in Box 2. There were no significant differences between the groups in either mean duration of symptoms or mean severity scores at Days 7, 14 or 28, although the placebo group (30 mg vitamin C daily) had the shortest duration of nasal, systemic and overall symptoms, and the lowest mean severity score at 14 days, and the second lowest at 7 and 28 days. A box plot of cumulative severity scores at Day 28 (Box 3) revealed that the distribution of values was more dispersed in the 1 g and 3 g vitamin C groups, with the lowest median values occurring in the placebo and Bio C groups. A box plot of cold duration showed a similar pattern (Box 3). Only 31 participants (17%) recorded a guess about the dose of vitamin C they had taken, and 14 guessed correctly that they had taken a high dose. Seventeen gussed incorrectly that they had taken either a high or low dose. Actual power of the study Because the mean cold duration for the whole group was 9.8 days with a standard deviation of 6.6 days, the number of completed cold episodes returned per group provided 80% power to detect a 40% difference in cold duration with a 95% level of confidence. Similarly, given that the mean severity score at Day 28 was 32 with a standard deviation of 32.3, the number of completed cold episodes provided 80% power to detect a 50% difference in severity at the 95% level of confidence. Discussion Our study found no significant differences in severity or duration of cold symptoms between groups who took low-dose (placebo) and high-dose vitamin C as treatment for the common cold. The lack of benefit from high-dose therapeutic vitamin C is consistent with the findings of four other randomised controlled trials2-5 (Box 1). The Cochrane and other reviews of the published evidence on high-dose vitamin C and the common cold have drawn attention to the relatively consistent trend for those taking prophylactic doses in excess of 1 g daily to experience some reduction in duration or severity of colds.1,7-9 Although high-dose prophylactic vitamin C was also found not to reduce the incidence of colds in well-nourished adult populations,1,7 Hemila has proposed that it may have an effect in groups who are physically stressed or have low nutritional intake.8-10 The main weakness of our study is that it necessarily relied on study participants to decide when the criteria for commencing medication were met and to provide all outcome data. In such a study, double-blindness must be rigorously preserved, and allocation to intervention arms must avoid selection bias. We are confident that our study met these requirements and that the few participants who correctly guessed their medication dose did so by chance. The focus on the university community meant a potential bias in socioeconomic and educational status of participants. The observed spectrum of cold experience may not have been representative of the cold experience of the rest of the Canberra community. Many potential volunteers in our study were ruled ineligible because of their regular use of vitamin C and other, non-traditional approaches for cold therapy and prophylaxis. A recent US study found that 67% of patients seeking medical care for cold episodes believed that vitamin C reduces cold symptoms.11 Our target of 75 colds in each treatment group was not reached, despite extension of the study and repeated reminder letters to participants. Fewer than half those enrolled returned a completed respiratory event card. As we expected most to suffer at least one cold during the 18 months of the study, based on their previous history, we assume that many did not use the medication as instructed. Although those who completed a respiratory event card were older than those who did not, both groups had similar previous cold experience. The double-blind nature of the study makes it unlikely that greater compliance would have changed the result. Our study had medication groups of comparable size, and for each medication group colds were found to have occurred across the entire study period. The Bio-C group was slightly older than the other groups and, probably in consequence, experienced fewer colds in the previous year, as the incidence of colds tends to decrease with age. However, these differences were not associated with significant differences in outcomes. The average time between symptom onset and medication use was 13 hours, although we encouraged participants to begin medication as soon as four hours after they were certain that a cold was developing. However, the time to beginning medication did not differ significantly between groups. The power of our study to detect a possible significant difference in symptom severity and duration after high-dose vitamin C treatment was limited by the smaller than expected participation rate. However, the non-significant trend that was observed was the reverse: symptoms tended to be less severe and of shorter duration in the placebo group. The lack of observed benefit in this trial is fully consistent with the observations from the four previous randomised controlled trials that have sought to evaluate this issue.2-5 It is time to question again the wisdom and utility of the wide practice of well nourished adults taking mega-doses of vitamin C to treat the common cold, a practice which has become prevalent worldwide since the advocacy of Linus Pauling in the early 1970s.12,13 Acknowledgements The project was supported by a grant from Blackmores Ltd, who also provided the study medications. We thank all those who participated in the study for their patience and compliance. Competing interests Blackmores Ltd were not involved in conduct or analysis of the trial or preparation of this article. References Douglas RM, Chalker EB, Treacy B. Vitamin C for preventing and treating the common cold (Cochrane Review). In: The Cochrane Library, 3, 2001. Oxford: Update Software. Anderson TN, Suranyi B, Beaton GW. The effect on winter illness of large doses of vitamin C. Can Med Assoc J 1974; 111: 31-38. Karlowski TR, Chalmers TC, Frenkel LD, et al. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. JAMA 1975; 231: 1038-1042. Elwood PC, Hughes SJ, St Leger AS. A randomized controlled trial of the therapeutic effect of vitamin C in the common cold. Practitioner 1977; 218: 133-137. Tyrrell DA, Craig JW, Meada TW, White T. A trial of ascorbic acid in the treatment of the common cold. Br J Prev Soc Med 1977; 31: 189-191. SPSS [computer program]. Version 10.0 for Windows. Chicago, Ill: SPSS Inc, 1999. Hemila H. Vitamin C and the common cold. Br J Nutr 1992; 31: 3-16. Hemila H. Vitamin C supplementation and the common cold: was Linus Pauling right or wrong? Int J Vitam Nutr Res 1997; 67: 329-325. Hemila H. Vitamin C and common cold incidence: A review of studies with subjects under heavy physical stress. Int J Sports Med 1996; 17: 379-383. Hemila H, Douglas RM. Vitamin C and acute respiratory infections. Int J Tuberc Lung Dis 1999; 3: 756-761. Braun BL, Fowles JB, Solberg L, et al. Patient beliefs about the characteristics, causes, and care of the common cold: an update. J Fam Pract 2000; 49: 153-156. Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Natl Acad Sci USA 1971; 68: 2678-2681. Pauling L. Vitamin C, the common cold, and the flu. San Francisco: Freeman, 1976. Authors' details National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT. Carmen Audera, MD, MPH, Lecturer; Roger V Patulny, BEc, BA (Hons), Research Assistant; Beate H Sander, BAppSc (Nursing), MEcDev, Research Assistant; Robert M Douglas, MD, FRACP, FAFPHM, Visiting Fellow. Reprints will not be available from the authors. Correspondence: Emeritus Professor R M Douglas, National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT 0200. Bob. DouglasATanu.edu.au Make a comment 1: Previous randomised controlled trials of the therapeutic effect of high-dose vitamin C on cold symptoms Study Participants and setting Interventions Outcomes Anderson et al2 (1974) Toronto, Canada Hospital and business employees (>275 per arm) 4 arms: 2 placebo, 2 therapeutic (4g or 8g vitamin C taken on day of symptom onset) The two placebo arms unfortunately differed in outcome. Mean days of respiratory symptoms over 3 months: placebo, 5.4 and 4.16 days (combined placebo mean, 4.77 days); intervention, 4.82 days (4g dose) and 4.52 days (8g) Karlowski et al3 (1975) Bethesda, USA National Institutes of Health employees (46 placebo, 43 therapy) 3g vitamin C daily or placebo for the first 5 days of a cold Problem in blinding, as over half the participants correctly guessed their medication through taste. Although mean duration of colds was longer in the placebo than therapy group (7.1 v 6.5 days), difference was confined to those who guessed their medication ("unblinded"). Unblinded group: 8.6 (placebo) v 4.7 days (therapy); blinded group: 6.3 (placebo) versus 6.7 days (therapy). Elwood et al,4 (1977) South Wales, UK Community volunteers (119 placebo, 145 therapy) 3g vitamin C daily or placebo for 3 days Vitamin C significantly reduced duration of "simple" colds in men (5.7 days [placebo] v 3.97 days [therapy]), but had no benefit in women (4.97 days [placebo] v 6.05 [therapy]), or in "chest" colds in either sex. Tyrrell et al5 (1977) Salisbury, UK 482 volunteers 4g of vitamin C or an identical-tasting placebo daily for 2.5 days No evidence that vitamin C alleviated or shortened upper respiratory or general constitutional symptoms. Back to text 2: Characteristics of participants and outcomes of a study of the effect of therapeutic vitamin C on the common cold Vitamin C formulation (daily dose) 0.03g (n=42)* 1g (n=47)* 3g (n=50)* Participant characteristics Mean age in years (95% CI) 38.6 (34.2-43.0) 40.1 (35.8-44.4) 39.9 (36.2-43.6) Male sex (95% CI) 45% (30%-61%) 38% (26%-54%) 50% (36%-65%) Cold history in previous year Mean number of colds (95% CI) 2.2 (1.7-2.7) (n=40) 2.25 (1.9-2.6) (n=46) 2.2 (1.8-2.7) (n=49) Mean number of days unwell from colds (95% CI) 8.0 (3.4-12.5) (n=39) 7.7 (6.2-9.3) (n=46) 7.7 (6.5-9.2) (n=49) Mean hours from symptom onset to medication (95% CI) 13.3 (9.4-17.2) (n=39) 11.6 (8.7-14.7) (n=44) 10.2 (8.2-12.3) (n=48) Outcome measures Mean days of symptom (95% CI) 8.5 (6.6-10.5) 10.1 (8.1-12.1) 10.4 (8.5-12.2) Cough 5.3 (3.0-7.6) 6.4 (4.1-8.6) 6.3 (4.4-8.3) Nasal symptoms 7.3 (5.4-9.1) 8.4 (6.7-10.1) 9.2 (7.4-11.1) Throat symptoms 5.4 (3.6-7.2) 6.1 (4.3-7.9) 6.3 (4.6-7.9) Systemic symptoms 3.5 (2.1-4.9) 3.7 (2.3-5.2) 3.8 (2.7-4.8) Mean severity score‡ (95% CI) Day 7 20.2 (16.5-24.0) 22.1 (18.1-26.0) 23.0 (19.3-26.6) Day 14 25.6 (19.0-32.1) 31.1 (23.5-38.8) 30.8 (24.9-36.6) Day 28 29.0 (19.5-38.6) 35.4 (23.4-47.5) 34.3 (26.6-42.1) Doctor visit (95% CI) 7% (2%-20%) 19% (8%-31%) 4% (0.5%-14%) Other medication taken for symptoms (95% CI) 57% (41%-72%) 55% (40%-70%) 55% (39%-68%) Vitamin C formulation (daily dose) "Bio C" (3g plus additives) (n=45)* Total (n=184)* Participant characteristics Mean age in years (95% CI) 45.1 (40.6-49.5)† 40.9 (38.8-43.0) Male sex (95% CI) 51% (36%-66%) 46% (39%-54%) Cold history in previous year Mean number of colds (95% CI) 1.5 (1.3-1.8)† (n=44) 2.1 (1.9-2.3) (n=179) Mean number of days unwell from colds (95% CI) 6.8 (5.4-8.2) (n=43) 7.5 (6.4-8.9) (n=177) Mean hours from symptom onset to medication (95% CI) 18.6 (11.2-26) (n=44) 13.4 (11.1-15.8) (n=175) Outcome measures Mean days of symptom (95% CI) 9.9 (7.9-11.9) 9.8 (8.8-10.7) Cough 4.4 (2.2-6.5) 5.6 (4.6-6.7) Nasal symptoms 8.1 (6.1-10.1) 8.3 (7.4-9.2) Throat symptoms 5.4 (3.8-6.9) 5.8 (5.0-6.7) Systemic symptoms 4.4 (3.2-5.6) 3.9 (3.2-4.5) Mean severity score‡ (95% CI) Day 7 19.2 (15.4-23.0) 21.2 (19.3-23.0) Day 14 25.9 (19.1-32.6) 28.5 (25.2-32.8) Day 28 28.6 (20.0-37.3) 32.0 (27.3-36.7) Doctor visit (95% CI) 9% (3%-21%) 9% (6%-14%) Other medication taken for symptoms (95% CI) 53% (38%-68%) 55% (47%-62%) *Number of completed cold episodes; 35 participants were counted twice, as they reported two medicated colds. For variables with missing data, numbers of participants who provided information are shown in parentheses. †P Back to text 3: Box plots of cold severity and duration in groups taking different vitamin C formulations Back to text

Carmen Audera · Roger V Patulny · Beate H Sander · Robert M Douglas

Cannabis has been advocated as a treatment for nausea, vomiting, wasting, pain and muscle spasm in cancer, HIV/AIDS, and neurological disorders. Such uses are prohibited by law; cannabinoid drugs are not registered for medical use in Australia and a smoked plant product is unlikely to be registered. A New South Wales Working Party has recommended granting exemption from prosecution to patients who are medically certified to have specified medical conditions. This proposal deserves to be considered by other State and Territory governments. Wayne D Hall, Louisa J Degenhardt and David Currow MJA 2001; 175: 39-40 In August 1999, the New South Wales Premier convened a Working Party on the Use of Cannabis for Medical Purposes1 to advise on whether cannabis and cannabinoid drugs had any medical uses and, if so, to suggest how these substances could be made available for medical use without decriminalising cannabis for non-medical use. The Working Party's report was tabled in Parliament on 1 November 2000. Its recommendations were endorsed in principle by the Premier and are currently being considered by the NSW government. We believe that they deserve wider consideration. The Working Party reviewed the scientific evidence on the safety and efficacy of the medical uses of the crude cannabis plant (which is usually smoked) and of cannabinoid drugs (pharmaceutically pure substances found in the cannabis plant, such as tetrahydrocannabinol [THC], or synthetic drugs that act on the same receptors in the brain as THC).2 It agreed with the United States Institute of Medicine2 and the UK House of Lords Standing Committee on Science and Technology3 that THC can be useful in treating nausea, vomiting and appetite loss in patients with HIV and in cancer patients undergoing chemotherapy.1 It noted the suggestive evidence from animal studies and clinical case series that THC may relieve painful muscle spasms in neurological disorders and chronic pain that has not responded to conventional analgesics.2 It recommended further research on the therapeutic use of cannabis and cannabinoid drugs in these conditions. These recommendations do not address the needs of those currently using cannabis for medical purposes, as THC is not registered for medical use in Australia. THC is registered in the US, and a synthetic cannabinoid, nabilone, is registered in the United Kingdom to treat nausea caused by cancer chemotherapy and HIV-related wasting. These drugs could be registered in Australia if a pharmaceutical company applied. No company has done so to date. Smoked cannabis can not be medically prescribed in Australia, as it does not satisfy the requirements for registration as a "therapeutic good" under the Therapeutic Goods Act 1989 (Cwth). Smoking is an unsafe and unreliable way to deliver a drug that may be used daily to treat a chronic illness.1 The risks are much lower if cannabis is smoked for a limited time (eg, to treat nausea during a course of cancer chemotherapy, or to intermittently stimulate appetite in patients with HIV/AIDS or terminal cancer).1 The best chance for establishing the medical use of cannabinoids lies in the development, testing and registration of new synthetic cannabinoid drugs. This is likely to take considerable time.2 The next-best option is to find ways of administering THC that are more efficient than the oral route and do not involve smoking a crude cannabis plant product.2 However, existing technologies (eg, transpulmonary delivery systems used for opioid drugs) are not readily adapted for delivering THC, which is not water soluble.4 In the meantime, under existing NSW law (and in other States/Territories except South Australia, the Australian Capital Territory and the Northern Territory), patients who smoke cannabis for medical reasons face criminal prosecution if detected by the police. The Working Party's view was that the law should not compound the predicament of seriously ill patients. Accordingly, it recommended that a limited exemption from criminal prosecution should be given to specific classes of patients who wished to use cannabis for medical purposes. The exemption would be an interim measure until pharmaceutical cannabinoids were registered, and the effects of this exemption would be evaluated after a two-year trial period. The exemption would be limited to patients who had been certified by an approved medical practitioner to have HIV-related or cancer-related wasting, nausea caused by cancer chemotherapy, muscle spasm in neurological disorders or spinal cord injury, or pain unrelieved by conventional analgesics. Certification would have to be obtained before medical cannabis use. This would allow the practitioner to counsel the patient about alternative treatments and the risks of smoking cannabis, and to review their health regularly. The patient would have to renew the certificate after six months. To allow patients to avoid resorting to the black market, the Working Party recommended that these patients be allowed to grow a small number of cannabis plants for their own use. In the case of seriously ill and debilitated patients, a carer would be allowed to grow the plants on behalf of the certified patient. How many patients are likely to use such provisions? According to estimates derived from data supplied by the New South Wales Cancer Council, around 12 000 patients suffer from nausea during cancer chemotherapy or cancer-related wasting in any year.5 Another 2000 suffer from HIV-related wasting and neurological disorders and 4500 from chronic pain unrelieved by conventional treatments in New South Wales in any year. The total estimate of about 19 000 (Box) is likely to be an upper limit on the number of medical cannabis users, as the symptoms of many of these patients will be managed with existing treatments and others may not want to use cannabis.5 The size of the current cannabis black market makes it unlikely that cannabis grown for medical purposes will be diverted to the black market. The number of people who would be permitted under these recommendations to use cannabis for medical purposes is less than 2.5% of the 820 000 New South Wales adults estimated to have used cannabis for non-medical purposes in 1998.7 It is also unlikely that allowing exemptions for medical uses of cannabis will be seen as condoning the non-medical use of cannabis. In the US, survey evidence (and passage of citizen-initiated referenda)2 show majority support for medical uses of cannabis, yet there is strong support for the continued prohibition of non-medical cannabis use.8 We believe that the Working Party's recommendations balance the needs of patients with community concern about non-medical cannabis use in a way that deserves to be considered by all State and Territory governments. Ultimately, patients with certain illnesses will be able to use pharmaceutical cannabinoids or other drugs, but, in the meantime, the Working Party's recommendations will allow these patients to use cannabis for medical reasons without changing the legal prohibition on non-medical use of cannabis, and without expanding the black market for cannabis products. References Report of the Working Party on the Use of Cannabis for Medical Purposes. Volume I: Executive summary; Volume II: Main report. Sydney: NSW Government, 2000. Available at <http://www.druginfo.nsw.gov.au/druginfo/reports/medical_cannabis.html>. Institute of Medicine (United States). Marijuana and medicine: assessing the science base. Washington: National Academy Press, 1999. House of Lords Select Committee on Science and Technology (United Kingdom). Cannabis: the scientific and medical evidence. London: The Stationery Office, 1998. Mather L. Delivery systems for medical cannabis. Appendix D in the Report of the Working Party on the Use of Cannabis for Medical Purposes. Volume II: Main report. Sydney: NSW Government, 2000. Available at <http://www.druginfo.nsw.gov.au/druginfo/reports/medical_cannabis.html>. Hall W, Degenhardt L. Estimated number of potential medical users of cannabis. Sydney: National Drug and Alcohol Research Centre, 2000. Available at <http://www.med.unsw.edu.au/ndarc/>. Blyth FM, March LM, Brnabic AJM, et al. Chronic pain in Australia: a prevalence study. Pain 2001; 89: 127-134. National Drug Strategy household survey: first results. Canberra: Australian Institute of Health and Welfare, 1999. (Drug Statistics Series; AIHW catalogue no. PHE 15.) Johnston L, O'Malley P, Bachman J. National survey results on drug use from the monitoring the future study, 1975-1999. Rockville, MD: National Institute on Drug Abuse, 2000. Authors' details The National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW. Wayne D Hall, PhD, Executive Director, and Chair, Working Party on the Use of Cannabis for Medical Purposes; Louisa J Degenhardt, BA(Hons), Research Assistant, and Research Officer, Working Party on the Use of Cannabis for Medical Purposes. Flinders University, Adelaide, SA. David Currow, MPH, FRACP, Professor of Palliative Care, and Member, Working Party on the Use of Cannabis for Medical Purposes. Reprints: Dr W D Hall, The National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052. w.hallATunsw.edu.au Make a comment Estimated number of potential medical users of cannabis It is difficult to estimate the potential number of people in New South Wales who suffer from conditions that might be alleviated by cannabis or cannibinoids for several reasons: we are uncertain about the prevalence of these diseases; we do not know what proportion of these patients have the symptoms which cannabis has been claimed to relieve; and we do not know the proportion of these patients whose symptoms are unrelieved by existing treatments. Cancer-related wasting: In 1997, 11 594 people died of cancer in NSW (NSW Central Cancer Registry, 2000). If we assume that almost all of these persons suffered from cancer-related wasting, then about 11 000 people might have benefited from cannabis use to improve appetite. This does not take into account people who experienced cancer-related wasting but who did not die. Severe nausea from chemotherapy: Cancers vary in type, severity of symptoms and therapeutic regimen, so it is difficult to provide an accurate estimate of the number who may receive cancer chemotherapy that causes severe nausea and vomiting. Platinum-based chemotherapy is the most emetogenic form of chemotherapy, and is used in the treatment of ovarian cancer, testicular cancer, soft tissue sarcoma, 20% of head and neck cancers, 33% of distal oesophagus cancers, and about 10% of non-small-cell lung cancers. Based on 1997 estimates of these cancers, about 1000 people might have experienced severe nausea from platinum-based chemotherapy. HIV-related wasting: According to the Australian Research Centre in Sex, Health and Society at La Trobe University (Vic.), there were 2289 people with clinical AIDS in 1999, and 55% of them lived in NSW. A survey of 924 AIDS patients conducted by La Trobe University suggested that a third of people with HIV/AIDS experience weight loss. If these figures are applied to the estimate in NSW, then there would be around 400 people with HIV/AIDS in NSW in any one year who would be potential medical consumers of cannabis or cannabinoids. Muscle spasticity: According to the Multiple Sclerosis Society of Australia, patients with the disease known to the society represent 0.3% of the Australian adult population: about 11 000 people in NSW. To take account of patients not known to the society and to include people with less common neurological disorders whose symptoms may be alleviated by cannabis or cannabinoids (eg, patients with spinal cord injuries), we double this estimate, to 20 000. There are no Australian data on the prevalence of muscle spasticity among these patients. If we assume 10% prevalence, then about 2000 people with neurological conditions might benefit from cannabis or cannabinoids. Chronic pain: In any year, 11% of males and 13.5% of females have chronic pain that interferes with daily activities.6 Of these, 2.9% will have seen a pain specialist and 20% of them will have incomplete pain relief (Dr F M Blyth, Pain Management and Reseach Centre, University of Sydney, personal communication). In NSW, this amounts to 4500 people. Therefore, about 18 900 people in any year might benefit from the medical use of cannabis or cannabinoids. To this should be added the unknown number of persons with acute and chronic pain that is unrelieved by existing treatment. Back to text

Wayne D Hall · Louisa J Degenhardt · David Currow