Ronald A. Greenfield

A Controlled Trial of Fluconazole to Prevent Fungal Infections in Patients Undergoing Bone Marrow Transplantation

BACKGROUND AND METHODS Superficial and systemic fungal infections are a major problem among severely immunocompromised patients who undergo bone marrow transplantation. We performed a double-blind, randomized, multicenter trial in which patients receiving bone marrow transplants were randomly assigned to receive placebo or fluconazole (400 mg daily). Fluconazole or placebo was administered prophylactically from the start of the conditioning regimen until the neutrophil count returned to 1000 per microliter, toxicity was suspected, or a systemic fungal infection was suspected or proved. RESULTS By the end of the treatment period, 67.2 percent of the 177 patients assigned to placebo had a positive fungal culture of specimens from any site, as compared with 29.6 percent of the 179 patients assigned to fluconazole. Among these, superficial infections were diagnosed in 33.3 percent of the patients receiving placebo and in 8.4 percent of the patients receiving fluconazole (P less than 0.001). Systemic fungal infections occurred in 28 patients who received placebo as compared with 5 who received fluconazole (15.8 percent vs. 2.8 percent, P less than 0.001). Fluconazole prevented infection with all strains of candida except Candida krusei. Fluconazole was well tolerated, although patients who received it had a higher mean increase in alanine aminotransferase levels than patients who received placebo. Although there was no significant difference in overall mortality between the groups, fewer deaths were ascribed to acute systemic fungal infections in the group receiving fluconazole than in the group receiving placebo (1 of 179 vs. 10 of 177, P less than 0.001). CONCLUSIONS Prophylactic administration of fluconazole to recipients of bone marrow transplants reduces the incidence of both systemic and superficial fungal infections.

Microbiological, Biological, and Chemical Weapons of Warfare and Terrorism

&NA; Microbiological, biological, and chemical toxins have been employed in warfare and in terrorist attacks. In this era, it is imperative that health care providers are familiar with illnesses caused by these agents. Botulinum toxin produces a descending flaccid paralysis. Staphylococcal enterotoxin B produces a syndrome of fever, nausea, and diarrhea and may produce a pulmonary syndrome if aerosolized. Clostridium perfringens ∈‐toxin could possibly be aerosolized to produce acute pulmonary edema. Ricin intoxication can manifest as gastrointestinal hemorrhage after ingestion, severe muscle necrosis after intramuscular injection, and acute pulmonary disease after inhalation. Nerve agents inhibit acetylcholinesterase and thus produce symptoms of increased cholinergic activity. Ammonia, chlorine, vinyl chloride, phosgene, sulfur dioxide, and nitrogen dioxide, tear gas, and zinc chloride primarily injure the upper respiratory tract and the lungs. Sulfur mustard (and nitrogen mustard) are vesicant and alkylating agents. Cyanide poisoning ranges from suddenonset headache and drowsiness to severe hypoxemia, cardiovascular collapse, and death. Health care providers should be familiar with the medical consequences of toxin exposure, and understand the pathophysiology and management of resulting illness.

Invasion of the Central Nervous System by Intracellular Bacteria

SUMMARY Infection of the central nervous system (CNS) is a severe and frequently fatal event during the course of many diseases caused by microbes with predominantly intracellular life cycles. Examples of these include the facultative intracellular bacteria Listeria monocytogenes, Mycobacterium tuberculosis, and Brucella and Salmonella spp. and obligate intracellular microbes of the Rickettsiaceae family and Tropheryma whipplei. Unfortunately, the mechanisms used by intracellular bacterial pathogens to enter the CNS are less well known than those used by bacterial pathogens with an extracellular life cycle. The goal of this review is to elaborate on the means by which intracellular bacterial pathogens establish infection within the CNS. This review encompasses the clinical and pathological findings that pertain to the CNS infection in humans and includes experimental data from animal models that illuminate how these microbes enter the CNS. Recent experimental data showing that L. monocytogenes can invade the CNS by more than one mechanism make it a useful model for discussing the various routes for neuroinvasion used by intracellular bacterial pathogens.

Rhodococcus equi infections of humans. 12 cases and a review of the literature.

Increased recognition of Rhodococcus equi as a human pathogen has occurred since 1983, when the first review article summarized the worlds literature of 12 cases. In this article, we present 12 cases from the University of Oklahoma Health Sciences Center and review 60 from the literature. Most cases occur in immunocompromised hosts and present as chronic cavitary pneumonias. Associated extrapulmonary disease is seen at diagnosis in 7% of patients with pneumonia, and relapse occurs at extrapulmonary sites in 13%, often without reappearance of pulmonary disease. Relapse may follow a course of antimicrobial therapy that is too brief, but can also occur during treatment. Infections also occur in the gastrointestinal tract, causing enteritis and regional adenitis with abscesses. Contaminated wounds may become infected. Isolated bacteremias may be a manifestation of latent infection recurring during a period of immune suppression. A common feature of human R. equi infection is delay in diagnosis. The insidious course of disease contributes to delay, as does failure to identify the organism. R. equi is easily cultured on nonselective media but commonly mistaken for a diphtheroid or occasionally for a mycobacterium based on acid-fast appearance. Form and duration of treatment are closely related to host immune status. Immunocompromised patients require prolonged or indefinite therapy with multiple antibiotics. Infections in immunocompetent hosts are easily treated with short courses of single agents. Infections related to contaminated wounds are treated primarily by irrigation and debridement. Infections in immunocompromised hosts are increasing in frequency largely due the AIDS epidemic. Infections in immunocompetent hosts, reported rarely before this series, may be underdiagnosed, perhaps because R. equi resembles common commensals and has limited virulence in this population. This report demonstrates that R. equi infections, including community-acquired pneumonias, occur in immunocompetent hosts.

Bacterial pathogens as biological weapons and agents of bioterrorism.

&NA; Bacterial pathogens have been identified as agents that have been, or could be, used as weapons of biological warfare and/or biological terrorism. These agents are relatively easily obtained, prepared, and dispersed, either as weapons of mass destruction or for more limited terrorist attacks. Although phylogenetically diverse, these agents all have the potential for aerosol dissemination. Physicians in the United States and most of the developed world have never encountered most of these agents and the diseases they produce. Public health programs must be prepared, and individual primary care providers must be able to recognize, diagnose, treat, and prevent infection with these agents.

Infectious disease outbreaks in competitive sports: a review of the literature.

Recent outbreaks of infectious diseases in athletes in competitive sports have stimulated considerable interest. The environments in which these athletes compete, practice, receive therapy for injuries, and travel, both domestically and internationally, provide varied opportunities for the transmission of infectious organisms. The purpose of this medical literature review is to identify the agents most commonly reported in the medical literature as responsible for infectious disease outbreaks in specific sports and their modes of transmission and to guide targeted prevention efforts. A literature review of English-language articles in medical publications that reported outbreaks of infectious diseases in competitive athletes was conducted in PubMed MEDLINE from 1966 through May 2005. Outbreaks that were solely food borne were excluded. Fifty-nine reports of infectious disease outbreaks in competitive sports were identified in the published medical literature. Herpes simplex virus infections appear to be common among wrestlers and rugby players, with no single strain responsible for the outbreaks. Methicillin-resistant Staphylococcus aureus was responsible for several recent outbreaks of soft tissue and skin infections among collegiate and professional athletes. The most common mode of transmission in outbreaks was direct, person-to-person (primarily skin-to-skin) contact. Blood-borne exposure was implicated in 2 confirmed outbreaks of hepatitis. Airborne and vector transmissions were rarely reported. This review provides an overview of infectious disease outbreaks thought to be either serious enough or unusual enough to report. Appropriate surveillance of the frequency of infections will allow sports medicine staff to identify outbreaks quickly and take necessary measures to contain further transmission and prevent future outbreaks.

Viral Agents as Biological Weapons and Agents of Bioterrorism

Multiple viral agents have been classified by the CDC as potential weapons of mass destruction or agents for biologic terrorism. Agents such as smallpox, viral hemorrhagic fever viruses, agents of viral encephalitis, and others are of concern because they are highly infectious and relatively easy to produce. Although dispersion might be difficult, the risk is magnified by the fact that large populations are susceptible to these agents and only limited treatment and vaccination strategies exist. Although the risk of large-scale bioterrorism using viral agents is small, public health programs and health care providers must be prepared for this potentially devastating impact on public health.

Prevention and treatment of bacterial diseases caused by bacterial bioterrorism threat agents.

There is general consensus that the bacterial agents or products most likely to be used as weapons of mass destruction are Bacillus anthracis, Yersinia pestis, Francisella tularensis and the neurotoxin of Clostridium botulinum. Modern supportive and antimicrobial therapy for inhalational anthrax is associated with a 45% mortality rate, reinforcing the need for better adjunctive therapy and prevention strategies. Pneumonic plague is highly contagious, difficult to recognize and is frequently fatal. Therefore, the development of vaccines against this agent is crucial. Although tularemia is associated with low mortality, the highly infectious nature of aerosolized F. tularensis poses a substantive threat that is best met by vaccine development. Safer antitoxins and a vaccine are required to meet the threat of the use of botulinum toxin as a weapon of mass destruction. In this article, the current status of research in these areas is reviewed.

Apophysomyces elegans infection in a renal transplant recipient.

A 50-year-old cadaveric renal transplant recipient on immunosuppressive therapy is described with post-traumatic cutaneous infection caused by Apophysomyces elegans. He showed no evidence of hematogenous dissemination and recovered fully after therapy with extensive local debridement and amphotericin B lipid complex. An apparent drug-drug interaction between amphotericin B lipid complex and cyclosporine was encountered. The course of A elegans infection in transplant recipients may be similar to that described in immunocompetent hosts. A elegans infection should be considered in evaluation of post-traumatic cutaneous infection not readily responsive to antibacterial therapy.

Tickborne Infections in the Southern United States

Established and emerging tickborne infections are significant causes of human illness in the southern United States. Rocky Mountain spotted fever, human monocytic ehrlichiosis, human ewingii ehrlichiosis and tularemia are known pathogens in this geographic distribution. Rickettsia parkeri and novel ehrlichioses are more recently described tickborne infections reviewed in this article. An understanding of the tick vectors, pathogenesis, epidemiology, clinical presentation, diagnosis and treatment is useful for the clinician treating patients potentially infected with any of these pathogens. Prevention measures, the optimal method for removing an attached tick and current and future vaccine development conclude this review.