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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.

Treating Severe Bacterial and Fungal Infections: the Ongoing Search for Optimal First-Line Strategies

To provide infectious disease specialists with the most recent treatment options for patients with severe bacterial or fungal infections.

This activity is designed for infectious disease specialists. No prerequisites required.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of the CME activity. At the conclusion of this activity, participants should be able to:

  • Describe and practice the most updated strategies for empirical antimicrobial use.
  • Identify trends in emergent pathogens in their hospital settings.
  • Apply appropriate strategies to curtail the emergence and spread of resistant pathogens.
  • Recognize the relative prevalence of the different species of Candida in their hospital settings and select appropriate antifungal therapy accordingly.
  • Identify and assess the different clinical manifestations of aspergillosis in patients and apply the optimal anti-Aspergillus therapies in each case.

The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 3 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

The estimated time to complete this educational activity: 3 hours.

Release date: April 15, 2004. Expiration date: April 15, 2006.

The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an unrestricted educational grant from Merck & Co, Inc.

Full Disclosure Policy Affecting CME Activities:
As a sponsor accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Directors and Participating Faculty reported the following:


    John G. Bartlett, MD
    Department of Medicine
    Chief, Division of Infectious Diseases
    Johns Hopkins University School of Medicine
    Baltimore, Maryland
    Dr Bartlett reports serving on the HIV advisory board for Abbott Laboratories and Bristol-Myers Squibb Company; and receiving
    honoraria from Pfizer, Inc.

    John R. Graybill, MD
    Department of Medicine
    Chief, Division of Infectious Diseases
    University of Texas Health Science Center
    San Antonio, Texas
    Dr Graybill reports receiving grants/research support and serving as a consultant to Fujisawa Pharmaceutical Co, Ltd, Merck & Co, Inc, Schering-Plough Corporation, and Vicuron Pharmaceuticals; serving as a consultant to Pfizer, Inc; and receiving honoraria from Merck & Co, Inc.


    George H. Karam, MD
    Paula Garvey Manship Professor of Medicine
    Louisiana State University School of Medicine
    Head, Department of Internal Medicine
    Earl K. Long Medical Center
    Baton Rouge, Louisiana
    Dr Karam reports serving on the speakers bureau for and receiving honoraria from Merck & Co, Inc, Pfizer, Inc, and Wyeth.

    John R. Perfect, MD
    Department of Medicine
    Division of Infectious Diseases
    Director, Duke University Mycology Research Unit
    Duke School of Medicine
    Durham, North Carolina
    Dr Perfect reports receiving grants/research support from Mayer Laboratories, Fujisawa Pharmaceutical Co, Ltd, Merck & Co, Inc, Pfizer, Inc, Pliva, and Schering-Plough Corporation.

    Michael A. Pfaller, MD
    Professor of Pathology
    Director, Moleclular Epidemiology and Fungus Testing Laboratory
    Division of Medical Microbiology
    Department of Pathology
    University of Iowa College of Medicine
    Iowa City, Iowa
    Dr Pfaller reports receiving grants/research support from Bristol-Myers Squibb Company, Merck & Co, Inc, Pfizer, Inc, Schering-Plough
    Corporation, and Vicuron Pharmaceuticals; serving as a consultant to Fujisawa Pharmaceutical Co, Ltd, Merck & Co, Inc, and Pfizer, Inc; and receiving honoraria from Bristol-Myers Squibb Company, Merck & Co, Inc, Pfizer, Inc, and Schering-Plough Corporation.

    John P. Quinn, MD
    Division of Infectious Diseases
    Rush University
    Rush-Presbyterian–St Luke's Medical Center
    Chicago, Illinois
    Dr Quinn reports receiving grants/research support, serving as a consultant to, and receiving honoraria from Abbott Laboratories, AstraZeneca LP, Bristol-Myers Squibb Company, Merck & Co, Inc, and Pfizer, Inc.

    In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. The following faculty members have disclosed that their articles have referenced the following unlabeled/unapproved uses of drugs or devices:

    Dr Graybill–triazoles, amphotericin B, and echinocandins
    Dr Perfect–triazoles, polyenes, and echinocandins
    Dr Pfaller–voriconazole, posaconazole, and echinocandins

    All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

    Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Treating Severe Bacterial and Fungal Infections: The Ongoing Search for Optimal First-Line Strategies
John G. Bartlett, MD,* and John R. Graybill, MD†

This issue of Advanced Studies in Medicine (ASiM) is divided into 2 components, one dealing with severe bacterial infections and one dealing with severe fungal infections.

Bacterial Infections: Recent Observations
Changes in bacteriology and outcome of sepsis in the United States, shown in a recent review by Martin et al, are based on data from the National Center for Health Statistics from 1979 to 2000, with observations in 750 million hospitalizations.1 These results showed a 3-fold increase in the number of cases of bacteremia, a shift to dominance of Gram-positive cocci, and a significant reduction in mortality.

With regard to antibiotic options, we see a paradoxical and disturbing shift toward more frequent resistance among both nosocomial and community-acquired pathogens, accompanied by a relatively dry pipeline of new antibacterial agents. The problem of increasing resistance among Gram-negative bacteria in intensive care units in the United States has recently been reviewed by Neuhauser et al based on the cumulative results from multiple hospitals.2 This analysis showed that no currently available antibiotic was effective against more than 90% of the Gram-negative bacilli. The most active were amikacin (active against 90% of isolates), imipenem (89%), tobramycin (83%), ciprofloxacin (81%), cefepime (78%), and ceftazidime (78%). The trends in antibiotic resistance have included a disturbing shift in community-acquired pathogens as well, primarily Staphylococcus pneumoniae and methicillin-resistant S aureus, and a paucity of new antibiotics to deal with them. There were no new antibacterial agents introduced in 2002, and daptomycin was the only important addition in 2003.

With regard to management, 2 important developments deal with nonantibiotic issues. The first is the availability of drotrecogin for the treatment of severe sepsis. This drug has demonstrated efficacy and cost-effectiveness in patients with severe sepsis and an Acute Physiology and Chronic Health Evaluation score exceeding 25.3 There have also been the recent observations regarding the use of corticosteroids, which have had such a checkered track record in management of sepsis during the past 3 decades. The recent data support their use in "stress doses" in patients who fail an adrenocorticotropic hormone stimulation test.4

Finally, with respect to Gram-positive bacteria as the cause of sepsis, the recent review of pneumococcal bacteremia by Yu et al shows some instructive messages regarding this organism as the most important cause of serious community-acquired pneumonia.5 The review included 844 cases from 21 hospitals in 10 countries from 1998 to 2001. Sensitivity testing showed that 9.6% of strains were resistant to penicillin. Resistance correlated with severe associated disease and recent antibiotic exposure, but there were substantial geographic variations as well. The overall mortality was 17%, 65% of deaths occurred in the first 72 hours, and most importantly, there did not seem to be a clear correlation between in vitro activity and outcome. An unexamined aspect was the time of initiating antibiotic therapy, which has become one of the most significant variables in terms of mortality according to Medicare audits of community-acquired pneumonia. This significance accounts for the current standard expectation that antibiotic treatment will begin within 8 hours of registration.

The issues that seem worthy of emphasis as recent developments in the field, as summarized above, include the shift in bacteriology patterns with more Gram-positive bacteria, a substantial increase in rates of bacteremia in hospitalized patients, significant improvement in mortality, increasing resistance by both nosocomial and community-acquired pathogens, new tactics for managing severe sepsis with drotrecogin and corticosteroids, and new emphasis on the importance of rapid initiation of antibiotic treatment based on strong supporting clinical outcome data. These issues represent what are considered to be the most important recent advances in the field of bacterial infections. They also represent the background for and introduction to the 2 articles in this issue of ASiM: a discussion of managing nosocomial infections by Dr George H. Karam and a discussion of therapeutic options by Dr John P. Quinn.

Changing Approaches to Systemic Mycotic Infections
Mycoses have been rapidly evolving in recent years. Candida species remain the predominant pathogens in medical and surgical intensive care units. Candida albicans continues to account for approximately 50% of deep Candida infections, with the remainder divided among C glabrata, C tropicalis, C parapsilosis, C krusei, and rare species. C glabrata, which is relatively resistant to fluconazole, appears more commonly in the oncology unit, and it is not clear to what degree this is due to the pressure of fluconazole use. Also on the oncology ward, and to some degree in the liver and lung solid-organ transplant services areas, mycelial infections account for up to one third of deep mycoses. In past years, we had, based on histopathology, attributed many of these infections to aspergillosis. More recently we have appreciated that histopathology may be a poor way to tell Aspergillus from Fusarium, Pseudallescheria, Scedosporium, or Paecilomyces. Some of these organisms are innately resistant to amphotericin B, and zygomycetes are resistant to most triazoles.

Mycelial fungal infections are also spreading to new groups of patients, such as those receiving stem cell or nonmyeloablative transplants. A newly appreciated risk factor has been identified: late graft-versus-host disease. Patients may not be neutropenic at the time of transplant; however, the frequent accompanying cytomegalovirus disease, corticosteroids, and antilymphocyte agents may strongly predispose them to late aspergillosis.

In these changing times, how have our patients fared? Dr Michael Pfaller notes in his article that mycoses-attributable mortality in 2001 is not any better than it was 15 years ago. That 15-year period between studies covers the initial development of lipid amphotericin B preparations and fluconazole as anticandidal agents. However, use of these newer drugs was quite variable during those years. Also, it is difficult to compare case-control studies of the real world with the highly selected study patient populations that give us our evolving treatment recommendations.6 Recently there have been dramatic declines of Candida and Aspergillus treatment failures and mortality.

Indeed times are changing, aided in part by susceptibility testing, in part by new diagnostic aids, and in part by new antifungal drugs. In his article, Dr Pfaller reviews the importance of antifungal susceptibility testing, the general correlation of yeast susceptibility with improved clinical response, and the high correlation of outcome of aspergillosis with the severity of underlying disease. He notes that both Candida and mycelial species are associated with high rates of resistance to various antifungals and gives us practical recommendations on which isolates to subject to antifungal testing.

For treatment of systemic mycoses, we now have a much broader selection of agents compared with 1986. Ostrosky-Zeichner et al have noted that the time of amphotericin B desoxycholate (amBd) is passing and that it should be replaced.7 There are 2 lipid formulations that have been used for some time. Both have much less nephrotoxicity than amBd, and both are similarly efficacious, though higher doses are needed. A major drawback is cost, which tends to limit these agents as antifungal prophylactic agents. No longer do clear indications exist for amBd as the drug of choice.

For antifungal prophylaxis, a strategy targeting patients vulnerable to infection by fungi, fluconazole has been highly effective in preventing C albicans, C tropicalis, and C parapsilosis in the oncology unit, and as Dr John Perfect notes in his article, recent studies have also shown efficacy in the general surgical intensive care unit, particularly for patients on respirators and those anticipating a long stay. For prevention of aspergillosis, there has been interest in using inhaled amphotericin B or amphotericin B lipid complex, itraconazole, or micafungin, a new echinocandin.

For empiric therapy of febrile neutropenia, a strategy aimed at identifying high-risk patients with "prediagnosed" invasive mycoses, there has been interest in liposomal amphotericin B, voriconazole, and most recently, caspofungin. A definitive study presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy showed that caspofungin was as effective as liposomal amphotericin B in preventing development of breakthrough mycoses and was more effective at treating undiagnosed baseline fungal infections.8

Major aids in the early treatment of systemic mycoses will likely come in the form of polymerase chain-reaction panfungal or specific-pathogen tests and in the recently licensed Platelia test for Aspergillus galactomannan.9,10 These are quite new and in their "trial run." Nevertheless, they offer the chance of making a specific fungal diagnosis well before clinical findings appear. By pointing to a diagnosis even before fever appears, they may aid in considerably whittling down the number of patients with
"possible" fungal infections and receiving costly and potentially toxic drugs. The so-called "febrile neutropenic" population may be redefined as "early" candidiasis, aspergillosis, or fusariosis. Glucan detection tests are also under development. The Aspergillus test is the only one commercially available at this time.

Further, we have major advances in an old class, the triazoles. A new and potent triazole, voriconazole, is clearly the drug of choice for invasive aspergillosis and may offer some hope in central nervous system infection with Aspergillus.11,12 Voriconazole has also been used against a number of uncommon mycelial pathogens, with varying results.13 Another contender, posaconazole, may have an even broader spectrum, including zygomycetes, and may have potentially fewer problems with drug interactions and intolerance.14 Ravuconazole offers the potential of treatment with a broad spectrum triazole that can be administered only once or twice weekly. At present, only voriconazole is licensed, and there may be as yet unappreciated subtle factors swaying us to one drug or the other. It appears that CdR-mediated resistance to fluconazole crosses all triazole antifungals, and the new triazoles may offer limited benefit for fully fluconazole-resistant Candida. Thus, the new triazoles may have their greatest impact against mycelial pathogens.

Finally, there is a new class, the echinocandins. These drugs are fungicidal against Candida, inactive against Cryptococcus, and fungistatic against Aspergillus. Although they may have other applications as yet undeveloped, they are not truly broad spectrum. Echinocandins target the glucans of the fungal cell wall and function independently of polyenes or triazoles (ie, no problems with fluconazole-resistant Candida).15 Echinocandins are metabolized slowly (caspofungin, micafungin) or not at all (anidulafungin) and do not engage the cytochrome enzyme system. Thus, they are almost free of the drug toxicities of the triazoles. They are not nephrotoxic and may be used in full doses with other nephrotoxic agents. Echinocandins are soluble in water and administered intravenously. They are, in effect, excellent antifungal drugs for Candida in the intensive care unit. Their primary use is likely to be against Candida in invasive disease, particularly the fluconazole-resistant organisms and in the patient with existing renal damage or the critically ill patient with hypotension and multiple organ dysfunction.16 They also have a role in aspergillosis as salvage therapy. There is potential for favorable interaction with other antifungals. Some animal studies have suggested benefits with echinocandin/triazole combinations, and some physicians are already using caspofungin in this manner. The most recent large trial of combined therapy, using fluconazole and amphotericin B versus fluconazole alone for candidiasis, suggested a modest benefit of the combination.16 Whether this is worth the cost in renal toxicity for amphotericin B, or the economic cost to replace amphotericin B with lipid formulations, is unknown. This whole area deserves a systematic trial, as these drugs are quite expensive. There is a paucity of good studies on combined antifungal therapy, and we should develop evidence to validate this approach before adopting combination therapy uncritically.

The next year will see further establishment of early serodiagnostic tests for Candida and mycelial pathogens, expansion of studies in prophylaxis and febrile neutropenia, completion of additional studies of micafungin and anidulafungin in candidemia, and expanded data on the newer triazoles ravuconazole and posaconazole. AmBd use will continue to decline, and the role of the lipid-associated forms of amphotericin B in relation to triazoles and echinocandins may become more clear.


1. Martin GS, Mannino GM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546-1554.

2. Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic resistance among Gram-negative bacilli in US intensive care units: implications for fluoroquinolone use. JAMA. 2003;289(7):885-888.

3. Angus DC, Linde-Zwirble WT, Clermont G, et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med. 2003;31(1):1-11.

4. Manglik S, Flores E, Lubarsky L, Fernandez F, Chhibber VL, Tayek JA. Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial. Crit Care Med. 2003;31(6):1668-1675.

5. Yu VL, Chiou CC, Feldman C, et al. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis. 2003;37(2):230-237.

6. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis. 2003;36(10):1221-1228.

7. Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: time for a new Ògold standard.Ó Clin Infect Dis. 2003;37(3):415-425.

8. Walsh T, Sable C, DePauw B, et al. A randomized, double-blind, multicenter trials of caspofungin vs liposomal amphotericin B for empirical antifungal therapy of persistently febrile neutropenic patients. Paper presented at: the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract M-1761.

9. Maertens J, Van Eldere J, Verhaegen J, Verbeken E, Verschakelen J, Boogaerts M. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis. 2002;186(9):1297-1306.

10. Hebart H, Loffler, J, Meisner C, et al. Early detection of Aspergillus infection after allogeneic stem cell transplantation by polymerase chain reaction screening. J Infect Dis. 2000;181(5):1713-1719.

11. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415.

12. Troke PF, Schwarz S, Ruhnke M, et al. Voriconazole (VRC) therapy (Rx) in 86 patients with CNS aspergillosis (CNSa): a retrospective study. Paper presented at: the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract M1775.

13. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003;36(5):630-637.

14. Greenberg RN, Anstead G, Herbrecht R, et al. Posaconazole (POS) experience in the treatment of zygomycosis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract M-1757.

15. Letscher-Bru V, Herbrecht R. Caspofungin: the first representative of a new antifungal class. J Antimicrob Chemother. 2003;51(3):513-521.

16. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020-2029.

*Professor, Department of Medicine, Chief, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland.

 Professor, Department of Medicine, Chief, Division of Infectious Diseases, University of Texas Health Science Center, San Antonio, Texas.

Address correspondence to: John G. Bartlett, MD, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 437, Baltimore, MD 21205.


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