Monica A. Slavin

Echinocandin Antifungal Drugs in Fungal Infections A Comparison

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections.The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤2 mg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC90) values are typically <2 mg/mL but 100-fold higher MIC90 values are seen with Candida parapsilosis (1–2mg/mL) and Candida guilliermondii (1–4 mg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed.Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2mg/mL. Of the three echinocandins, the in vitro ‘paradoxical effect’ (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin.All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9–20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors.All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only mica-fungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutro-penia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.

Treatment of Scedosporiosis with Voriconazole: Clinical Experience with 107 Patients

ABSTRACT The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with >98% of those responding receiving ≥28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with Scedosporium prolificans infection had significantly reduced survival times (P = 0.0259) and were more likely to die from fungal infection (P = 0.002) than were Scedosporium apiospermum-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for S. apiospermum-infected patients (54% response; MIC50, 0.25 μg/ml) than for S. prolificans-infected patients (40% response; MIC50, 4.0 μg/ml). Voriconazole demonstrated clinically useful activity in the treatment of both S. apiospermum and S. prolificans infections and was well tolerated.

Successful Control of Disseminated Scedosporium prolificans Infection with a Combination of Voriconazole and Terbinafine

Disseminated Scedosporium prolificans infections are almost uniformly fatal because of their resistance to antifungal agents. Recently, synergy between triazoles and terbinafine has been demonstrated against Scedosporium prolificans in vitro. Reported here is a patient who developed disseminated Scedosporium prolificans infection following bone marrow transplantation and who was successfully treated with a combination of voriconazole and terbinafine in addition to aggressive surgical debridement. Antifungal synergy testing and combination therapy should be considered in cases of disseminated infection with Scedosporium prolificans.

Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial

BACKGROUND Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients. METHODS In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered with ClinicalTrial.gov, number NCT00163722. FINDINGS 240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4-26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20). INTERPRETATION Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients. FUNDING Australian National Health and Medical Research Council, Cancer Council New South Wales, Pfizer, Merck, Gilead Sciences.

Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab*.

There is an increasing use of monoclonal antibodies in the treatment of haematological malignancies. Alemtuzumab (Campath‐1H; Ilex Pharmaceuticals, San Antonio, TX, USA) is a monoclonal antibody reactive with the CD52 antigen used as first and second line therapy for two types of lymphoproliferative disorders: chronic lymphocytic leukaemia (CLL), and T‐cell lymphomas [both peripheral (PTCL) and cutaneous (CTCL)]. With alemtuzumab therapy, viral, bacterial and fungal infectious complications are frequent, and may be life threatening. An understanding of the patients at highest risk and duration of risk are important in developing recommendations for empirical management, antimicrobial prophylaxis and targeted surveillance. This review discusses the infection risks associated with these lymphoproliferative disorders and their treatment, and provide detailed recommendations for screening and prophylaxis.

Not Just Little Adults: Candidemia Epidemiology, Molecular Characterization, and Antifungal Susceptibility in Neonatal and Pediatric Patients

OBJECTIVE. The purpose of this work was to identify differences in incidence, risk factors, microbiology, treatment, and clinical outcome of candidemia in neonates, children, and adults that might impact on management. PATIENTS AND METHODS. Cases of candidemia in Australia were identified prospectively by blood culture surveillance over 3 years. Episodes of candidemia in neonatal, pediatric, and adult age groups were analyzed and compared. RESULTS. Of 1005 incident cases, 33 occurred in neonates, 110 in children, and 862 in adults. The respective annual age-specific incidences were 4.4, 0.9, and 1.8 per 100 000 population. Prematurity and ICU admission were major risk factors in neonates. Hematologic malignancy and neutropenia were significantly more frequent in children than in neonates and adults. Diabetes, renal disease, hemodialysis, and recent surgery were more common in adults. Candidemia was attributed to a vascular access device in 58% of neonates, 70% of children, and 44% of adults. Candida albicans caused ∼48% of cases in all of the age groups. Candida parapsilosis was significantly more common in neonates and children (42% and 38% vs 15%). Candida glabrata was infrequent in neonates and children (9% and 3% vs 17%). Significantly more isolates from children were susceptible to fluconazole compared with those from adults (95% vs 75%). Fluconazole-resistant candidal isolates were infrequent in all of the age groups. Neonates and children were more likely to receive amphotericin B compared with adults. Adults were more likely to receive fluconazole. Survival rates at 30 days were 78% in neonates, 90% in children, and 70% in adults. CONCLUSIONS. This study identifies significant differences in candidemia in neonates, children, and adults. Neonatologists and pediatricians must consider age-specific differences when interpreting adult studies and developing treatment and prevention guidelines.

Active surveillance for candidemia, Australia.

This infection has a high death rate and is predominantly associated with healthcare.

Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death

BACKGROUND Candidaemia in cancer patients is associated with increasing fluconazole resistance. Models for predicting such isolates and their clinical impact are required. METHODS Clinical, treatment and outcome data from a population-based candidaemia survey (2001-2004) were collected at 5 and 30 days after diagnosis. Speciation and antifungal susceptibility testing was performed. RESULTS There were 138 candidaemia episodes (33% Candida albicans) in adults with haematological malignancies and 150 (51% C. albicans) in adults with solid organ malignancies. Thirty-nine isolates had fluconazole MICs of >or=64 mg/L and 40 had MICs of 16-32 mg/L (predominantly Candida glabrata and Candida krusei). By multivariate analysis, triazole therapy, gastrointestinal tract (GIT) surgery in the 30 days before candidaemia and age >65 years were predictive of fluconazole-resistant candidaemia. Thirty day crude mortality was 40% in haematology patients and 45% in oncology patients. Fluconazole-resistant isolates were associated with increased risk of mortality by univariate (P = 0.04) and Kaplan-Meier survival analyses. By Cox proportional hazards modelling, the strongest predictors of mortality at onset of candidaemia were invasive ventilation, elevated creatinine, intensive care unit (ICU) admission and receipt of systemic triazoles or corticosteroids in the previous 30 days. Removal of a central venous access device (CVAD) at or within 5 days of onset was associated with decreased mortality. CONCLUSIONS Risk factors for fluconazole-resistant candidaemia in adults with cancer include fluconazole/triazole exposure and GIT surgery. ICU admission, invasive ventilation, renal impairment, age >65 years and prior exposure to corticosteroids and triazoles are risk factors for death. CVAD removal reduced mortality. These findings should be integrated into surveillance and treatment algorithms.

Candidemia in nonneutropenic critically ill patients: risk factors for non-albicans Candida spp.

Objective:The objective of this study was to determine the clinical features associated with candidemia caused by non-albicans Candida spp. and with potentially fluconazole-resistant Candida spp. (C. glabrata and C. krusei) among candidemic intensive care unit patients. Design:The authors conducted a nationwide prospective cohort study. Setting:The study was conducted in Australian intensive care units. Patients:All patients with intensive care unit-acquired candidemia over a 3-yr period were included in the study. Measurements:Clinical risk factors occurring up to 30 days before candidemia, Candida spp. associated with candidemia, and outcomes were determined. Risk factors associated with either non-albicans Candida spp. or with potentially fluconazole-resistant Candida spp. (C. glabrata or C. krusei) were assessed using multivariate logistic regression. Main Results:Among 179 episodes of intensive care unit-acquired candidemia, C. albicans accounted for 62%, C. glabrata 18%, C. krusei 4%, and other Candida spp. 16%. Independently significant variables associated with non-albicans Candida bloodstream infection included recent prior gastrointestinal surgery (adjusted odds ratio, 2.87; 95% confidence interval, 1.68–4.91) and recent prior systemic antifungal exposure (4.6; 1.36–15.53). Those associated with potentially fluconazole-resistant candidemia included recent prior gastrointestinal surgery (3.31; 1.79–6.11) and recent prior fluconazole exposure (5.47; 1.23–24.32). No significant differences in outcomes were demonstrated for non-albicans or potentially fluconazole-resistant candidemia. Conclusions:Among candidemic intensive care unit patients, prior gastrointestinal surgery and systemic antifungal exposure were significantly associated with both a non-albicans Candida spp. and a potentially fluconazole-resistant Candida spp. LEARNING OBJECTIVESOn completion of this article, the reader should be able to:List clinical features discriminating between candidemia caused by C. albicans and those caused by other species.Describe predisposing factors that help discriminate between candidemia which are potentially fluconazole-resistant.Use this information in a clinical setting.Dr. Playford has disclosed that he was a consultant/advisor for Pfizer and Merck; was on the advisory board for Schering-Plough; and is a recipient of grant/research funds from Pfizer and Merck. Dr. Marriott has disclosed that she was/is a recipient of grant/research funds from Pfizer; was/is a consultant/advisor for Merck, Sharpe & Dohme and Sanofi-Pasteur; and was/is on the advisory board for Roche. Dr. Nguyen has disclosed that he has no financial relationships with or interests in any commercial companies pertaining to this educational activity. Dr. Chen has disclosed that she was a recipient of grant/research funds from Pfizer; is a recipient of grant/research funds from Gilead Sciences, Inc.; and is on the advisory board for Gilead Sciences, Inc. and Pfizer Australia. Dr. Ellis has disclosed that he was/is a recipient of grant/research funds from Pfizer Australia, Merck, Sharpe & Dohme Australia, Gilead Sciences Australia, and Schering-Plough Australia; was/is a consultant/advisor for Pfizer Australia, Merck, Sharpe & Dohme Australia, Gilead Sciences Australia, and Schering-Plough Australia; and was/is on the speakers bureau for Pfizer Australia, Merck, Sharpe & Dohme Australia, Gilead Sciences Australia, and Schering-Plough Australia. Dr. Slavin has disclosed that she was/is a recipient of grant/research funds from Pfizer Inc., Gilead Sciences, Schering-Plough, and Merck and Co.; and was/is on the advisory board for Pfizer Inc., Gilead Sciences, Schering-Plough, and Merck and Co. Dr. Sorrell has disclosed that she was/is a recipient of grant/research funds from Merck, Sharpe & Dohme Australia, Pfizer, and Gilead; and was/is a consultant/advisor for Pfizer, Merck, Gilead, and Schering-Plough.All faculty and staff in a position to control the content of this CME activity have disclosed that they have no financial relationship with, or financial interests in, any commercial companies pertaining to this educational activity.Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity.Visit the Critical Care Medicine Web Site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia.

Resistance in virus-infected stem cell transplant recipients illustrates the need for surveillance.