George A. Pankey

Practice Guidelines for Diseases Caused by Aspergillus

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)

Cryptococcosis in Human Immunodeficiency Virus-Negative Patients in the Era of Effective Azole Therapy

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

Itraconazole treatment of phaeohyphomycosis.

Nineteen patients with phaeohyphomycosis were treated with itraconazole. Of these, 17 were assessable for clinical outcome. Of these, two had received no prior therapy, five had failed amphotericin B therapy, four had failed ketoconazole or miconazole therapy, and five had failed both amphotericin B and azole therapy. One patient had received only prior surgical intervention. Fungi of seven different genera caused disease of the skin in nine patients, soft tissue in nine, sinuses in eight, bone in five, joints in two, and lungs in two. Itraconazole was given in dosages ranging from 50 to 600 mg/day for 1 to 48 months. Clinical improvement or remission occurred in nine patients. Two patients have had stabilization of disease. Six patients failed treatment, one had a relapse after initially successful treatment. Itraconazole appears to be highly effective in some patients with phaeohyphomycosis, including patients refractory to other antifungal agents.

Evaluation of Vancomycin and Daptomycin Potency Trends (MIC Creep) against Methicillin-Resistant Staphylococcus aureus Isolates Collected in Nine U.S. Medical Centers from 2002 to 2006

ABSTRACT Vancomycin MIC creep has been reported by some institutions but not confirmed in large surveillance studies. We evaluated the possible occurrence of MIC creep when testing vancomycin and daptomycin against methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) by using precise incremental reference MIC methods. Nine hospitals (one in each U.S. census region) randomly selected bloodstream MRSA strains (target, 40/year) from 2002 to 2006. MICs were determined by the reference broth microdilution method using incremental dilutions (eight for each log2 dilution step). Isolates for which vancomycin MICs were >1 μg/ml were typed by pulsed-field gel electrophoresis (PFGE). The vancomycin MIC mode was either 0.625 μg/ml (for eight hospitals) or 0.813 μg/ml (for one hospital), and vancomycin MIC results for 72.9% of strains were between 0.563 and 0.688 μg/ml. No yearly variation in the central tendency of vancomycin MICs for the wild-type population in any medical center was observed; however, when data were analyzed by the geometric mean statistic, vancomycin MIC increases (at three sites) and declines (at three sites) were observed. The daptomycin MIC mode varied from 0.156 μg/ml (2003 to 2005) to 0.219 μg/ml (2002 and 2006), and MIC results for 83.5% (80.3 to 89.2% in each of the centers) of isolates fell between these values. Among PFGE-typed strains, 43 of 55 (78%; from seven hospitals) showed a pattern consistent with that of the USA100 clone, which was represented by all strains from two hospitals and 64 to 88% of strains from five other medical centers; only one strain (2%) was USA300. In conclusion, the perception of MIC creep may vary according to the methods used to analyze the data. Geometric mean MIC data revealed a possible, very-low-level MIC creep at three of nine sites over the 5-year period, which was not evident using modal MICs or the data from all nine hospitals (+0.02 μg/ml). The occurrence of isolates for which the vancomycin MIC was >1 μg/ml was very unusual, with no increased trend, but these organisms were usually clonal (USA100).

Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease

Cryptococcus neoformans is an uncommonly recognized cause of pneumonia in HIV-negative patients. Because of its propensity to disseminate to the meninges and other sites, a lumbar puncture is recommended for patients with pulmonary cryptococcosis, regardless of other risk factors. This study explored clinical and laboratory features to help predict which patients had pulmonary disease alone versus those who had pulmonary plus extrapulmonary disease. A retrospective chart review at 15 medical centers was performed from 1990 to 2000 of all HIV-negative patients who had pulmonary cryptococcosis. Demographic, clinical, radiographic, and laboratory features were evaluated to determine factors that differentiated those patients who had extrapulmonary disease. Among 166 patients who had pulmonary cryptococcosis, 122 had pulmonary infection only and 44 had pulmonary plus extrapulmonary (disseminated) disease. A negative serum cryptococcal antigen titer was more common in patients with pulmonary disease alone (p < 0.01). Multivariate analysis demonstrated that patients who had disseminated disease were more likely than those who only had pulmonary disease to have cirrhosis (p = 0.049), headache (p < 0.001), weight loss (p = 0.003), fever (p = 0.035), altered mental status (p < 0.001), and to be receiving high-dose corticosteroids (p = 0.008). In this large cohort of HIV-negative patients with pulmonary cryptococcosis, there were easily distinguished clinical and laboratory features among patients with pulmonary disease alone versus those with pulmonary plus extrapulmonary disease. These findings may be helpful in the evaluation of HIV-negative patients with pulmonary cryptococcosis with regard to the need for lumbar puncture or to search for disseminated disease.

Subacute Bacterial Endocarditis at the University of Minnesota Hospital, 1939 through 1959

Excerpt Subacute bacterial endocarditis, an infection of the valvular or mural endocardium, or of both, is usually considered to be caused by a microorganism of low virulence that results in the cl...

In Vitro Synergy of Daptomycin plus Rifampin against Enterococcus faecium Resistant to both Linezolid and Vancomycin

ABSTRACT In vitro synergy testing of daptomycin plus rifampin was performed against 24 unique isolates of Enterococcus faecium resistant to both linezolid and vancomycin. Synergy testing showed that 21/24 (88%) were synergistic and 3/24 (12%) were indifferent by the Etest method. Time-kill assays revealed synergy for 18/24 (75%) and indifference for 6/24 (25%).

In Vitro Synergy of Ciprofloxacin and Gatifloxacin against Ciprofloxacin-Resistant Pseudomonas aeruginosa

ABSTRACT Multidrug-resistant Pseudomonas aeruginosa with combined decreased susceptibility to ceftazidime, ciprofloxacin, imipenem, and piperacillin is increasingly being found as a cause of nosocomial infections. It is important to look for combinations of drugs that might be synergistic. Ciprofloxacin resistance by P. aeruginosa is mediated in part by an efflux pump mechanism. Gatifloxacin, an 8-methoxyfluoroquinolone, inhibits a staphylococcal efflux pump. An earlier in vitro study using an Etest synergy method and time-kill assay suggested synergy of ciprofloxacin and gatifloxacin against P. aeruginosa. Synergy testing was performed by Etest and time-kill assay for 31 clinically unique, plasmid DNA distinct, U.S. P. aeruginosa isolates. Etest MICs for ciprofloxacin were 4 to >32 μg/ml, and for gatifloxacin they were >32 μg/ml. Ciprofloxacin plus gatifloxacin showed synergy by the Etest method for 6 (19%) of the 31 P. aeruginosa isolates using a summation fractional inhibitory concentration of ≤0.5 for synergy. Synergy was demonstrated for 13/31 (42%) of isolates by time-kill assay. No antagonism was detected. The remaining isolates were indifferent to the combination. The Etest method and time-kill assay were 65% (20/31) concordant. The mechanism of the in vitro synergy may include P. aeruginosa ciprofloxacin efflux pump inhibition by gatifloxacin.

Resolution of Rhinocerebral Zygomycosis Associated with Adjuvant Administration of Granulocyte-Macrophage Colony-Stimulating Factor

We successfully treated 3 consecutive patients who had nonneutropenic rhinocerebral zygomycosis, by use of subcutaneous granulocyte-macrophage colony-stimulating factor therapy combined with traditional surgical and medical treatment. All patients are currently free of disease. Granulocyte-macrophage colony-stimulating factor should be considered as adjuvant therapy for rhinocerebral zygomycosis; however, optimum dose and length of therapy are unknown.

Detection of a New cfr-Like Gene, cfr(B), in Enterococcus faecium Isolates Recovered from Human Specimens in the United States as Part of the SENTRY Antimicrobial Surveillance Program

ABSTRACT Two linezolid-resistant Enterococcus faecium isolates (MICs, 8 μg/ml) from unique patients of a medical center in New Orleans were included in this study. Isolates were initially investigated for the presence of mutations in the V domain of 23S rRNA genes and L3, L4, and L22 ribosomal proteins, as well as cfr. Isolates were subjected to pulsed-field gel electrophoresis (just one band difference), and one representative strain was submitted to whole-genome sequencing. Gene location was also determined by hybridization, and cfr genes were cloned and expressed in a Staphylococcus aureus background. The two isolates had one out of six 23S rRNA alleles mutated (G2576T), had wild-type L3, L4, and L22 sequences, and were positive for a cfr-like gene. The sequence of the protein encoded by the cfr-like gene was most similar (99.7%) to that found in Peptoclostridium difficile, which shared only 74.9% amino acid identity with the proteins encoded by genes previously identified in staphylococci and non-faecium enterococci and was, therefore, denominated Cfr(B). When expressed in S. aureus, the protein conferred a resistance profile similar to that of Cfr. Two copies of cfr(B) were chromosomally located and embedded in a Tn6218 similar to the cfr-carrying transposon described in P. difficile. This study reports the first detection of cfr genes in E. faecium clinical isolates in the United States and characterization of a new cfr variant, cfr(B). cfr(B) has been observed in mobile genetic elements in E. faecium and P. difficile, suggesting potential for dissemination. However, further analysis is necessary to access the resistance levels conferred by cfr(B) when expressed in enterococci.