Leonard B. Johnson

Voriconazole: A New Triazole Antifungal Agent

Voriconazole is a second-generation azole antifungal agent that shows excellent in vitro activity against a wide variety of yeasts and molds. It can be given by either the intravenous or the oral route; the oral formulation has excellent bioavailability. The side effect profile of voriconazole is unique in that non-sight-threatening, transient visual disturbances occur in approximately 30% of patients given the drug. Rash (which can manifest as photosensitivity) and hepatitis also occur. The potential for drug-drug interactions is high and requires that careful attention be given to dosage regimens and monitoring of serum levels and effects of interacting drugs. Voriconazole has been approved for the treatment of invasive aspergillosis and refractory infections with Pseudallescheria/Scedosporium and Fusarium species, and it will likely become the drug of choice for treatment of serious infections with those filamentous fungi.

Vancomycin MIC plus Heteroresistance and Outcome of Methicillin-Resistant Staphylococcus aureus Bacteremia: Trends over 11 Years

ABSTRACT Vancomycin MICs (V-MIC) and the frequency of heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) isolates are increasing among methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates, but their relevance remains uncertain. We compared the V-MIC (Etest) and the frequency of hVISA (Etest macromethod) for all MRSA blood isolates saved over an 11-year span and correlated the results with the clinical outcome. We tested 489 isolates: 61, 55, 187, and 186 isolates recovered in 1996-1997, 2000, 2002-2003, and 2005-2006, respectively. The V-MICs were ≤1, 1.5, 2, and 3 μg/ml for 74 (15.1%), 355 (72.6%), 50 (10.2%), and 10 (2.1%) isolates, respectively. We detected hVISA in 0/74, 48/355 (13.5%), 15/50 (30.0%), and 8/10 (80.0%) isolates with V-MICs of ≤1, 1.5, 2, and 3 μg/ml, respectively (P < 0.001). The V-MIC distribution and the hVISA frequency were stable over the 11-year period. Most patients (89.0%) received vancomycin. The mortality rate (evaluated with 285 patients for whose isolates the trough V-MIC was ≥10 μg/ml) was comparable for patients whose isolates had V-MICs of ≤1 and 1.5 μg/ml (19.4% and 27.0%, respectively; P = 0.2) but higher for patients whose isolates had V-MICs of ≥2 μg/ml (47.6%; P = 0.03). However, the impact of V-MIC and hVISA status on mortality or persistent (≥7 days) bacteremia was not substantiated by multivariate analysis. Staphylococcal chromosome cassette mec (SCCmec) typing of 261 isolates (including all hVISA isolates) revealed that 93.0% of the hVISA isolates were SCCmec type II. These findings demonstrate that the V-MIC distribution and hVISA frequencies were stable over an 11-year span. A V-MIC of ≥2 μg/ml was associated with a higher rate of mortality by univariate analysis, but the relevance of the V-MIC and the presence of hVISA remain uncertain. A multicenter prospective randomized study by the use of standardized methods is needed to evaluate the relevance of hVISA and determine the optimal treatment of patients whose isolates have V-MICs of ≥2.0 μg/ml.

Zygomycosis in Solid Organ Transplant Recipients: A Prospective, Matched Case-Control Study to Assess Risks for Disease and Outcome

BACKGROUND Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. METHODS In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. RESULTS Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables. CONCLUSIONS The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Persistence in Staphylococcus aureus bacteremia: Incidence, characteristics of patients and outcome

Staphylococcus aureus bacteremia often persists. The reasons for persistence and its outcome are poorly defined. We conducted a prospective-observational study among 245 consecutive S. aureus (MRSA: n=125; MSSA: n=120) bacteremias (≥1 positive blood cultures (BC)) among 234 adults (18–103-y-old; median = 59 y) hospitalized during 1 January 2002–31 December 2002 at a 600-bed teaching hospital. Measurements included bacteremia duration, complication-rate (metastatic infection, relapse or attributable mortality) and outcome. Bacteremia duration was measured based on follow-up BC among 193 patients and estimated based on symptoms resolution in the rest. Measured (1–59 d; median = 2) and estimated (median = 1 d) duration correlated (r=0.885) though positive follow-up BC was often detected without fever (57/105 patients, 54.3%). Persistence (defined as bacteremia for ≥3 d) was noted in 84 cases (38.4%). Complication-rate increased steadily with bacteremia duration (6.6%, 24.0% and 37.7% in bacteremia for 1–2, 3 and ≥4 d, respectively; p=0.05). Cox regression analysis revealed that bacteremia duration correlated positively with endovascular sources (p=0.006), vancomycin treatment (p=0.016), cardiovascular prosthesis (p=0.025), metastatic infections (p=0.025) and diabetes (p=0.038). It is concluded that persistent bacteremia is a feature of S. aureus infection, irrespective of oxacillin susceptibility, associated with worse outcome. Risk factors include endovascular sources, cardiovascular prosthesis, metastatic infections, vancomycin treatment and diabetes. Patients at risk may benefit from novel treatment strategies.

Ceftaroline: A Novel Cephalosporin with Activity against Methicillin-resistant Staphylococcus aureus

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.

Time to Positivity in Staphylococcus aureus Bacteremia: Possible Correlation with the Source and Outcome of Infection

BACKGROUND Staphylococcus aureus bacteremia often persists and causes metastatic infections. It is unknown whether the time between blood culture incubation and growth detection (i.e., the time to positivity) in a continuously monitored system--a probable surrogate marker of bacteremia severity--correlates with outcome. METHODS We performed a prospective, observational study involving adult inpatients who had S. aureus bacteremia between 1 January 2002 and 30 June 2003 at a 600-bed teaching hospital. Measurements included time to positivity in initial blood culture series, duration of bacteremia, rate of metastatic infection, and outcome. RESULTS A total of 376 S. aureus bacteremias (> or = 1 positive blood culture result) were reported for 357 patients aged 18-103 years (median age, 59 years); 64 bacteremias were excluded because blood was drawn after antibiotic therapy was started (n = 59) or through an intravascular catheter (n = 5). The source of infection was identified in 244 series (78.2%). Metastatic infection was detected in 25 bacteremias (8.0%). The mortality rate was 25.6%. The duration of bacteremia (determined in 251 series) was 1-59 days (median duration, 1 day; 70th percentile, 3 days). The time to positivity ranged from 4.2 to 98.2 h (median time to positivity, 15.5 h) and was significantly shorter for patients with an endovascular source of infection (14.9+/-5.4 vs. 19.5+/-10.6 h; P < .0005), extended duration (i.e., > or = 3 days) of bacteremia (14.1+/-4.2 vs. 18.6+/-9.2 h; P < .0005), and metastatic infection (12.9+/-5.9 vs 18.0+/-9.3 h; P = .007). Analysis of a range of cutoff values demonstrated that a time to positivity of < or = 14 h yielded the best sensitivity and specificity for predicting the source and outcome of infection. Logistic regression analyses revealed that a time to positivity of < or = 14 h was an independent predictor of an endovascular source of infection (P < .0005), extended bacteremia (P < .0005), metastatic infection (P < .0005), and attributable mortality (P = .017). CONCLUSIONS Time to positivity in S. aureus bacteremia may provide useful diagnostic and prognostic information. Growth of S. aureus within 14 h after the initiation of incubation may identify patients with a high likelihood of endovascular infection sources, delayed clearance, and complications.

Telavancin: A Novel Lipoglycopeptide

Telavancin, a derivative of vancomycin, is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of complicated skin and skin-structure infections. It has also been effective in the treatment of gram-positive pneumonia. This antibiotic has a dual mechanism of action by inhibiting peptidoglycan synthesis and causing membrane depolarization. Telavancin is consistently active against Staphylococcus aureus, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus, linezolid-resistant S. aureus, and daptomycin-nonsusceptible strains. The drug is usually administrated intravenously at 10 mg/kg every 24 h. Telavancin is excreted by the kidneys, and thus, dosage adjustments are required in cases of renal failure. Clinical trials have demonstrated non-inferiority, compared with vancomycin, in the treatment of complicated skin and skin-structure infections and pneumonia. Telavancin is associated with higher rates of renal events, altered taste, nausea, and vomiting but lesser rates of pruritus and infusion-related events, compared with vancomycin.

Staphylococcus aureus Bacteremia: Compliance with Standard Treatment, Long-term Outcome and Predictors of Relapse

The long-term outcome of compliance with standard treatment recommendations for Staphylococcus aureus bacteremia was assessed. Cases of S. aureus bacteremia at our institution over a 2-y period were reviewed and follow-up performed by review of subsequent admissions or contact with primary care physicians. We encountered 226 cases (age 64.7±15.8 y) and most (171/226, 75.7%) had no removable source. In-hospital mortality rate was 32.7% (74/226). Follow-up of 104/152 (68.4%) survivors (for 386.7±449.8 d) revealed 23.1% (24/104) relapses: recurrent bacteremia (n=19), distant site (n=3) and local recurrence (n=2). Most relapses (21/24; 87.5%) occurred within 90 d of therapy. Relapse rate was higher with vancomycin treatment (20/48 vs. 4/56; p<0.001), bacteremia for ≥3 d (9/20 vs. 15/84; p=0.001), and failure to remove the source (6/7 vs. 6/22; p=0.006). Vancomycin effect was independent of oxacillin susceptibility. Treatment for less than the standard 2-week duration among 19 patients with short duration of bacteremia (<3 d) did not increase relapse rate (1/19; 5.3%). Duration of bacteremia, vancomycin therapy and failure to remove the source were predictors of relapse. Prospective studies are needed to determine if S. aureus bacteremias of short duration can be treated for 2 weeks or less, and define the optimal duration for prolonged bacteremia when vancomycin is used.

In Vitro Activity of Ceftaroline against Community-Associated Methicillin-Resistant, Vancomycin-Intermediate, Vancomycin-Resistant, and Daptomycin-Nonsusceptible Staphylococcus aureus Isolates

ABSTRACT This study assessed the in vitro activities of ceftaroline and five comparator agents against a collection of Staphylococcus aureus isolates. Ceftaroline demonstrated potent activity against community-associated methicillin-resistant S. aureus (CA-MRSA) isolates and showed bactericidal activity against vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), heteroresistant VISA (hVISA), and daptomycin-nonsusceptible S. aureus (DNSSA) isolates. Ceftaroline may represent a bactericidal treatment option for infections caused by these pathogens.

Frequency of Reduced Vancomycin Susceptibility and Heterogeneous Subpopulation in Persistent or Recurrent Methicillin-Resistant Staphylococcus aureus Bacteremia

Vancomycin susceptibility was checked in isolates from initial and final blood samples obtained from 22 patients with persistent or recurrent methicillin-resistant Staphylococcus aureus bacteremia. The minimum inhibitory concentration of vancomycin was determined using Etest and found to have increased in 2 pairs of isolates, and results of screening in 4 mu g vancomycin and a modified population analysis profile suggested heteroresistance in 3 isolates (13.6%). Heteroresistance is not a common cause of persistent or recurrent bacteremia.