Brian A. Potoski

Treatment Outcome of Bacteremia Due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial Regimens

ABSTRACT Klebsiella pneumoniae producing Klebsiella pneumoniae carbapenemase (KPC) has been associated with serious infections and high mortality. The optimal antimicrobial therapy for infection due to KPC-producing K. pneumoniae is not well established. We conducted a retrospective cohort study to evaluate the clinical outcome of patients with bacteremia caused by KPC-producing K. pneumoniae. A total of 41 unique patients with blood cultures growing KPC-producing K. pneumoniae were identified at two medical centers in the United States. Most of the infections were hospital acquired (32; 78%), while the rest of the cases were health care associated (9; 22%). The overall 28-day crude mortality rate was 39.0% (16/41). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (odds ratio, 0.07 [95% confidence interval, 0.009 to 0.71], P = 0.02). The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (P = 0.01). The most commonly used combinations were colistin-polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despite in vitro susceptibility, patients who received monotherapy with colistin-polymyxin B or tigecycline had a higher mortality of 66.7% (8/12). The use of combination therapy for definitive therapy appears to be associated with improved survival in bacteremia due to KPC-producing K. pneumoniae.

Measurement of adherence to antiretroviral medications.

Summary: Measurement of adherence may be important in determining why patients fail antiretroviral therapy. Although patient self‐report is by far the most frequently used means of assessing adherence, it overestimates adherence. However, patients who state they are nonadherent almost always are. The pill identification test is a recently described tool that may be useful in clinical practice. The best methods of adherence measurement are pill counts and electronic monitoring. Pill counts suffer from inability to record the time of consumption of therapy. Electronic monitoring enables timing of pill consumption and is the closest to a gold standard for measuring adherence. However, this is only the case if patients are carefully instructed in how to use the device, e.g., not to remove extra doses from their pill bottle. A composite adherence score has been developed that uses electronic monitoring, pill counts, and patient self‐report. The authors believe that careful measurement of adherence is essential in the assessment of a patient failing to respond to antiretroviral therapy.

Genetic Basis of Multidrug Resistance in Acinetobacter baumannii Clinical Isolates at a Tertiary Medical Center in Pennsylvania

ABSTRACT A total of 49 unique clinical isolates of multidrug-resistant (MDR) Acinetobacter baumannii identified at a tertiary medical center in Pittsburgh, Pennsylvania, between August 2006 and September 2007 were studied for the genetic basis of their MDR phenotype. Approximately half of all A. baumannii clinical isolates identified during this period qualified as MDR, defined by nonsusceptibility to three or more of the antimicrobials routinely tested in the clinical microbiology laboratory. Among the MDR isolates, 18.4% were resistant to imipenem. The frequencies of resistance to amikacin and ciprofloxacin were high at 36.7% and 95.9%, respectively. None of the isolates was resistant to colistin or tigecycline. The presence of the carbapenemase gene blaOXA-23 and the 16S rRNA methylase gene armA predicted high-level resistance to imipenem and amikacin, respectively. blaOXA-23 was preceded by insertion sequence ISAba1, which likely provided a potent promoter activity for the expression of the carbapenemase gene. The structure of the transposon defined by ISAba1 differed from those reported in Europe, suggesting that ISAba1-mediated acquisition of blaOXA-23 may occur as an independent event. Typical substitutions in the quinolone resistance-determining regions of the gyrA and parC genes were observed in the ciprofloxacin-resistant isolates. Plasmid-mediated quinolone resistance genes, including the qnr genes, were not identified. Fifty-nine percent of the MDR isolates belonged to a single clonal group over the course of the study period, as demonstrated by pulsed-field gel electrophoresis.

Failure of Current Cefepime Breakpoints To Predict Clinical Outcomes of Bacteremia Caused by Gram-Negative Organisms

ABSTRACT For commonly encountered gram-negative bacilli, a MIC of cefepime of 8 μg/ml or less was defined by the Clinical and Laboratory Standards Institute as “susceptible” prior to the commercial release of the antibiotic. We assessed 204 episodes of bacteremia caused by gram-negative organisms for which patients received cefepime (typically 1 to 2 g every 12 h) as the primary mode of therapy. The cefepime MIC breakpoint derived by classification and regression tree (CART) software analysis to delineate the risk of 28-day mortality was 8 μg/ml. Patients infected with gram-negative organisms treated with cefepime at a MIC of ≥8 μg/ml had a mortality rate of 54.8% (17/31 died), compared to 24.1% (35/145 died) for those treated with a cefepime MIC of <8 μg/ml. The rate of mortality for those treated with a cefepime MIC of 8 μg/ml was 56.3% (9/16 died), compared to 53.3% (8/15 died) for those treated with cefepime at a MIC of >8 μg/ml. A multivariable analysis including severity of illness indices showed that treating patients with bacteremia due to gram-negative organisms with a cefepime MIC of ≥8 μg/ml was an independent predictor of mortality (P ≤ 0.001). There was no significant difference in outcome according to the dosage regimen utilized. Pharmacodynamic assessments that were presented previously would suggest that cefepime treatment (particularly a dosage of 1 g every 12 h) has a low probability of target attainment associated with successful in vivo outcome when the cefepime MIC is ≥8 μg/ml. It would appear reasonable, based on pharmacodynamic and clinical grounds, to lower the breakpoints for cefepime in countries where the cefepime dosage of 1 to 2 g every 12 h is the licensed therapy for serious infections, so that organisms with a cefepime MIC of 8 μg/ml are no longer regarded as susceptible to the antibiotic.

Simple Disk-Based Method for Detection of Klebsiella pneumoniae Carbapenemase-Type β-Lactamase by Use of a Boronic Acid Compound

ABSTRACT A disk potentiation method using carbapenems as substrates and 3-aminophenyl boronic acid as an inhibitor was evaluated for the detection of Klebsiella pneumoniae carbapenemase (KPC)-type β-lactamases. When combined with nonsusceptibility to ertapenem, the method was easy to perform and reliably differentiated isolates producing KPC-type β-lactamases from those producing other types of β-lactamases.

Epidemiological Profile of Linezolid-Resistant Coagulase-Negative Staphylococci

BACKGROUND Surveillance studies have shown that <0.1% of coagulase-negative staphylococci are linezolid resistant; however, at our institution, 4% of such organisms were found to be resistant. We investigated the risk factors for and the epidemiological profile of linezolid-resistant coagulase-negative staphylococci. METHODS Susceptibility testing and pulsed-field gel electrophoresis were performed to analyze the genetic relatedness of both linezolid-resistant and linezolid-susceptible isolates. Clinical data were retrieved from medical records, and a case-case-control study was performed to identify unique risk factors for linezolid resistance. RESULTS Isolates recovered from 25 patients with linezolid-resistant coagulase-negative staphylococci were examined; all but 1 of the isolates were identified as Staphylococcus epidermidis, and all but 1 had a minimum inhibitory concentration of linezolid of >256 microg/mL. Pulsed-field gel electrophoresis showed that 21 (84%) of 25 linezolid-resistant isolates exhibited genetic relatedness, whereas linezolid-susceptible isolates were of diverse clones. Unique, independent predictors of linezolid resistance included receipt of linezolid in the 3 months preceding isolation of the coagulase-negative staphylococci (odds ratio, 20.6; 95% confidence interval, 5.8-73.0). CONCLUSION Linezolid-resistant coagulase-negative staphylococci have emerged at our institution and are predominately of a single clone. We believe that the most likely scenario to explain this emergence is that person-to-person spread of linezolid-resistant coagulase-negative staphylococci led to establishment of skin colonization with the strain. Subsequent use of linezolid was followed by selection of the linezolid-resistant strain, which then became the dominant skin flora. The potential for a parallel scenario involving clonal dissemination followed by selection of linezolid-resistant methicillin-resistant Staphylococcus aureus is a real possibility.

Extensively drug-resistant Acinetobacter baumannii.

To the Editor: In the 1990s, patients infected with vancomycin-resistant Enterococcus faecium were successfully treated with new antimicrobial drugs. However, it is unlikely that new antimicrobial drugs will be available in the near future to treat patients infected with gram-negative pathogens such as Acinetobacter baumannii (1). No new antimicrobial drugs active against this organism are currently in clinical trials (www.clinicaltrials.gov). We report a patient infected with A. baumannii that lacked susceptibility to all commercially available antimicrobial drugs. The patient, a 55-year-old woman, had a prolonged stay in an intensive care unit at the University of Pittsburgh Medical Center (Pittsburgh, PA, USA) after undergoing lung transplantation. In the tenth postoperative week, ventilator-associated pneumonia developed, which was caused by A. baumanni that lacked susceptibility to all antimicrobial drugs tested except colistin (MIC 0.5 μg/mL). Therapy with colistin and tigecycline was begun. Colistin was administered intravenously and by inhalation. Although the pneumonia showed radiographic response to the antimicrobial drug therapy, A. baumannii continued to be isolated from respiratory secretions on numerous occasions. Despite another course of therapy with colistin and cefepime, the patient never recovered from respiratory failure. She eventually died of sepsis caused by vancomycin-resistant E. faecium. An A. baumannii isolate obtained just before she died lacked susceptibility to all commercially available antimicrobial drugs (Table). Table MICs and antimicrobial drug susceptibility for an extensively drug-resistant strain of Acinetobacter baumannii* Multidrug-resistant A. baumannii has emerged as a substantial problem worldwide (2). Such strains are typically resistant to all β-lactams and fluoroquinolones and require salvage therapy with colistin, amikacin, or tigecycline. Unfortunately, notably high-level resistance to colistin and amikacin was found in the isolate we have described (Table). Tigecycline, a newly available glycylcycline antimicrobial drug, showed intermediate susceptibility. No randomized trials have been performed to specifically evaluate combination antimicrobial drug therapy for treatment of infection with A. baumannii. Considerable media attention has been paid to extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (3). Infections with XDR strains are extremely difficult to treat and pose considerable infection control issues. We recently proposed that gram-negative bacilli lacking susceptibility to all commercially available antimicrobial drugs also be referred to as XDR because no therapeutic options are available (4). Numerous outbreaks of A. baumannii infection have been reported worldwide (5). Unfortunately, multidrug-resistant A. baumannii strains have become endemic in some institutions. Experimental and clinical isolates lacking susceptibility to colistin, often considered the drug of last resort, are increasingly being reported (6–8). Therefore, we alert healthcare workers to the need for stringent care in adhering to infection control precautions when caring for patients infected with XDR A. baumannii. Use of contact isolation precautions, enhanced environmental cleaning, removal of sources of infection from the hospital environment, and prudent use of antimicrobial drugs can contribute to control of such outbreaks (5). Fortunately, no spread of the XDR strain affecting this patient occurred. A crisis is looming should XDR A. baumannii become established pathogens in hospitals.

Interspecies Spread of Klebsiella pneumoniae Carbapenemase Gene in a Single Patient

Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, Escherichia coli, and Serratia marcescens were sequentially identified in a patient who underwent small bowel transplantation. Molecular typing and plasmid analysis suggested that the KPC gene was acquired by E. coli, most likely from K. pneumoniae, and was subsequently transferred to S. marcescens.

Epidemiology, Clinical Characteristics and Outcomes of Extensively Drug-Resistant Acinetobacter baumannii Infections among Solid Organ Transplant Recipients

Background Extensively drug-resistant Acinetobacter baumannii (XDR-Ab) has emerged as a major nosocomial pathogen, but optimal treatment regimens are unknown. Although solid organ transplant (SOT) recipients are particularly susceptible to XDR-Ab infections, studies in this population are limited. Our objectives were to determine the epidemiology, clinical characteristics and outcomes of XDR-Ab infections among SOT patients. Methods A retrospective study of SOT recipients at our center who were colonized or infected with XDR-Ab between November 2006 and December 2011 was conducted. Among infected patients, the primary outcome was survival at 28 days. Secondary outcomes included survival at 90 days and clinical success at 28 days, and XDR-Ab infection recurrence. Results XDR-Ab was isolated from 69 SOT patients, of whom 41% (28) and 59% (41) were colonized and infected, respectively. Infections were significantly more common among cardiothoracic than abdominal transplant recipients (p = 0.0004). Ninety-eight percent (40/41) of patients had respiratory tract infections, most commonly ventilator-associated pneumonia (VAP; 88% [36/41]). Survival rates at 28 and 90 days were 54% (22/41) and 46% (19/41), respectively. Treatment with a colistin-carbapenem regimen was an independent predictor of 28-day survival (p = 0.01; odds ratio = 7.88 [95% CI: 1.60–38.76]). Clinical success at 28 days was achieved in 49% (18/37) of patients who received antimicrobial therapy, but 44% (8/18) of successes were associated with infection recurrence within 3 months. Colistin resistance emerged in 18% (2/11) and 100% (3/3) of patients treated with colistin-carbapenem and colistin-tigecycline, respectively (p = 0.03). Conclusions XDR-Ab causes VAP and other respiratory infections following SOT that are associated with significant recurrence and mortality rates. Cardiothoracic transplant recipients are at greatest risk. Results from this retrospective study suggest that colistin-carbapenem combinations may result in improved clinical responses and survival compared to other regimens and may also limit the emergence of colistin resistance.

Intrapulmonary Penetration of Voriconazole in Patients Receiving an Oral Prophylactic Regimen

ABSTRACT Voriconazole penetrated well into the pulmonary epithelial lining fluid (ELF) in lung transplant patients receiving oral prophylaxis. The ELF concentrations exceeded those of the plasma, with an average ELF-to-plasma ratio of 11 (±8). A strong association between plasma and ELF concentrations (r2 = 0.95) was noted.