Marilyn M. Wagener

Enterobacter Bacteremia: Clinical Features and Emergence of Antibiotic Resistance during Therapy

OBJECTIVES To study the effect of previously administered antibiotics on the antibiotic susceptibility profile of Enterobacter, the factors affecting mortality, and the emergence of antibiotic resistance during therapy for Enterobacter bacteremia. DESIGN Prospective, observational study of consecutive patients with Enterobacter bacteremia. SETTING Three university tertiary care centers, one major university-affiliated hospital, and two university-affiliated Veterans Affairs medical centers. PATIENTS A total of 129 adult patients were studied. MEASUREMENTS The two main end points were emergence of resistance during antibiotic therapy and death. MAIN RESULTS Previous administration of third-generation cephalosporins was more likely to be associated with multiresistant Enterobacter isolates in an initial, positive blood culture (22 of 32, 69%) than was administration of antibiotics that did not include a third-generation cephalosporin (14 of 71, 20%; P less than 0.001). Isolation of multiresistant Enterobacter sp. in the initial blood culture was associated with a higher mortality rate (12 of 37, 32%) than was isolation of a more sensitive Enterobacter sp. (14 of 92, 15%; P = 0.03). Emergence of resistance to third-generation cephalosporin therapy (6 of 31, 19%) occurred more often than did emergence of resistance to aminoglycoside (1 of 89, 0.01%; P = 0.001) or other beta-lactam (0 of 50; P = 0.002) therapy. CONCLUSIONS More judicious use of third-generation cephalosporins may decrease the incidence of nosocomial multiresistant Enterobacter spp., which in turn may result in a lower mortality for Enterobacter bacteremia. When Enterobacter organisms are isolated from blood, it may be prudent to avoid third-generation cephalosporin therapy regardless of in-vitro susceptibility.

The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance

OBJECTIVES To assess the changing epidemiology of candidemia in the 1990s, to evaluate the clinical implications for the presence of non-Candida albicans in blood, and to evaluate the presence of antifungal resistance in relation to prior antifungal administration. DESIGN Multicenter prospective observational study of patients with positive blood cultures for Candida species or Torulopsis glabrata. SETTING Four tertiary care medical centers. RESULTS Four hundred twenty-seven consecutive patients were enrolled. The frequency of candidemia due to non-C. albicans species significantly increased in each hospital throughout the 3.5-year study period (P = 0.01). Thirteen percent of candidemias occurred in patients who were already receiving systemic antifungal agents. Candidemias developing while receiving antifungal therapy were more likely caused by non-C. albicans species than by C. albicans species (P = 0.0005). C. parapsilosis and C. krusei were more commonly seen with prior fluconazole therapy, whereas T. glabrata was more commonly seen with prior amphotericin B therapy. Candida species isolated during episodes of breakthrough candidemia exhibited a significantly higher MIC to the antifungal agent being administered (P < 0.001). CONCLUSION In this large scale study, the non-C. albicans species, especially T. glabrata, emerged as important and frequent pathogens causing fungemia. This finding has major clinical implications given the higher complication and mortality rate associated with the non-C. albicans species. The change in the pattern of candidemia might be partly attributed to the increase in number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy. This is an ominous sign given the in vitro resistance of the non-C. albicans species to currently available antifungal agents.

Determinants of compliance with antiretroviral therapy in patients with human immunodeficiency virus : prospective assessment with implications for enhancing compliance

Non-compliance with therapy is a significant problem, particularly when the disease process is chronic and therapeutic regimens are employed for prolonged periods. We assessed the prevalence and variables associated with compliance with antiretroviral therapy in patients with human immunodeficiency virus infection, by means of a longitudinal observational study of 46 patients aged 23 to 68 years, with human immunodeficiency virus infection, followed at the Pittsburgh VA Medical Center. Data on demographics, medical status, physical functioning (Karnofsky performance scores), CD4 lymphocyte count, depression (Beck depression inventory), coping (inventory of coping with illness scale scores), and psychological and emotional stress (profile of mood states scale scores), were prospectively assessed on all patients at baseline and every 6 months. Compliance was assessed at 6 and 12 months: patients taking > or = 80% of antiretroviral therapy were considered compliant. Overall, 63% of patients were compliant with antiretroviral therapy. Age, education, employment, religious support, and perceived quality of life did not correlate with compliance. By univariate analysis, lack of prior intravenous drug use was significantly associated with compliance (p = 0.01). Compliant patients had significantly better adaptive coping (p = 0.03), and less depression (p = 0.04). By multivariate analysis, black race was significantly associated with non-compliance independent of intravenous drug use and educational status. History of prior opportunistic infection (which presumably heightens the perceived severity of illness) (p = 0.02), and lesser psychological disturbance scores (p = 0.02) were associated with compliance. Compliance was observed despite the greater number of prescription medications taken by compliant patients (p = 0.04). At 12 months, Karnofsky scores were better in compliant patients (p = 0.02), although mortality was not different. Besides identifying predictors of compliance, our data suggest that symptoms of depression and psychological stress be sought in patients with non-adherence.

International Prospective Study of Klebsiella pneumoniae Bacteremia: Implications of Extended-Spectrum β-Lactamase Production in Nosocomial Infections

Context Worldwide prevalence of extended-spectrum -lactamase (ESBL)producing organisms is of great concern because of their broad antibiotic resistance. Contribution Analysis of consecutive cases of Klebsiella pneumoniae bacteremia at 12 hospitals on 6 continents shows that although incidence varies widely among institutions, almost one third of cases of nosocomial bacteremia and almost one half of intensive care unitbased infections were caused by ESBL-producing organisms. Patient-to-patient spread is common, and prevention requires careful attention to routine infection control measures. Cautions Specific antibiotic exposures before K. pneumoniae infection cannot be confirmed as risk factors for ESBL-related infections on the basis of this study. The Editors Since the discovery that resistance of Staphylococcus aureus to penicillin is mediated by a -lactamase, much effort has been made to create -lactam antibiotics that are stable to common -lactamases. Cephalosporin antibiotics containing an oxyimino side-chain represent a major advance in antibiotic development. The merger of the oxyimino chain and a 2-amino-5-thiazolyl nucleus (in such antibiotics as ceftriaxone, cefotaxime, and ceftazidime) resulted in stability to the effects of the common TEM-1 and SHV-1 -lactamases produced by gram-negative bacilli, such as Escherichia coli and Klebsiella pneumoniae. However, within a few years of the commercial release of these antibiotics, gram-negative bacilli (especially K. pneumoniae) that harbored mutated versions of the parent TEM and SHV enzymes were detected. These and other newly detected -lactamases (for example, the functionally similar CTX-M types) hydrolyze -lactam antibiotics containing the oxyimino side-chain. Genes encoding these extended-spectrum -lactamases (ESBLs) were carried on transferable plasmids. These plasmids frequently carried determinants of resistance to other classes of antibiotics, particularly the aminoglycosides (1, 2). Thus, ESBL-producing gram-negative bacilli were found to truly be multiresistant pathogens: The majority of these strains were resistant to all -lactam antibiotics (with the exception of cephamycins and carbapenems), most aminoglycosides, trimethoprimsulfamethoxazole, and sometimes the fluoroquinolones. Although the prevalence of ESBL production among gram-negative bacilli varies geographically (and may even vary from hospital to hospital within a city), widespread recognition of the advent of these -lactamases has been lacking (3). Previous studies of the epidemiology of ESBL-producing organisms have been largely limited to single institutions (4, 5). Because substantial information on the epidemiology of ESBL-producing K. pneumoniae or other gram-negative bacilli is lacking, we established a collaboration of researchers from 7 countries on 6 continents to prospectively enroll consecutive patients with K. pneumoniae bacteremia. Methods Study Design We performed a prospective observational study of 440 consecutive, sequentially encountered patients with K. pneumoniae bacteremia at 12 hospitals in South Africa, Taiwan, Australia, Argentina, the United States, Belgium, and Turkey. No patient was excluded from analysis. Patients were enrolled from 1 January 1996 to 31 December 1997. Patients were older than 16 years of age and had positive blood cultures for K. pneumoniae. The investigators completed a 188-item study form on each episode of K. pneumoniae bacteremia. Patients were followed for 1 month after the onset of bacteremia to assess clinical outcome, including death and infectious complications. The study was observational in that administration of antimicrobial agents and other therapeutic management was controlled by the patients physician rather than the investigators (6). The study was approved by institutional review boards as required by local hospital policy at the time of the study. Definitions All study definitions were established before data analysis. Nosocomial bacteremia was defined as K. pneumoniae bacteremia occurring more than 48 hours after admission to hospital. An episode of bacteremia was defined as the period of 14 days from the time of collection of the first blood culture positive for K. pneumoniae. Severity of acute illness was assessed at the time of the positive blood cultures by using the Pitt bacteremia score, a previously validated scoring system that is based on mental status, vital signs, requirement for mechanical ventilation, and recent cardiac arrest (Table 1) (7, 8). Severity of illness in patients in an intensive care unit at the time of onset of bacteremia was assessed by using the Acute Physiology and Chronic Health Evaluation-3 score (9). Site of infection was determined to be pneumonia, urinary tract infection, meningitis, incisional wound infection, other soft-tissue infection, intra-abdominal infection, or primary bloodstream infection according to Centers for Disease Control and Prevention definitions (10). Previous antibiotic therapy was defined as antibiotics given for at least 2 days within the 14 days before an episode of K. pneumoniae bacteremia (11). Antibiotic therapy for the episode of K. pneumoniae bacteremia was the receipt of antibiotics that are active in vitro against the blood culture isolate (that is, susceptible according to 1999 NCCLS breakpoints [12], given for at least 2 days within the first 5 days of collection of the first positive blood culture. Mortality was death from any cause within 14 days from the date of the first positive blood culture for K. pneumoniae. Table 1. The Pitt Bacteremia Score* Microbiological Analysis Production of ESBL was phenotypically determined by broth dilution using the NCCLS performance standards current as of January 1999 (12). A 3 twofold decrease in the minimal inhibitory concentration (MIC) for cefotaxime or ceftazidime tested in combination with clavulanic acid compared with its MIC when tested alone was considered phenotypic confirmation of ESBL production. For example, an isolate with a ceftazidime MIC of 8 g/mL and a ceftazidimeclavulanic acid MIC of 1 g/mL fulfills this definition of an ESBL-producing organism (12). The MICs of antibiotics commonly used in the treatment of gram-negative sepsis were determined for the ESBL-producing isolates by using the gradient diffusion method (Etest, AB Biodisk, Solna, Sweden). Pulsed-field gel electrophoresis was used to establish the genotypic relationships of ESBL-producing isolates from each hospital (11). Statistical Analysis All statistical comparisons were made by using PROPHET Statistics software, version 6.0 (ABTech-BBN Corp., Charlottesville, Virginia) or Stata software, version 7.0 (Stata Corp., College Station, Texas). For bivariate comparisons, the chi-square or Fisher exact test was used to compare categorical variables. Continuous variables were compared by using the t-test or the MannWhitney test. Length of stay before positive blood culture was missing for 10 (4%) patients, all of whom had been readmitted within 1 week of discharge. Length of stay for these 10 patients was therefore estimated by using a predictive model that assumed missing at random. Because previous receipt of antibiotics was not random, a propensity score model was used to further evaluate the effect of receipt of antibiotics containing an oxyimino group as a risk for ESBL production. The score was calculated by using a logistic model in which receipt of -lactam antibiotics containing an oxyimino group (cefuroxime, ceftriaxone, cefotaxime, ceftazidime, or aztreonam) was the dependent variable (scored as yes or no) and predictors were all available factors hypothesized to influence the receipt of antibiotic therapy (underlying patient conditions), with adjustment for center by using the indicator variables for site. Factors included in the calculation of this score were age, sex, admission from nursing home, underlying diseases (cancer, HIV infection, diabetes, or renal and liver disease), previous surgery, use of corticosteroids, presence of a central line, mechanical ventilatory support, presence of a nasogastric tube, and the indicator variables for site. A logistic model clustered on the patient that used receipt of antibiotics containing an oxyimino group and the quintile stratified score was then used to evaluate the risk for ESBL production. Role of the Funding Source Merck and Company provided support for laboratory studies but played no role in study design, conduct of the study, interpretation of the results, or approval of the study before publication. Results During the study period, 455 episodes of K. pneumoniae bacteremia occurred in 440 patients; of these, 202 (44.4%) episodes in 196 patients were community acquired and 253 (55.6%) episodes in 244 patients were nosocomially acquired. Table 2 shows the characteristics of the participants. Table 2. Characteristics of 244 Patients with Nosocomial Klebsiella pneumoniae Bacteremia Of the episodes of K. pneumoniae bacteremia, 18.7% (85 of 455) were due to ESBL-producing organisms and 81.1% (369 of 455) were due to nonESBL-producing organisms. One additional episode involved an isolate that showed a markedly elevated MIC for the oxyimino -lactam antibiotics but no decrease in MIC with the addition of clavulanic acid. This isolate had an MIC for cephamycin antibiotics in the resistant range and may have possessed an AmpC-like enzyme. This episode was excluded from further analysis. Seventy-eight of 253 (30.8%) episodes of nosocomial bacteremia were due to ESBL-producing organisms. Table 3 shows the sites of infection associated with nosocomial ESBL-producing K. pneumoniae bacteremia. Fewer episodes of community-acquired K. pneumoniae bacteremia (3.5% [7 of 202]) were due to ESBL-producing organisms (P <0.001) (risk ratio, 8.9 [95% CI, 4.2 to 18.8]). Of the 253 episodes of nosocomial bacteremia, 69 were acquired in the intensive care unit. Of these 69 episodes, 30 (43.5%) episodes o

Antibiotic Therapy for Klebsiella pneumoniae Bacteremia: Implications of Production of Extended-Spectrum β-Lactamases

The prevalence of extended-spectrum beta -lactamase (ESBL) production by Klebsiella pneumonia approaches 50% in some countries, with particularly high rates in eastern Europe and Latin America. No randomized trials have ever been performed on treatment of bacteremia due to ESBL-producing organisms; existing data comes only from retrospective, single-institution studies. In a prospective study of 455 consecutive episodes of Klebsiella pneumoniae bacteremia in 12 hospitals in 7 countries, 85 episodes were due to an ESBL-producing organism. Failure to use an antibiotic active against ESBL-producing K. pneumoniae was associated with extremely high mortality. Use of a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality than was use of other antibiotics active in vitro. Multivariate analysis including other predictors of mortality showed that use of a carbapenem during the 5-day period after onset of bacteremia due to an ESBL-producing organism was independently associated with lower mortality. Antibiotic choice is particularly important in seriously ill patients with infections due to ESBL-producing K. pneumoniae.

Staphylococcus aureus nasal carriage and infection in patients on hemodialysis: efficacy of antibiotic prophylaxis

We conducted a five-year prospective controlled study of prophylaxis of Staphylococcus aureus nasal carriage and infection among patients in a hemodialysis unit. Carriers tended to have chronic colonization with a single phage type. S. aureus infections occurred significantly more frequently in carriers than in noncarriers and, in 93 percent of the infected carriers, were caused by the same phage type as that carried in the nares. Neither intravenous vancomycin nor topical bacitracin was found to be efficacious in eradicating nasal carriage. However, oral rifampin given for five days decreased S. aureus carriage over a one-month follow-up period, but within three months colonization of the nares recurred in most carriers, often with an S. aureus of the original phage type. Carriers were then randomly assigned to receive either rifampin or no prophylaxis. Rifampin was readministered at three-month intervals if culture of the anterior nares yielded S. aureus. Infections with S. aureus occurred significantly more frequently in carriers given no prophylaxis than in those given a full course of rifampin. S. aureus resistant to rifampin was isolated from the anterior nares of four patients, but these isolates were not implicated in any infections. The incidence of infection at the dialysis access site, skin, and soft tissue of patients on hemodialysis can be decreased by interventions directed at nasal carriage of S. aureus.

Staphylococcus aureus Bacteremia Recurrence and the Impact of Antibiotic Treatment in a Prospective Multicenter Study

Staphylococcus aureus bacteremia is associated with substantial morbidity. Recurrence is common, but incidence and risk factors for recurrence are uncertain. The emergence of methicillin resistance and the ease of administering vancomycin, especially in patients who have renal insufficiency, have led to reliance on this drug with the assumption that it is as effective as β-lactam antibiotics, an assumption that remains open to debate.We initiated a multicenter, prospective observational study in 6 university hospitals and enrolled 505 consecutive patients with S. aureus bacteremia. All patients were monitored for 6 months and patients with endocarditis were followed for 3 years. Recurrence was defined as return of S. aureus bacteremia after documentation of negative blood cultures and/or clinical improvement after completing a course of antistaphylococcal antibiotic therapy. All blood isolates taken from patients with recurrent bacteremia underwent pulsed-field gel electrophoresis testing. Recurrence was subclassified as reinfection (different pulsed-field gel electrophoresis patterns) or relapse (same pulsed-field gel electrophoresis pattern).Forty-two patients experienced 56 episodes of recurrence (79% were relapses and 21% were reinfection). Relapse occurred earlier than reinfection (median, 36 versus 99 d, p < 0.06). Risk factors for relapse of S. aureus bacteremia included valvular heart disease, cirrhosis of the liver, and deep-seated infection (including endocarditis). Nafcillin was superior to vancomycin in preventing bacteriologic failure (persistent bacteremia or relapse) for methicillin-susceptible S. aureus (MSSA) bacteremia. Failure to remove infected intravascular devices/catheters and vancomycin therapy were common factors in patients experiencing multiple (greater than 2) relapses. However, by multivariate analysis, only endocarditis and therapy with vancomycin (versus nafcillin) were significantly associated with relapse.Recurrences occurred in 9.4% of S. aureus bacteremias following antistaphylococcal therapy, and most were relapses. Duration of antistaphylococcal therapy was not associated with relapse, but type of antibiotic therapy was. Nafcillin was superior to vancomycin in efficacy in patients with MSSA bacteremia.

Methicillin-Resistant Staphylococcal Colonization and Infection in a Long-Term Care Facility

OBJECTIVE To determine the natural history of colonization by methicillin-resistant Staphylococcus aureus (MRSA) among patients in a long-term care facility. We specifically sought to determine if MRSA colonization was predictive of subsequent infection. DESIGN Cohort study. SETTING Long-term Veterans Affairs Medical Center. PATIENTS A total of 197 patients residing on two units were followed with regular surveillance cultures of the anterior nares. MAIN OUTCOME MEASUREMENT The development of staphylococcal infection. RESULTS Thirty-two patients were persistent carriers of MRSA and 44 were persistent carriers of methicillin-susceptible strains (MSSA). Twenty-five percent of MRSA carriers had an episode of staphylococcal infection compared with 4% of MSSA carriers and 4.5% of non-carriers (P less than 0.01; relative risk 3.8; 95% CI, 2.0 to 6.4). The rate of development of infection among MRSA carriers was 15% for every 100 days of carriage. Using logistic regression analysis, persistent MRSA carriage was the most significant predictor of infection (P less than 0.001; odds ratio, 3.7). Seventy-three percent of all MRSA infections occurred among MRSA carriers. Isolates of MRSA from 7 patients were typed. Colonizing and infecting strains had the same phage type in all 7 patients and the same pattern of plasmid EcoRI restriction endonuclease fragments in 5 patients. CONCLUSIONS Colonization of the anterior nares by MRSA predicts the development of staphylococcal infection in long-term care patients; most infections arise from endogenously carried strains. Colonization by MRSA indicates a significantly greater risk for infection than does colonization by MSSA. The results offer a theoretic rationale for reduction in MRSA infections by interventions aimed at eliminating the carrier state.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.

Background. The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. Methods. Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. Results. Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30–1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12–0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16–0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. Conclusions. Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

Opportunistic Mycelial Fungal Infections in Organ Transplant Recipients: Emerging Importance of Non-Aspergillus Mycelial Fungi

To determine the spectrum and impact of mycelial fungal infections, particularly those due to non-Aspergillus molds, 53 liver and heart transplant recipients with invasive mycelial infections were prospectively identified in a multicenter study. Invasive mycelial infections were due to Aspergillus species in 69.8% of patients, to non-Aspergillus hyalohyphomycetes in 9.4%, to phaeohyphomycetes in 9.4%, to zygomycetes in 5.7%, and to other causes in 5.7%. Infections due to mycelial fungi other than Aspergillus species were significantly more likely to be associated with disseminated (P=.005) and central nervous system (P=.07) infection than were those due to Aspergillus species. Overall mortality at 90 days was 54.7%. The associated mortality rate was 100% for zygomycosis, 80% for non-Aspergillus hyalohyphomycosis, 54% for aspergillosis, and 20% for phaeohyphomycosis. Thus, non-Aspergillus molds have emerged as significant pathogens in organ transplant recipients. These molds are more likely to be associated with disseminated infections and to be associated with poorer outcomes than is aspergillosis.