Ann M. Evans

Relationship between Vancomycin MIC and Failure among Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia Treated with Vancomycin

ABSTRACT There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia ≥10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was ≥1.5 mg/liter. The 66 patients with vancomycin MICs of ≥1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of ≤1.0 mg/liter (36.4% and 15.4%, respectively; P = 0.049). In the Poisson regression, a vancomycin MIC of ≥1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of ≥1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.

Predictors of high vancomycin MIC values among patients with methicillin-resistant Staphylococcus aureus bacteraemia

BACKGROUND Recent evidence suggests that vancomycin demonstrates reduced activity against methicillin-resistant Staphylococcus aureus (MRSA) infections when vancomycin MIC values are at the high end of the susceptibility range (> or = 1.5 mg/L). However, scant research exists on factors predictive of high vancomycin MICs (> or = 1.5 mg/L) among MRSA bacteraemic patients. Empirical therapy decisions would greatly benefit from such information. OBJECTIVES To identify the parameters predictive of high vancomycin MICs (> or = 1.5 mg/L) among MRSA bacteraemic patients and to develop an evidence-based clinical prediction tool. METHODS This observational cohort study included adult patients with MRSA bloodstream infections between January 2005 and May 2007. Demographics, co-morbid conditions, and microbiology and antibiotic exposure data were collected. Vancomycin MICs were determined by Etest. Stepwise logistic regression was used to identify independent predictors of high vancomycin MICs. RESULTS Of the 105 patients who met the inclusion criteria, 77 patients (73.3%) exhibited a high vancomycin MIC (> or = 1.5 mg/L). In the bivariate analysis, prior vancomycin exposure within 30 days of index culture collection [15 patients (19.5%) versus 1 patient (3.6%), P = 0.05] and residence in an intensive care unit (ICU) at the onset of infection [27 patients (35.1%) versus 3 patients (10.7%), P = 0.02] were both significantly associated with a high vancomycin MIC value and both were independent predictors of high MICs in the logistic regression. CONCLUSIONS Patients with MRSA bloodstream infections in the ICU or with a history of vancomycin exposure should be considered at high risk of infection with strains for which vancomycin MICs are elevated. Appropriate and aggressive empirical therapy is required for these patients.

Clinical epidemiology of carbapenem-intermediate or -resistant Enterobacteriaceae

OBJECTIVES Despite the increasing incidence of carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE), risk factors associated with CIRE infections have not been well defined. This study characterizes factors associated with CIRE among two different source populations. METHODS A case-control study was performed at a tertiary care medical centre between January 2005 and December 2009. Cases were adults with a culture-confirmed Enterobacteriaceae infection with reduced susceptibility to meropenem or ertapenem. The CIRE cases were matched 1:1 to patients from two different control series: (i) those with carbapenem-susceptible Enterobacteriaceae (CSE) infections; and (ii) inpatients residing on the same ward within 30 days of CIRE culture date. Logistic regression was used to identify variables independently associated with CIRE among each source population. Restricted multivariate analyses were performed to determine if covariates predictive of CIRE varied by infecting organism or presence of the bla(KPC) gene. RESULTS There were 102 cases of CIRE during the study period. The only covariate independently associated with CIRE in all multivariate analyses was the cumulative number of prior antibiotic exposures. Compared with CSE controls, the odds ratios (95% confidence interval) were 1.43 (1.19-1.72), 2.05 (1.70-2.47) and 2.93 (2.43-3.53) for 1, 2 and ≥ 3 antibiotic exposures, respectively. The strength of this association was comparable for the hospitalized control group and analyses stratified by organism and presence of the bla(KPC) gene. CONCLUSIONS A patients cumulative antibiotic exposure history is likely to be more important than any one specific exposure when determining the likelihood of developing a CIRE infection.

Low Prevalence of Listeria monocytogenes in Human Stool

Listeria monocytogenes is a foodborne pathogen that is found widely in the environment and in a variety of ready-to-eat foods, yet human invasive infection is relatively rare (five cases per million people annually in the United States). Despite wide exposure to this organism, little is known about the prevalence of L. monocytogenes in human stool, and it is not known whether human fecal dispersal contributes to human foodborne transmission. We cultured 827 stool specimens (well formed and loose-watery) from individuals from four large metropolitan areas of New York state for L. monocytogenes and found only 1 (0.12%) positive specimen. L. monocytogenes was also isolated from the blood of the person with the single positive specimen, and the two isolates were indistinguishable by molecular subtyping (both were ribotype DUP-1042B). This provides further evidence that human L. monocytogenes fecal carriage among persons with and without diarrheal disease is remarkably low. Unlike the case for other foodborne pathogens (e.g., Salmonella), human shedders probably do not contribute significantly to L. monocytogenes contamination of foods. However, we observed a single individual with invasive listeriosis that shed the pathogen in feces, indicating the potential for fecal dispersal of L. monocytogenes from persons with listeriosis.

Correlation between Vancomycin MIC Values and Those of Other Agents against Gram-Positive Bacteria among Patients with Bloodstream Infections Caused by Methicillin-Resistant Staphylococcus aureus

ABSTRACT An increase in the distribution of vancomycin MIC values among methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates has been noted. It is postulated that the shift in vancomycin MIC values may be associated with a concurrent rise in the MIC values of other anti-MRSA agents. Scant data are available on the correlation between vancomycin MIC values and the MIC values of other anti-MRSA agents. This study examined the correlation between vancomycin MIC values and the MIC values of daptomycin, linezolid, tigecycline, and teicoplanin among 120 patients with bloodstream infections caused by MRSA at a tertiary care hospital between January 2005 and May 2007. For each included patient, the MIC values of the antibiotics under study were determined by the Etest method and were separated into the following two categories: day 1 (index) and post-day 1 (subsequent). For subsequent isolates, the MIC values for each antibiotic from the post-day 1 terminal isolate were used. Among the index isolates, there was a significant correlation (P value, <0.01) between the MIC values for vancomycin and daptomycin and between the MIC values for vancomycin and teicoplanin. The MIC values for daptomycin were significantly correlated with linezolid, tigecycline, and teicoplanin MIC values. Among the 48 patients with subsequent isolates, vancomycin MIC values were significantly correlated with MIC values for daptomycin, linezolid, and teicoplanin (ρ value of ≥0.38 for all comparisons). This study documented an association between vancomycin MIC values and the MIC values of other anti-MRSA antibiotics among patients with bloodstream infections caused by MRSA primarily treated with vancomycin.

Survey of Plasmid-Associated Genetic Markers in Enterobacteriaceae with Reduced Susceptibilities to Cephalosporins

ABSTRACT Clinical isolates of Enterobacteriaceae with reduced susceptibilities to cephalosporins were collected from 1993 to 2000. The organisms were screened for the extended-spectrum β-lactamase (ESBL) phenotype, and plasmid extracts were screened for genetic markers by hybridization. A blaTEM probe was derived from pUC19; other probes were derived from pACM1, the plasmid responsible for the first known appearance of an ESBL in our institution. These probes included blaSHV, int, aac(3)-Ia, dfrA1, IS6100, tetA, IncM markers, and Anon 13, a marker for the Klebsiella pneumoniae chromosomal sequences that flank blaSHV-5. There were 42 hybridization patterns among 237 isolates. Patterns designated pACM1-like occurred in 44% of the isolates (eight species) and were always associated with the clavulanic acid (CA)-susceptible ESBL phenotype. The TEM marker was not predictive of the ESBL phenotype. Mapping indicated the presence of an SHV marker and up to 7.5 kb of its flanking chromosomal sequences in three non-IncM plasmids obtained in transformation experiments. We theorize that this DNA segment spread to other plasmids from pACM1-like sources. CA insensitivity became more frequent with time and was usually associated with either the TEM marker or the absence of both bla markers. One plasmid-encoded enzyme with characteristics of an AmpC β-lactamase was observed in a transformant lacking both TEM and SHV markers. Although SHV type ESBLs were a continuing source of reduced susceptibility to cephalosporins in our institution, organisms with different resistance mechanisms were added to the hospital microflora in later years. These changes might be related, in part, to ESBL control strategies implemented in 1995.

Increased oxacillin activity associated with glycopeptides in coagulase-negative staphylococci

Vancomycin resistance in methicillin-resistant staphylococci presents a potential therapeutic problem. In order to understand the impact of low-level vancomycin resistance in coagulase-negative Staphylococci, stepwise selection of vancomycin resistance was accomplished by growingstaphylococcus haemolyticus in culture media with increasing concentrations of vancomycin. A >40-fold increase in susceptibility to β-lactam antibiotics was observed. No obvious alterations in the growth curve, the presence of themecA gene, total DNA restriction fragment length polymorphism (RFLP), β-lactamase production, or the crude protein fraction were detected in thestaphylococcus haemolyticus-derived clones when compared to the original isolate. The proportion of the oxacillin-heteroresistant population also remained similar. A comparable phenomenon occurred with the selection ofstaphylococcus epidermidis exhibiting low-level resistance to vancomycin. Additionally, it was observed that clinical isolates of coagulase-negative Staphylococci grown in the presence of sub-minimum inhibitory concentrations of either vancomycin or teicoplanin lost their high-level resistance to oxacillin. Checkerboard tests showed that the combination of vancomycin and oxacillin was synergistic for two isolates ofStaphylococcus haemolyticus, two of four isolates ofStaphylococcus epidermidis, and one isolate ofStaphylococcus hominis.

Assessment of Time to Clinical Response in Patients with Sepsis Treated Before and After Implementation of a Matrix-Assisted Laser Desorption Ionization Time-of-Flight Blood Culture Identification Algorithm

OBJECTIVE To evaluate time to clinical response before and after implementation of rapid blood culture identification technologies. DESIGN Before-and-after trial. SETTING Large, tertiary, urban, academic health-sciences center. PATIENTS Patients >18 years old with sepsis and concurrent bacteremia or fungemia were included in the study; patients who were pregnant, had polymicrobial septicemia, or were transferred from an outside hospital were excluded. INTERVENTION Prior to the intervention, polymerase chain reaction was used to identify Staphylococcus species from positive blood cultures, and traditional laboratory techniques were used to identify non-staphylococcal species. After the intervention, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) assay and FilmArray were also used to identify additional species. During both periods, the antimicrobial stewardship team provided prospective audit and feedback for all patients on antibiotics. RESULTS A total of 219 patients were enrolled in the study: 115 patients prior to the intervention and 104 after the intervention. The median time to clinical response was statistically significantly shorter in the postintervention group than in the preintervention group (2 days vs 4 days, respectively; P=.002). By Cox regression, the implementation of MALDI-TOF and FilmArray was associated with shorter time to clinical response (hazard ratio [HR], 1.360; 95% confidence interval [CI], 1.018-1.816). After controlling for potential confounders, the study group was not independently associated with clinical response (adjusted HR, 1.279; 95% CI, 0.955-1.713). Mortality was numerically, but not statistically significantly, lower in the postintervention group than in the preintervention group (7.6% vs 11.4%; P=.342). CONCLUSIONS In the setting of an existing antimicrobial stewardship program, implementation of MALDI-TOF and FilmArray was associated with improved time to clinical response. Further research is needed to fully describe the effect of antimicrobial stewardship programs on time to clinical response. Infect Control Hosp Epidemiol 2016;37:916-923.

Quantifying the matrix of relationships between reduced vancomycin susceptibility phenotypes and outcomes among patients with MRSA bloodstream infections treated with vancomycin

OBJECTIVES Several phenotypic characteristics of Staphylococcus aureus have been identified as aetiological factors responsible for adverse outcomes among patients receiving vancomycin. However, characterization of the outcomes associated with these reduced vancomycin susceptibility phenotypes (rVSPs) remains largely incomplete and it is unknown if these features contribute to deleterious treatment outcomes alone or in concert. This study described the interrelationship between rVSPs and assessed their individual and combined effects on outcomes among patients who received vancomycin for a methicillin-resistant S. aureus (MRSA) bloodstream infection. METHODS An observational study of adult, hospitalized patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and June 2009 was performed. The rVSPs evaluated included the following: (i) Etest MIC; (ii) broth microdilution MIC; (iii) MBC : MIC ratio; and (iv) heteroresistance to vancomycin by the Etest macromethod. Failure was defined as any of the following: (i) 30 day mortality; (ii) bacteraemia ≥ 7 days on therapy; or (iii) recurrence of MRSA bacteraemia within 60 days of therapy discontinuation. RESULTS During the study period, 184 cases met the study criteria and 41.3% met the failure criteria. There was a clear linear exposure-response relationship between the number of these phenotypic markers and outcomes. As the number of phenotypes escalated, the incidence of overall failure increased incrementally by 10%-18%. CONCLUSIONS The data suggest that rVSPs contribute to deleterious treatment outcomes in concert.

A Triple Disk Enrichment Method for CRE Screening

The global emergence of carbapenem-resistant Enterobacteriaceae (CRE) is a major concern for public health. The Centers for Disease Control and Prevention (CDC)-recommended procedure for surveillance is overnight incubation of a rectal/perianal swab in 5 ml of tryptic soy broth (TSB) supplemented