Defining optimal treatment for recurrent Clostridioides difficile infection (OpTION study): A randomized, double-blind comparison of three antibiotic regimens for patients with a first or second recurrence.

BACKGROUND: Although many large, randomized controlled trials (RCT) have been conducted on antibiotic therapy for patients with primary C. difficile infections (CDI), few RCTs have been performed for patients with recurrent CDI (rCDI). In addition, fecal microbial transplant (FMT) is neither FDA-approved or guideline-recommended for patients with pauci-rCDI (first or second recurrences). Therefore, a rigorous RCT of sufficient size was designed to determine the optimal treatment among three antibiotic regimens in current practice for treatment of pauci-rCDI. METHODS: VA Cooperative Studies Program (CSP) #596 is a prospective, double-blind, multi-center clinical trial of veteran patients with pauci-rCDI comparing fidaxomicin (FDX) 200 mg twice daily for 10 days and vancomycin (VAN) 125 mg four times daily for 10 days followed by a 3-week vancomycin taper and pulse (VAN-T/P) regimen to a standard course of VAN 125 mg four times daily for 10 days. The primary endpoint is sustained clinical response at day 59, with sustained response measured as a diarrhea composite outcome (D-COM) that includes symptom resolution during treatment (before day 10) without recurrence of diarrhea or other clinically important outcomes through day 59. DISCUSSION: CSP study 596 is designed to compare three current antibiotic treatments for recurrent CDI that are in clinical practice, but which lack high-quality evidence to support strong guideline recommendations. The design of the study which included a pilot phase initiated at six sites with expansion to 24 sites is described along with protocol modifications based on early trial experience and clinical realities including the COVID-19 pandemic. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (Identifier: NCT02667418).

Effect of daily chlorhexidine bathing on hospital-acquired infection.

BACKGROUND: Results of previous single-center, observational studies suggest that daily bathing of patients with chlorhexidine may prevent hospital-acquired bloodstream infections and the acquisition of multidrug-resistant organisms (MDROs). METHODS: We conducted a multicenter, cluster-randomized, nonblinded crossover trial to evaluate the effect of daily bathing with chlorhexidine-impregnated washcloths on the acquisition of MDROs and the incidence of hospital-acquired bloodstream infections. Nine intensive care and bone marrow transplantation units in six hospitals were randomly assigned to bathe patients either with no-rinse 2% chlorhexidine-impregnated washcloths or with nonantimicrobial washcloths for a 6-month period, exchanged for the alternate product during the subsequent 6 months. The incidence rates of acquisition of MDROs and the rates of hospital-acquired bloodstream infections were compared between the two periods by means of Poisson regression analysis. RESULTS: A total of 7727 patients were enrolled during the study. The overall rate of MDRO acquisition was 5.10 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.03), the equivalent of a 23% lower rate with chlorhexidine bathing. The overall rate of hospital-acquired bloodstream infections was 4.78 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.007), a 28% lower rate with chlorhexidine-impregnated washcloths. No serious skin reactions were noted during either study period. CONCLUSIONS: Daily bathing with chlorhexidine-impregnated washcloths significantly reduced the risks of acquisition of MDROs and development of hospital-acquired bloodstream infections. (Funded by the Centers for Disease Control and Prevention and Sage Products; ClinicalTrials.gov number, NCT00502476.).

Evaluation of postprescription review and feedback as a method of promoting rational antimicrobial use: a multicenter intervention.

OBJECTIVE: To evaluate the impact of postprescription review of broad-spectrum antimicrobial (study-ABX) agents on rates of antimicrobial use. DESIGN: Quasi-experimental before-after study. SETTING: Five academic medical centers. PATIENTS: Adults receiving at least 48 hours of study-ABX. METHODS: The baseline, intervention, and follow-up periods were 6 months each in 2 units at each of 5 sites. Adults receiving at least 48 hours of study-ABX entered the cohort as case-patients. During the intervention, infectious-diseases physicians reviewed the cases after 48 hours of study-ABX. The provider was contacted with alternative recommendations if antimicrobial use was considered to be unjustified on the basis of predetermined criteria. Acceptance rates were assessed 48 hours later. The primary outcome measure was days of study-ABX per 1,000 study-patient-days in the baseline and intervention periods. RESULTS: There were 1,265 patients in the baseline period and 1,163 patients in the intervention period. Study-ABX use decreased significantly during the intervention period at 2 sites: from 574.4 to 533.8 study-ABX days/1,000 patient-days (incidence rate ratio [IRR], 0.93; 95% confidence interval [CI], 0.88-0.97; P = .002) at hospital B and from 615.6 to 514.4 study-ABX days/1,000 patient-days (IRR, 0.83; 95% CI, 0.79-0.88; P < .001) at hospital D. Both had established antimicrobial stewardship programs (ASP). Study-ABX use increased at 2 sites and stayed the same at 1 site. At all institutions combined, 390 of 1,429 (27.3%) study-ABX courses were assessed as unjustified; recommendations to modify or stop therapy were accepted for 260 (66.7%) of these courses. CONCLUSIONS: Postprescription review of study-ABX decreased antimicrobial utilization in some of the study hospitals and may be more effective when performed as part of an established ASP.

USA300 methicillin-resistant Staphylococcus aureus bacteremia and the risk of severe sepsis: is USA300 methicillin-resistant Staphylococcus aureus associated with more severe infections?

USA300 methicillin-resistant Staphylococcus aureus (MRSA) is increasing as a cause of severe community-associated bacteremic infections. We assessed severe sepsis in response to infection in patients with USA300 MRSA compared to non-USA300 MRSA bacteremia. A cohort study was conducted from 1997 to 2008 comparing sepsis in response to infection in 271 patients with MRSA bacteremia from 4 VA hospitals. Sixty-seven (25%) patients with MRSA bacteremia were USA300 MRSA; 204 (75%) were non-USA300 MRSA. The proportion of MRSA bacteremia caused by USA300 MRSA increased over time (χ² P < 0.0001). Adjusting for age and nosocomial infection, patients with USA300 MRSA bacteremia were more likely to have severe sepsis or septic shock in response to infection than patients with non-USA300 MRSA bacteremia (adjusted relative risk = 1.82; 95% confidence interval, 1.16-2.87; P = 0.01). This suggests that patients with USA300 MRSA are more likely to develop severe sepsis in response to their infection, which could be due to host or bacterial differences.

Illicit drug use and risk for USA300 methicillin-resistant Staphylococcus aureus infections with bacteremia.

To assess the association of illicit drug use and USA300 methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, a multicenter study was conducted at 4 Veterans Affairs medical centers during 2004-2008. The study showed that users of illicit drugs were more likely to have USA300 MRSA bacteremia (in contrast to bacteremia caused by other S. aureus strains) than were patients who did not use illicit drugs (adjusted relative risk 3.0; 95% confidence interval 1.9-4.4). The association of illicit drug use with USA300 MRSA bacteremia decreased over time (p = 0.23 for trend). Notably, the proportion of patients with USA300 MRSA bacteremia who did not use illicit drugs increased over time. This finding suggests that this strain has spread from users of illicit drugs to other populations.

The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial.

OBJECTIVE: Spread of multidrug-resistant organisms within the intensive care unit (ICU) results in substantial morbidity and mortality. Novel strategies are needed to reduce transmission. This study sought to determine if the use of daily chlorhexidine bathing would decrease the incidence of colonization and bloodstream infections (BSI) because of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) among ICU patients. DESIGN, SETTING, AND PATIENTS: Six ICUs at four academic centers measured the incidence of MRSA and VRE colonization and BSI during a period of bathing with routine soap for 6 months and then compared results with a 6-month period where all admitted patients received daily bathing with a chlorhexidine solution. Changes in incidence were evaluated by Poisson and segmented regression modeling. INTERVENTIONS: Daily bathing with a chlorhexidine-containing solution. MEASUREMENTS AND MAIN RESULTS: Acquisition of MRSA decreased 32% (5.04 vs. 3.44 cases/1000 patient days, p = 0.046) and acquisition of VREdecreased 50% (4.35 vs. 2.19 cases/1000 patient days, p = 0.008) following the introduction of daily chlorhexidine bathing. Segmented regression analysis demonstrated significant reductions in VRE bacteremia (p = 0.02) following the introduction of chlorhexidine bathing. VRE-colonized patients bathed with chlorhexidine had a lower risk of developing VRE bacteremia (relative risk 3.35; 95% confidence interval 1.13-9.87; p = 0.035), suggesting that reductions in the level of colonization led to the observed reductions in BSI. CONCLUSION: We conclude that daily chlorhexidine bathing among ICU patients may reduce the acquisition of MRSA and VRE. The approach is simple to implement and inexpensive and may be an important adjunctive intervention to barrier precautions to reduce acquisition of VRE and MRSA and the subsequent development of healthcare-associated BSI.

Legislative mandates for use of active surveillance cultures to screen for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: Position statement from the Joint SHEA and APIC Task Force.

Legislation aimed at controlling antimicrobial-resistant pathogens through the use of active surveillance cultures to screen hospitalized patients has been introduced in at least 2 US states. In response to the proposed legislation, the Society for Healthcare Epidemiology of America (SHEA) and the Association for Professionals in Infection Control and Epidemiology, Inc., (APIC) have developed this joint position statement. Both organizations are dedicated to combating health care-associated infections with a wide array of methods, including the use of active surveillance cultures in appropriate circumstances. This position statement reviews the proposed legislation and the rationale for use of active surveillance cultures, examines the scientific evidence supporting the use of this strategy, and discusses a number of unresolved issues surrounding legislation mandating use of active surveillance cultures. The following 5 consensus points are offered. (1) Although reducing the burden of antimicrobial-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), is of preeminent importance, the APIC and the SHEA do not support legislation to mandate use of active surveillance cultures to screen for MRSA, VRE, or other antimicrobial-resistant pathogens. (2) The SHEA and the APIC support the continued development, validation, and application of efficacious and cost-effective strategies for the prevention of infections caused by MRSA, VRE, and other antimicrobial-resistant and antimicrobial-susceptible pathogens. (3) The APIC and the SHEA welcome efforts by health care consumers, together with private, local, state, and federal policy makers, to focus attention on and formulate solutions for the growing problem of antimicrobial resistance and health care-associated infections. (4) The SHEA and the APIC support ongoing additional research to determine and optimize the appropriateness, utility, feasibility, and cost-effectiveness of using active surveillance cultures to screen both lower-risk and high-risk populations. (5) The APIC and the SHEA support stronger collaboration between state and local public health authorities and institutional infection prevention and control experts.

Legislative mandates for use of active surveillance cultures to screen for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: position statement from the Joint SHEA and APIC Task Force.

Legislation aimed at controlling antimicrobial-resistant pathogens through the use of active surveillance cultures to screen hospitalized patients has been introduced in at least 2 US states. In response to the proposed legislation, the Society for Healthcare Epidemiology of America (SHEA) and the Association of Professionals in Infection Control and Epidemiology (APIC) have developed this joint position statement. Both organizations are dedicated to combating healthcare-associated infections with a wide array of methods, including the use of active surveillance cultures in appropriate circumstances. This position statement reviews the proposed legislation and the rationale for use of active surveillance cultures, examines the scientific evidence supporting the use of this strategy, and discusses a number of unresolved issues surrounding legislation mandating use of active surveillance cultures. The following 5 consensus points are offered. (1) Although reducing the burden of antimicrobial-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), is of preeminent importance, APIC and SHEA do not support legislation to mandate use of active surveillance cultures to screen for MRSA, VRE, or other antimicrobial-resistant pathogens. (2) SHEA and APIC support the continued development, validation, and application of efficacious and cost-effective strategies for the prevention of infections caused by MRSA, VRE, and other antimicrobial-resistant and antimicrobial-susceptible pathogens. (3) APIC and SHEA welcome efforts by healthcare consumers, together with private, local, state, and federal policy makers, to focus attention on and formulate solutions for the growing problem of antimicrobial resistance and healthcare-associated infections. (4) SHEA and APIC support ongoing additional research to determine and optimize the appropriateness, utility, feasibility, and cost-effectiveness of using active surveillance cultures to screen both lower-risk and high-risk populations. (5) APIC and SHEA support stronger collaboration between state and local public health authorities and institutional infection prevention and control experts.

Lack of relationship between purine biosynthesis and vancomycin resistance in Staphylococcus aureus: a cautionary tale for microarray interpretation.

Previous microarray data (E. Mongodin, J. Finan, M. W. Climo, A. Rosato, S. Gill, and G. L. Archer, J. Bacteriol. 185:4638-4643, 2003) noted an association in two vancomycin-intermediate Staphylococcus aureus (VISA) strains between high-level, passage-induced vancomycin resistance, a marked increase in the transcription of purine biosynthetic genes, and mutation of the putative purine regulator purR. Initial studies to report on the possible association between vancomycin resistance and alterations in purine metabolism in one of these strains (VP-32) confirmed, by Western analysis, an increase in the translation of PurH and PurM, two purine pathway enzymes. In addition, PurR was identified, by knockout and complementation in a vancomycin-susceptible strain, as a repressor of the purine biosynthetic operon in S. aureus, and the PurR missense mutation was shown to inactivate the repressor. However, despite the apparent relationship between increased purine biosynthesis and increased vancomycin resistance in VP-32, neither the addition of exogenous purines to a defined growth medium nor the truncation or inactivation of purR improved the growth of vancomycin-susceptible S. aureus in the presence of vancomycin. Furthermore, the passage of additional vancomycin-susceptible and VISA strains to high-level vancomycin resistance occurred without changes in cellular purine metabolism or mutation of purR despite the development of thickened cell walls in passaged strains. Thus, we could confirm neither a role for altered purine metabolism in the development of vancomycin resistance nor its requirement for the maintenance of a thickened cell wall. The failure of biochemical and physiological studies to support the association between transcription and phenotype initially found in careful microarray studies emphasizes the importance of follow-up investigations to confirm microarray observations.

Improving methicillin-resistant Staphylococcus aureus surveillance and reporting in intensive care units.

BACKGROUND: Routine culturing of patients in intensive care units (ICUs) for methicillin-resistant Staphylococcus aureus (MRSA) identifies unrecognized carriers and facilitates timely isolation. However, the benefit of surveillance in detecting prevalent and incident carriers likely varies among ICUs. In addition, many assessments underestimate the incidence of acquisition by including prevalent carriers in the at-risk population. METHODS: We performed a retrospective cohort study using accurate at-risk populations to evaluate the range of benefit of admission and weekly surveillance cultures in detecting otherwise unrecognized MRSA in 12 ICUs in 5 states. RESULTS: We assessed 142 ICU-months. Among the 12 ICUs, the admission prevalence of imported MRSA was 5%-21%, with admission surveillance providing 30%-135% increases in rates of detection. The monthly hospital-associated incidence was 2%-6%, with weekly surveillance providing 7%-157% increases in detection. The common practice of reporting incidence using the total number of patients or total patient-days underestimated incidence by one-third. Surgical ICUs had lower MRSA importation but higher MRSA incidence. Overall, routine surveillance prevented the misclassification of 17% (unit range, 11%-29%) of "incident" carriers, compared with clinical cultures, and increased precaution days by 18% (unit range, 11%-91%). CONCLUSIONS: Routine surveillance significantly increases the detection of MRSA, but this benefit is not uniform across ICUs, even with high compliance and the use of correct denominators.

Successful therapy of experimental endocarditis caused by vancomycin-resistant Staphylococcus aureus with a combination of vancomycin and beta-lactam antibiotics.

VRS1 is the first isolated strain of vancomycin-resistant Staphylococcus aureus (VRSA) found to carry the vanA gene complex previously described in Enterococcus. Under vancomycin pressure, VRS1 makes aberrant cell walls consisting of stem tetrapeptide and depsipeptide that lack the terminal D-Ala-D-Ala residues targeted by vancomycin. Previous data have suggested that this aberrant cell wall is not cross-linked by PBP2a, the enzyme responsible for cell wall transpeptidation in the presence of beta-lactam antibiotics. We examined the efficacy of treating VRS1 with a combination of vancomycin and beta-lactam antibiotics in vitro and in vivo. We found that the MIC of oxacillin for VRS1 decreased from >256 microg/ml to <1 microg/ml in the presence of vancomycin. Using the rabbit model of endocarditis, we treated VRS1-infected rabbits with nafcillin alone, vancomycin alone, or a combination of nafcillin and vancomycin. Treatment with nafcillin in combination with vancomycin cleared bloodstream infections within 24 h and sterilized 12/13 spleens (92%), as well as 8/13 kidneys (62%), following 3 days of treatment. Mean aortic valve vegetation counts were reduced 3.48 log(10) CFU/g with the combination therapy (compared to untreated controls) and were significantly lower than with either vancomycin or nafcillin given alone. VRS1 was extremely virulent in this model, as no untreated rabbits survived the 3-day trial. Treatment of clinical infections due to VRSA with the combination of vancomycin and beta-lactams may be an option, based on these results.

A multicenter intervention to prevent catheter-associated bloodstream infections.

BACKGROUND: Education-based interventions can reduce the incidence of catheter-associated bloodstream infection. The generalizability of findings from single-center studies is limited. OBJECTIVE: To assess the effect of a multicenter intervention to prevent catheter-associated bloodstream infections. DESIGN: An observational study with a planned intervention. SETTING: Twelve intensive care units and 1 bone marrow transplantation unit at 6 academic medical centers. PATIENTS: Patients admitted during the study period. INTERVENTION: Updates of written policies, distribution of a 9-page self-study module with accompanying pretest and posttest, didactic lectures, and incorporation into practice of evidence-based guidelines regarding central venous catheter (CVC) insertion and care. MEASUREMENTS: Standard data collection tools and definitions were used to measure the process of care (ie, the proportion of nontunneled catheters inserted into the femoral vein and the condition of the CVC insertion site dressing for both tunneled and nontunneled catheters) and the incidence of catheter-associated bloodstream infection. RESULTS: Between the preintervention period and the postintervention period, the percentage of CVCs inserted into the femoral vein decreased from 12.9% to 9.4% (relative ratio, 0.73; 95% confidence interval [CI], 0.61-0.88); the total proportion of catheter insertion site dressings properly dated increased from 26.6% to 34.4% (relative ratio, 1.29; 95% CI, 1.17-1.42), and the overall rate of catheter-associated bloodstream infections decreased from 11.2 to 8.9 infections per 1,000 catheter-days (relative rate, 0.79; 95% CI, 0.67-0.93). The effect of the intervention varied among individual units. CONCLUSIONS: An education-based intervention that uses evidence-based practices can be successfully implemented in a diverse group of medical and surgical units and reduce catheter-associated bloodstream infection rates.

Duration of colonization with methicillin-resistant Staphylococcus aureus among patients in the intensive care unit: implications for intervention.

OBJECTIVES: To determine the duration of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection before entry and during hospitalization in the intensive care unit (ICU) and the characteristics of patients who tested positive for MRSA. DESIGN: Prospective observational cohort survey. SETTING: A combined medical and coronary care ICU with 16 single-bed rooms in a 427-bed tertiary care Veteran Affairs Medical Center. PATIENTS: A total of 720 ICU patients associated with 845 ICU admissions were followed up for the detection of MRSA from January 13, 2003, to October 12, 2003. MRSA colonization was detected in patients by using active surveillance cultures (ASCs) of nasal swab specimens obtained within 48 hours of ICU entry and 3 times weekly thereafter. The duration of colonization during ICU stay and before ICU entry was calculated after a review of surveillance culture results, clinical culture results, and medical history. RESULTS: Ninety-three (11.0%) of 845 ICU admissions involved patients who were colonized with MRSA at the time of ICU entry, and 21 admissions (2.5%) involved patients who acquired MRSA during ICU stay. ASCs were positive for MRSA in 84 (73.6%) of the 114 admissions associated with MRSA positivity and were the sole means of identifying MRSA in 50 cases (43.8%). More than half of the MRSA-associated admissions involved patients who were transferred from hospital wards. The total bed-days of care for 38 admissions involving patients who tested positive for MRSA before ICU entry (1131 days) was nearly 20% higher than the total bed-days of care for all admissions associated with MRSA positivity (970 days). Admissions involving MRSA-positive patients were associated with a longer length of hospitalization before ICU entry (P < .001), longer length of ICU stay (P < .001), longer overall length of hospitalization (P < .001), and greater inpatient mortality than admissions involving MRSA-negative patients (P < .001). A total of 22.8% of all bed-care days were dedicated to MRSA-positive patients in the ICU, and 55 (48.2%) of 114 admissions associated with MRSA positivity involved patients who were colonized for the duration of their ICU stay. CONCLUSIONS: In our unit, ASCs were an effective means to identify MRSA colonization among patients admitted to the ICU. Unfortunately, the majority of identified patients had long durations of stay in our own hospital before ICU entry, with prolonged MRSA colonization. Enhanced efforts to control MRSA will have to account for the prevalence of MRSA within hospital wards and to direct control efforts at these patients in the future.

Preventing catheter-associated bloodstream infections: a survey of policies for insertion and care of central venous catheters from hospitals in the prevention epicenter program.

OBJECTIVE: To determine the extent to which evidence-based practices for the prevention of central venous catheter (CVC)-associated bloodstream infections are incorporated into the policies and practices of academic intensive care units (ICUs) in the United States and to determine variations in the policies on CVC insertion, use, and care. DESIGN: A 9-page written survey of practices and policies for nontunneled CVC insertion and care. SETTING: ICUs in 10 academic tertiary-care hospitals. PARTICIPANTS: ICU medical directors and nurse managers. RESULTS: Twenty-five ICUs were surveyed (1-6 ICUs per hospital). In 80% of the units, 5 separate groups of clinicians inserted 24%-50% of all nontunneled CVCs. In 56% of the units, placement of more than two-thirds of nontunneled CVCs was performed in a single location in the hospital. Twenty units (80%) had written policies for CVC insertion. Twenty-eight percent of units had a policy requiring maximal sterile-barrier precautions when CVCs were placed, and 52% of the units had formal educational programs with regard to CVC insertion. Eighty percent of the units had a policy requiring staff to perform hand hygiene before inserting CVCs, but only 36% and 60% of the units required hand hygiene before accessing a CVC and treating the exit site, respectively. CONCLUSION: ICU policy regarding the insertion and care of CVCs varies considerably from hospital to hospital. ICUs may be able to improve patient outcome if evidence-based guidelines for CVC insertion and care are implemented.

Microarray transcription analysis of clinical Staphylococcus aureus isolates resistant to vancomycin.

The transcriptomes of vancomycin intermediate-resistance Staphylococcus aureus (VISA) clinical isolates HIP5827 and Mu50 (MIC = 8 micro g/ml) were compared to those of highly vancomycin-resistant S. aureus (VRSA; MIC = 32 micro g/ml) passage derivatives by microarray. There were 35 genes with increased transcription and 16 genes with decreased transcription in common between the two VRSAs compared to those of their VISA parents. Of the 35 genes with increased transcription, 15 involved purine biosynthesis or transport, and the regulator (purR) of the major purine biosynthetic operon (purE-purD) was mutant. We hypothesize that increased energy (ATP) is required to generate the thicker cell walls that characterize resistant mutants.

mecA-blaZ corepressors in clinical Staphylococcus aureus isolates.

The presence and nucleotide sequences of the two mecA repressors, mecI and blaI, were assessed in 73 clinical Staphylococcus aureus isolates. Isolates with mecI mutations were grouped into unique clonal types based on their spa nucleotide repeat patterns. Forty-three of the 45 (96%) isolates with mutant mecI or with a deletion of mecI contained blaI, while blaI was present in only 21 of 28 (78%) isolates with wild-type mecI (P < 0.05). Among 22 additional isolates that did not contain blaI, all had wild-type mecI sequences. We conclude that oxacillin-resistant S. aureus must have at least one of the two functional mecA regulators.

Occurrence of extended-spectrum and AmpC beta-lactamases in bloodstream isolates of Klebsiella pneumoniae: isolates harbor plasmid-mediated FOX-5 and ACT-1 AmpC beta-lactamases.

We tested 190 Klebsiella pneumoniae bloodstream isolates recovered from 189 patients in 30 U.S. hospitals in 23 states to determine the occurrence of extended-spectrum beta-lactamase (ESBL) and AmpC beta-lactamase producers. Based on growth inhibition by clavulanic acid by disk and MIC test methods, 18 (9.5%) of the isolates produced ESBLs. Although the disk diffusion method with standard breakpoints identified 28 cefoxitin-nonsusceptible isolates, only 5 (18%) of these were confirmed as AmpC producers. Of two AmpC confirmatory tests, the three-dimensional extract test was easier to perform than was the double-disk approximation test using a novel inhibitor, Syn2190. Three of the five AmpC producers carried the bla(FOX-5) gene, while the other two isolates harbored the bla(ACT-1) gene. All AmpC genes were transferable. In vitro susceptibility testing with standard inocula showed that all five AmpC-producing strains were susceptible to cefepime, imipenem, and ertapenem but that with a high inoculum, more of these strains were susceptible to the carbapenems than to cefepime. All but 1 of 14 screen-positive AmpC nonproducers (and ESBL nonproducers) were susceptible to ceftriaxone and cefepime at the standard inoculum as were 6 of 6 isolates that were randomly selected and tested with a high inoculum. These results indicate that (i). a significant number of K. pneumoniae bloodstream isolates harbor ESBL or AmpC beta-lactamases, (ii). confirmatory tests are necessary to identify true AmpC producers, and (iii). in vitro, carbapenems are active against AmpC-producing strains of K. pneumoniae.

Combinations of lysostaphin with beta-lactams are synergistic against oxacillin-resistant Staphylococcus epidermidis.

Oxacillin-resistant Staphylococcus aureus is rapidly killed by the endopeptidase lysostaphin, and the addition of beta-lactam antibiotics provides synergistic killing. We investigated the possibility that beta-lactams given in combination with lysostaphin would improve the activity of lysostaphin against oxacillin-resistant Staphylococcus epidermidis (ORSE), which is normally less susceptible to lysostaphin. Checkerboard synergy testing was performed for lysostaphin given in combination with oxacillin against 10 ORSE isolates for which the lysostaphin MICs were > o r= 8 microg/ml. The fractional inhibitory concentration index ranged from 0.0234 to 0.2656, indicating synergy, which was confirmed in growth curve experiments. In the rabbit model of experimental aortic valve endocarditis using an ORSE strain, the combination of lysostaphin and nafcillin was as effective as vancomycin alone and significantly better than lysostaphin or nafcillin alone. We conclude that beta-lactam antibiotics given in combination with lysostaphin are synergistic against many strains of ORSE.