Vancomycin taper followed by pulse and fidaxomicin are two common treatments for recurrent C. difficile infection (rCDI) but they have not been formally compared.Kaplan-Meier plot of days from symptom resolution to recurrences of diarrhea [A] and recurrent C. difficile infection (rCDI) [B] in the modified intent-to-treat population. We conducted a randomized, double-blind trial of vancomycin taper and pulse (VAN-TP, 125 mg four times daily for 10d, followed by a once daily, once every other day, and once every third day, each for 7 days) and fidaxomicin (FDX, 200 mg twice daily for 10d) compared to vancomycin (VAN, 125 mg four times daily for 10d) for patients with a first or second rCDI episode. The primary study endpoint was sustained clinical response (SCR) at day 59 using a diarrhea composite outcome (D-COM) in modified intent to treat analysis (mITT). Secondary outcomes included SCR without rCDI (CDI-COM), diarrhea resolution at day 10, recurrent diarrhea and rCDI. 308 participants were randomized to 1 of the 3 arms. Sustained D-COM was higher for VAN-TP (58.6%) than for VAN (44.1%) at day 59 (Unadjusted P=0.04, Z-statistic scores at 2.03-2.08, efficacy boundary 2.234 controlling the FWER at 0.05, mITT). Sustained CDI-COM was also higher for VAN-TP (64.8%) than for VAN (48.4%) (P=0.05). There was no difference in D-COM or CDI-COM at day 59 between FDX and VAN (D-COM: 44.1% vs. 44.1%, P=1.00; CDI-COM: 51.8% vs. 48.4%, P=0.86). Symptom resolution by day 10 was greater than 90% for all three groups. CDI recurrence, but not diarrhea recurrence was less common in VAN-TP than in VAN at day 59 (rCDI: 26.6% versus 43.6%, P=0.05; diarrhea recurrence: 34.1% vs. 49.4%, P=0.08). Survival estimates for days from symptom resolution to diarrhea recurrence (Fig A) and CDI recurrence (Fig B) show separation by day 20 which continues to day 90 for VAN-TP compared to VAN. A tapered and pulsed regimen of vancomycin following a standard treatment course was superior to a standard course of vancomycin for sustained resolution of diarrhea and CDI at day 59 in patients with recurrent CDI. A standard course of fidaxomicin was not different from a standard course of vancomycin in this population. All Authors: No reported disclosures

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 paucirCDI. 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).

BACKGROUND—Results of previous single center observational studies suggest that daily bathing of patients with chlorhexidine may prevent hospital-acquired bloodstream infections (HABSIs) and acquisition of multidrug-resistant organisms (MDROs). METHODS—We conducted a multicenter, cluster randomized, non-blinded crossover trial to evaluate the effect of daily bathing with chlorhexidine impregnated washcloths on the acquisition of MDROs and incidence of HABSIs. Nine intensive care and bone marrow transplant units in 6 hospitals were randomly assigned to bathe patients with either 2% no-rinse chlorhexidineimpregnated or non-antimicrobial washcloths for a six-month period, exchanged for the alternate product during the subsequent six months. The incidence rates of acquisition of MDRO and HABSI rates were compared between the two time periods by Poisson regression analysis. RESULTS—A total of 7735 patients were enrolled during the study. The overall MDRO acquisition rate was 21% lower when chlorhexidine bathing was used (5.10 cases per 1000 patient days) than when non-antimicrobial washcloths were used (6.60 cases per 1000 patient days, p=0.028). The overall HABSI rate was 31% lower when chlorhexidine was used (4.45 cases per 1000 patient days) than when non-antimicrobial cloths were used (6.60 cases per 1000 patient days, p=0.007) No serious skin reactions were noted in either study period. CONCLUSIONS—Daily bathing with chlorhexidine-impregnated washcloths significantly reduced the risk of acquiring MDROs and developing HABSI. Corresponding Author: Michael Climo, M.D., McGuire VAMC, 1201 Broad Rock Boulevard, Section 111-C, Richmond, Virginia 23236, Telephone (804) 675-5018, Fax (804) 675-5437, michael.climo@va.gov. Alternate Corresponding Author: Edward Wong, McGuire VAMC, 1201 Broad Rock Boulevard, Section 111-C, Richmond, Virginia 23236, Telephone (804) 675-5000 ext 6792, Fax (804) 675-5437, Edward.wong@va.gov. HHS Public Access Author manuscript N Engl J Med. Author manuscript; available in PMC 2017 November 27. Published in final edited form as: N Engl J Med. 2013 February 07; 368(6): 533–542. doi:10.1056/NEJMoa1113849. A uhor M anscript

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.).

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 В 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.

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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.

ABSTRACT Among 23 patients carrying methicillin-resistant Staphylococcus aureus (MRSA) in their anterior nares, 6 (26%) also carried methicillin-susceptible S. aureus (MSSA) as less prevalent flora. In 4 of the 6 patients, the MSSA was unrelated to prevalent MRSA, as determined by pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and staphylococcal protein A (spa) typing. However, in two patients, the strains were identical except for the absence of spontaneous staphylococcal cassette chromosome mec (SCCmec). We consider this evidence of spontaneous SCCmec excision in vivo.

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.

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Background. Screening methods that use automated data may streamline surgical site infection (SSI) surveillance and improve the accuracy and comparability of data on SSIs. We evaluated the use of automated inpatient diagnosis codes and pharmacy data to identify SSIs after arthroplasty.Methods. This retrospective cohort study at 8 hospitals involved weighted, random samples of medical records from 2128 total hip arthroplasty (THA) procedures performed from 1 July 2002 through 30 June 2004, and 4194 total knee arthroplasty (TKA) procedures performed from 1 July 2003 through 30 June 2005. We compared routine surveillance with screening of inpatient pharmacy data and diagnoses codes followed by medical record review to confirm SSI status.Results. Records from 696 THA and 1009 TKA procedures were reviewed. The SSI rates were nearly double those determined by routine surveillance (1.32% [95% confidence interval, 0.83%-1.81%] vs. 0.75% for THA; 1.83% [95% confidence interval, 1.43%-2.23%] vs. 0.71% for TKA). An inpatient diagnosis code for infection within a year after the operation had substantially higher sensitivity (THA, 89%; TKA, 81%), compared with routine surveillance (THA, 56%; TKA, 39%). Adding antimicrobial exposure of >= 7 days after the procedure increased the sensitivity (THA, 93%; TKA, 86%). Record review confirmed SSIs after 51% of THAs and 55% of TKAs that met diagnosis code criteria and after 25% of THAs and 39% of TKAs that met antimicrobial exposure and/or diagnosis code criteria.Conclusions. Focused surveillance among a subset of patients who met diagnosis code screening criteria with or without the addition of antimicrobial exposure-based screening was more sensitive than routine surveillance for detecting SSIs after arthroplasty and could be an efficient and readily standardized adjunct to traditional methods.

Objective: Spread of multidrug-resistant organisms within the intensive rare 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 patents.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 patents bathed with chlorhexidine had a lower risk of developing VRE bacteremia (relative risk 3.35; 95% confidence interval 1.13-937; 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 (Crit Care Med 2009; 37:1858-1865)

INVASIVE INFECTIONS WITH METHICILLIN-RESISTANT STAPHYlococcus aureus (MRSA) have become a focus of national attention over the past several years due to their potentially lethal complications and reports indicating that their frequency is on the rise in most US hospitals. Hospitalizations with infections due to MRSA steadily increased between 2000 and 2005, nearly doubling in many areas of the country. Klevens et al estimated that up to 18 650 deaths in the United States in 2005 may have been associated with invasive MRSA infection. These statistics coupled with the increasing number of outbreaks of MRSA infections in community settings have helped ignite a contentious public debate about the best means of control, including calls for increased surveillance for MRSA infections, new prevention activities such as screening of all patients admitted to hospitals to detect colonization with MRSA (universal screening), and public reporting of hospitalacquired MRSA infections. Now amidst this alarm, the report by Burton and colleagues in this issue of JAMA documents decreases in the rate of MRSA-related central line–associated bloodstream infections (CLABSI) in hospitals participating in a voluntary surveillance network. This network was initially known as the National Nosocomial Infection Surveillance system (NNIS, 1997-2004) and later as the National Healthcare Safety Network (NHSN, 2006-2007). Facilities participating in NNIS/NSHN report to the Centers for Disease Control and Prevention (CDC) all health care–acquired infections detected during prospective surveillance in a variety of units. The current report details the experience with MRSA CLABSI in intensive care units (ICUs) from 1997 to 2007 and demonstrates that despite an overall increase in the incidence of MRSA infections, the rate of MRSA CLABSI decreased 49.6% at NNIS/NSHN hospitals. Four types of ICUs (surgical, cardiothoracic, coronary, and medical/surgical without a major teaching affiliation) initially experienced an increase in MRSA CLABSI lasting until 2001, but this was followed by declining rates through 2007. All units, except pediatric ICUs, experienced an overall decline in infections from 2002-2007. Moreover, both the overall rate of CLABSI and methicillin-sensitive S aureus (MSSA) CLABSI showed steady declines from 1997 to 2007 among all types of ICUs. Although the report by Burton et al suggests ICUs are having increasing success limiting the spread of MRSA, the study is not without limitations. The first concern is the dynamic nature of NNIS/NHSN. Fewer than 6% of ICUs in the current study participated in the NNIS/NHSN for the entire 11-year study interval. A large number of hospitals entered the network for the first time in 2007 prompted by mandatory public reporting requirements in many states, highlighting the changing nature of the network and challenging its description as a voluntary, hospital-based reporting system. In addition, although the authors contend that voluntary self-reporting was most likely accurate, it has not been validated since 1998. The accuracy of selfreporting may be an important issue in the upcoming era of mandatory public reporting and increased scrutiny of hospital-acquired infections by regulatory agencies. The study also leaves the unsettling realization that the observed reductions in infection cannot be attributed to any particular intervention. Previous reports from NNISparticipating ICUs have demonstrated reductions in bloodstream infections, ventilator-associated pneumonias, and catheter-associated urinary tract infections. These reports have led to the conclusion that prospective surveillance followed by careful local risk assessment and adoption of interventions that include best practices can be used to reduce hospital-acquired infection rates. It is likely that the reductions in infections reported by Burton et al were related to a range of interventions that have been implemented during the last decade including better hand hygiene practices, adoption of standardized line insertion and care practices, proper barrier precautions, improved catheter technology, and shorter periods of indwelling catheter use in patients. Thus, it is impossible to determine which practices had the greatest effect or even which were implemented by participating ICUs. Can the end be justified by the means, when the means are unknown?

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BACKGROUNDRoutine 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.METHODSWe 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.RESULTSWe 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%).CONCLUSIONSRoutine 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.

OBJECTIVE:To determine whether the use of chlorhexidine bathing and intranasal mupirocin therapy among patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) would decrease the incidence of MRSA colonization and infection among intensive care unit (ICU) patients.METHODS:After a 9-month baseline period (January 13, 2003, through October 12, 2003) during which all incident cases of MRSA colonization or infection were identified through the use of active-surveillance cultures in a combined medical-coronary ICU, all patients colonized with MRSA were treated with intranasal mupirocin and underwent daily chlorhexidine bathing.RESULTS:After the intervention, incident cases of MRSA colonization or infection decreased 52% (incidence density, 8.45 vs 4.05 cases per 1,000 patient-days; P=.048). All MRSA isolates remained susceptible to chlorhexidine; the overall rate of mupirocin resistance was low (4.4%) among isolates identified by surveillance cultures and did not increase during the intervention period.CONCLUSIONS:We conclude that the selective use of intranasal mupirocin and daily chlorhexidine bathing for patients colonized with MRSA reduced the incidence of MRSA colonization and infection and contributed to reductions identified by active-surveillance cultures. This finding suggests that additional strategies to reduce the incidence of MRSA infection and colonization--beyond expanded surveillance--may be needed.

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.