Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.

Antimicrobial resistance is a global threat. As "proof-of-concept," we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting 30-day mortality. Isolates exposed to COL+CAZ/AVI had enhanced early bacterial killing compared to CAZ/AVI alone and fewer incidences of regrowth compared to COL and CAZ/AVI. The mean coefficient of determination (R2) for the observed versus predicted bacterial counts was 0.86 (range: 0.75 - 0.95). Bacterial subpopulation susceptibilities and drug mechanistic synergy were essential to describe bacterial killing and growth dynamics. The combination of clinical (hypotension), bacterial (IncR plasmid, aadA2, and sul3) and drug (KC50) variables were most predictive of 30-day mortality. This proof-of-concept study combined clinical, bacterial, and drug variables in a unified model to evaluate clinical outcomes.

Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections.

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).

Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-based Regimens for the Treatment of Drug-resistant Pseudomonas aeruginosa.

BACKGROUND: Ceftolozane/tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination that often retains activity against resistant Pseudomonas aeruginosa. The comparative safety and efficacy vs polymyxins or aminoglycosides in this setting remains unknown. METHODS: A retrospective, multicenter, observational cohort study was performed. Patients who received ceftolozane/tazobactam were compared with those treated with either polymyxin or aminoglycoside-based regimens for infections due to drug-resistant P. aeruginosa. Multivariate logistic regression was performed controlling for factors associated with treatment to assess the independent impact of ceftolozane/tazobactam on clinical cure, acute kidney injury (AKI), and in-hospital mortality. RESULTS: A total of 200 patients were included (100 in each treatment arm). The cohort represented an ill population with 69% in the intensive care unit, 63% mechanically ventilated, and 42% in severe sepsis or septic shock at infection onset. The most common infection type was ventilator-associated pneumonia (52%); 7% of patients were bacteremic. Combination therapy was more commonly used in polymyxin/aminoglycoside patients than those who received ceftolozane/tazobactam (72% vs 15%, P < .001). After adjusting for differences between groups, receipt of ceftolozane/tazobactam was independently associated with clinical cure (adjusted odds ratio [aOR], 2.63; 95% confidence interval [CI], 1.31-5.30) and protective against AKI (aOR, 0.08; 95% CI, 0.03-0.22). There was no difference in in-hospital mortality. The number needed to treat for a clinical cure with ceftolozane/tazobactam was 5, and the number needed to harm with AKI with a polymyxin/aminoglycoside was 4. CONCLUSIONS: These data support the preferential use of ceftolozane/tazobactam over polymyxins or aminoglycosides for drug-resistant P. aeruginosa infections.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.

The hypothetical impact of Accelerate Pheno™ system on time to effective therapy and time to definitive therapy in an institution with an established antimicrobial stewardship programme currently utilizing rapid genotypic organism/resistance marker identification.

Background: Rapid organism identification and antimicrobial susceptibility testing (AST) can optimize antimicrobial therapy in patients with bacteraemia. The Accelerate Pheno™ system (ACC) can provide identification and AST results within 7 h of a positive culture. Objectives: To assess the hypothetical impact of ACC on time to effective therapy (TTET), time to definitive therapy (TTDT) and antimicrobial usage at the Detroit Medical Center (DMC). Methods: Patients with positive blood cultures from 29 March to 24 June 2016 were included. ACC was performed in parallel with normal laboratory procedures, but results were not made available to the clinicians. The potential benefit of having ACC results was determined if clinicians modified therapy based on actual AST results. Potential changes in TTET, TTDT and antibiotic usage were calculated. Results: One hundred and sixty-seven patients were included. The median TTET was 2.4 h (IQR 0.5, 15.1). Had ACC results been available, TTET could have been improved in four patients (2.4%), by a median decrease of 18.9 h (IQR 11.3, 20.4). The median TTDT was 41.4 h (IQR 21.7, 73.3) and ACC results could have improved TTDT among 51 patients (30.5%), by a median decrease of 25.4 h (IQR 18.7, 37.5). ACC implementation could have led to decreases in usage of cefepime (16% reduction), aminoglycosides (23%), piperacillin/tazobactam (8%) and vancomycin (4%). Conclusions: ACC results could potentially improve time to de-escalation and reduce use of antimicrobials. The impact of ACC on TTET was small, likely related to the availability of other rapid diagnostic tests at DMC.

The Hypothetical Impact of Accelerate Pheno on Time to Effective Therapy and Time to Definitive Therapy for Bloodstream Infections Due to Drug-Resistant Gram-Negative Bacilli.

Strategies are needed to improve time to optimal therapy in patients with bloodstream infections (BSI) due to resistant Gram-negative (GN) pathogens. Accelerate Pheno (ACC) can provide antimicrobial susceptibility results within 7 h of a positive culture and may more rapidly optimize therapy. The primary objective of this study was to evaluate the hypothetical impact of ACC on time to effective therapy (TTET) and time to definitive therapy (TTDT) among patients with BSI due to resistant GN pathogens. ACC was performed on resistant GN BSI isolates, and results were not available to clinicians in real time. A potential benefit of having ACC on TTET or TTDT was determined if modifications to antimicrobial regimens could have been made sooner with ACC. Comparisons on the impact of ACC in the presence or absence of testing by the Verigene Gram-negative blood culture test (Verigene GN-BC) were performed. Sixty-one patients with resistant GN BSI were evaluated. The median actual TTET and TTDT in the cohort were 25.9 h (interquartile range [IQR], 18.5, 42.1) and 47.6 h (IQR, 24.9, 79.6), respectively. Almost half of the patients had potential improvement in TTET and/or TTDT with ACC. In patients who would have had a benefit the median potential decreases in TTET and TTDT were 16.6 h (IQR, 5.5 to 30.6) and 29.8 h (IQR, 13.6 to 43), respectively. The largest potential improvements were seen in patients for whom Verigene results were not available. In conclusion, among patients with resistant GN BSI in a setting where other rapid diagnostic technologies are utilized, ACC results could have further improved TTET and TTDT.

In Vitro Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae.

The multidrug resistance profiles of Klebsiella pneumoniae carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the in vitro activity of polymyxin B and minocycline combination therapy against six KPC-2-producing K. pneumoniae isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing K. pneumoniae is dependent on polymyxin B susceptibility. Further in vitro and animal studies must be performed to fully evaluate the efficacy of this drug combination.

Old antibiotics for multidrug-resistant pathogens: from in vitro activity to clinical outcomes.

Antimicrobial resistance is a major and emerging threat worldwide. New antimicrobials have been unable to meet the resistance challenge, and treatment options are limited for a growing number of resistant pathogens. More and more clinicians are relying on older antimicrobials for the treatment of multidrug-resistant (MDR) bacteria. Some older antimicrobials have maintained excellent in vitro activity against highly resistant pathogens. In some instances, use of older agents is limited by unfavourable pharmacokinetic/pharmacodynamic characteristics and/or toxicities. In general, clinical data pertaining to the use of older agents for the treatment of MDR pathogens are scarce. Research efforts should be focused on the evaluation of older agents for the treatment of MDR pathogens as well as evaluating how these agents perform in complex patient populations with various and multiple co-morbid conditions.

Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality.

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.

Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.

Vancomycin remains the mainstay treatment for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) despite increased treatment failures. Daptomycin has been shown to improve clinical outcomes in patients with BSIs caused by MRSA isolates with vancomycin MICs of >1 mg/liter, but these studies relied on automated testing systems. We evaluated the outcomes of BSIs caused by MRSA isolates for which vancomycin MICs were determined by standard broth microdilution (BMD). A retrospective, matched cohort of patients with MRSA BSIs treated with vancomycin or daptomycin from January 2010 to March 2015 was completed. Patients were matched using propensity-adjusted logistic regression, which included age, Pitt bacteremia score, primary BSI source, and hospital of care. The primary endpoint was clinical failure, which was a composite endpoint of the following metrics: 30-day mortality, bacteremia with a duration of ≥7 days, or a change in anti-MRSA therapy due to persistent or worsening signs or symptoms. Secondary endpoints included MRSA-attributable mortality and the number of days of MRSA bacteremia. Independent predictors of failure were determined through conditional backwards-stepwise logistic regression with vancomycin BMD MIC forced into the model. A total of 262 patients were matched. Clinical failure was significantly higher in the vancomycin cohort than in the daptomycin cohort (45.0% versus 29.0%; P = 0.007). All-cause 30-day mortality was significantly higher in the vancomycin cohort (15.3% versus 6.1%; P = 0.024). These outcomes remained significant when stratified by vancomycin BMD MIC. There was no significant difference in the length of MRSA bacteremia. Variables independently associated with treatment failure included vancomycin therapy (adjusted odds ratio [aOR] = 2.16, 95% confidence interval [CI] = 1.24 to 3.76), intensive care unit admission (aOR = 2.46, 95% CI = 1.34 to 4.54), and infective endocarditis as the primary source (aOR = 2.33, 95% CI = 1.16 to 4.68). Treatment of MRSA BSIs with daptomycin was associated with reduced clinical failure and 30-day mortality; these findings were independent of vancomycin BMD MIC.

Clinical and Epidemiological Significance of Carbapenem Resistance in Acinetobacter baumannii Infections.

Carbapenems are considered the treatment of choice for Acinetobacter baumannii infections. Many facilities implement preventive measures toward only carbapenem-resistant A. baumannii (CRAB). However, the independent role of the carbapenem resistance determinant on patient outcomes remains controversial. In a 6-year analysis of adults with A. baumannii bloodstream infection (BSI), the outcomes of 149 CRAB isolates were compared to those of 91 patients with carbapenem-susceptible A. baumannii In bivariable analyses, CRAB BSIs were significantly associated with worse outcomes and with a delay in the initiation of appropriate antimicrobial therapy (DAAT). However, in multivariable analyses, carbapenem resistance status was no longer associated with poor outcomes, while DAAT remained an independent predictor. The epidemiological significance of A. baumannii should not be determined by its resistance to carbapenems.

Hospital Readmissions in Patients With Carbapenem-Resistant Klebsiella pneumoniae.

BACKGROUND: Various transmission routes contribute to spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospitalized patients. Patients with readmissions during which CRKP is again isolated ("CRKP readmission") potentially contribute to transmission of CRKP. OBJECTIVE: To evaluate CRKP readmissions in the Consortium on Resistance against Carbapenems in K. pneumoniae (CRaCKLe). DESIGN: Cohort study from December 24, 2011, through July 1, 2013. SETTING: Multicenter consortium of acute care hospitals in the Great Lakes region. PATIENTS: All patients who were discharged alive during the study period were included. Each patient was included only once at the time of the first CRKP-positive culture. METHODS: All readmissions within 90 days of discharge from the index hospitalization during which CRKP was again found were analyzed. Risk factors for CRKP readmission were evaluated in multivariable models. RESULTS: Fifty-six (20%) of 287 patients who were discharged alive had a CRKP readmission. History of malignancy was associated with CRKP readmission (adjusted odds ratio [adjusted OR], 3.00 [95% CI, 1.32-6.65], P<.01). During the index hospitalization, 160 patients (56%) received antibiotic treatment against CRKP; the choice of regimen was associated with CRKP readmission (P=.02). Receipt of tigecycline-based therapy (adjusted OR, 5.13 [95% CI, 1.72-17.44], using aminoglycoside-based therapy as a reference in those treated with anti-CRKP antibiotics) was associated with CRKP readmission. CONCLUSION: Hospitalized patients with CRKP-specifically those with a history of malignancy-are at high risk of readmission with recurrent CRKP infection or colonization. Treatment during the index hospitalization with a tigecycline-based regimen increases this risk.

Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus.

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

Impact of different antimicrobial therapies on clinical and fiscal outcomes of patients with bacteremia due to vancomycin-resistant enterococci.

Vancomycin-resistant enterococci (VRE) are a growing health problem, and uncertainties exist regarding the optimal therapy for bloodstream infection due to VRE. We conducted systematic comparative evaluations of the impact of different antimicrobial therapies on the outcomes of patients with bloodstream infections due to VRE. A retrospective study from January 2008 to October 2010 was conducted at Detroit Medical Center. Unique patients with blood cultures due to VRE were included and reviewed. Three major therapeutic classes were analyzed: daptomycin, linezolid, and ß-lactams. Three multivariate models were conducted for each outcome, matching for a propensity score predicting the likelihood of receipt of one of the therapeutic classes. A total of 225 cases of bacteremia due to VRE were included, including 86 (38.2%) cases of VR Enterococcus faecalis and 139 (61.8%) of VR Enterococcus faecium. Bacteremia due to VR E. faecalis was more frequent among subjects treated with ß-lactams than among those treated with daptomycin or linezolid. The median dose of daptomycin was 6 mg/kg of body weight (range, 6 to 12 mg/kg). After controlling for propensity score and bacteremia due to VR E. faecalis, differences in mortality were nonsignificant among the treatment groups. Therapy with daptomycin was associated with higher median variable direct cost per day than that for linezolid. This large study revealed the three therapeutic classes (daptomycin, linezolid, and ß-lactams) are similarly efficacious in the treatment of bacteremia due to susceptible strains of VRE.

Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study.

BACKGROUND: Recent reports have described decreased effectiveness with vancomycin treatment for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) when the vancomycin minimum inhibitory concentration (MIC) is >1 µg/mL. METHODS: This matched, retrospective cohort study compared the clinical effectiveness of daptomycin with that of vancomycin for the treatment of MRSAB with vancomycin MICs >1 µg/mL. The primary outcome was clinical failure, defined as a composite of 30-day mortality or bacteremia persisting for ≥7 days. RESULTS: One hundred seventy patients were matched 1:1 with respect to the antimicrobial administered. In the daptomycin group, all patients received <72 hours of vancomycin (median, 1.7 days [interquartile range, 1.1-2.3 days]) prior to switching to daptomycin. The rate of clinical failure at 30 days was significantly lower in the daptomycin arm compared to the vancomycin arm (20.0% vs 48.2%; P < 0.001). Both 30-day mortality and persistent bacteremia were significantly lower in the daptomycin group compared to the vancomycin group (3.5% vs 12.9% [P = .047] and 18.8% vs 42.4% [P = .001], respectively). Logistic regression confirmed the association between vancomycin treatment and increased risk of clinical failure (adjusted odds ratio, 4.5; 95% confidence interval, 2.1-9.8). CONCLUSIONS: This is the first matched study comparing early daptomycin versus vancomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL. Treatment with daptomycin resulted in significantly improved outcomes, including decreased 30-day mortality and persistent bacteremia. These results support the practice of switching early from vancomycin to daptomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL.

Comparative epidemiology of bacteremia due to methicillin-resistant Staphylococcus aureus between older and younger adults: a propensity score analysis.

OBJECTIVE: We evaluated the clinical and molecular epidemiology of bloodstream infections (BSIs) due to methicillin-resistant Staphylococcus aureus (MRSA) in older versus younger patients treated with vancomycin, determining the independent effect of increased age on outcomes. DESIGN: Observational retrospective cohort study. SETTING: Detroit Medical Center, level I trauma center. PATIENTS: Adult older (65 years and older) and younger (younger than 65 years) patients with documented BSIs due to MRSA treated with vancomycin (2005-2010). METHODS: Collected demographics, comorbidities, microbiology, treatment, outcomes. Multivariable model used to generate propensity score for each patient on the basis of the probability of being 65 years of age or older. RESULTS: Three hundred twenty patients were eligible (69 patients 65 years and older; 251 patients younger than 65 years). Catheter-related infections and endocarditis were the most common sites of infection for older (20.3%) and younger (19.1%) adults, respectively. Median first total 24-hour vancomycin dose (1,000 vs 2,000 mg; [Formula: see text]) and initial trough (13.1 vs 15.0 mg/L; [Formula: see text]) was significantly lower in older versus younger patients. Vancomycin treatment failure rates were similar among older and younger patients (49.3% vs 53.4%; [Formula: see text]). In multivariable analysis of outcomes, after controlling for predictors of older age, there was no difference in clinical outcomes between older and younger adults. CONCLUSIONS: After accounting for confounders associated with increased age, failure rate of patients with BSIs due to MRSA treated with vancomycin was similar between older and younger patients. Older adults were less likely to have optimal vancomycin dosing and initial trough levels than younger patients. Efforts should be made to optimize dosing of medications such as vancomycin in older adults.

Treatment of methicillin-resistant Staphylococcus aureus infections with a minimal inhibitory concentration of 2 µg/mL to vancomycin: old (trimethoprim/sulfamethoxazole) versus new (daptomycin or linezolid) agents.

BACKGROUND: Guidelines recommend that agents other than vancomycin be considered for some types of infection due to methicillin-resistant Staphylococcus aureus (MRSA) when the minimum inhibitory concentration (MIC) to vancomycin is 2 µg/mL or more. Alternative therapeutic options include daptomycin and linezolid, 2 relatively new and expensive drugs, and trimethoprim/sulfamethoxazole (TMP/SMX), an old and inexpensive agent. OBJECTIVE: To compare the clinical efficacy and potential cost savings associated with use of TMP/SMX compared to linezolid and daptomycin. METHODS: A retrospective study was conducted at Detroit Medical Center. For calendar year 2009, unique adults (age >18 years) with infections due to MRSA with an MIC to vancomycin of 2 µg/mL were included if they received 2 or more doses of TMP/SMX and/or daptomycin and/or linezolid. Data were abstracted from patient charts and pharmacy records. RESULTS: There were 328 patients included in the study cohort: 143 received TMP/SMX alone, 89 received daptomycin alone, 75 received linezolid alone, and 21 patients received a combination of 2 or more of these agents. In univariate analysis, patients who received TMP/SMX alone had significantly better outcomes, including in-hospital (p = 0.003) and 90-day mortality (p < 0.001) compared to patients treated with daptomycin or linezolid. Patients receiving TMP/SMX were also younger (p < 0.001), had fewer comorbid conditions (p < 0.001), had less severe acute severity of illness (p < 0.001), and received appropriate therapy more rapidly (p = 0.001). In multivariate models the association between TMP/SMX treatment and mortality was no longer significant. Antimicrobial cost savings associated with using TMP/SMX averaged $2067.40 per patient. CONCLUSIONS: TMP/SMX monotherapy compared favorably to linezolid and daptomycin in terms of treatment efficacy and mortality. Use of TMP/SMX instead of linezolid or daptomycin could potentially significantly reduce antibiotic costs. TMP/SMX should be considered for the treatment of MRSA infection with MIC of 2 µg/mL to vancomycin.

Fluconazole-resistant Candida albicans vulvovaginitis.

OBJECTIVE: As a result of high recurrence rates of Candida albicans vaginitis, successful suppressive fluconazole is widely used, and drug resistance is considered rare. We report increased occurrence of secondary fluconazole resistance, analysis of risk factors thereof, and describe management of fluconazole-refractory vaginitis. METHODS: Patients referred to the Vaginitis Clinic at Wayne State University with clinically refractory fluconazole-resistant (minimum inhibitory concentration [MIC] 2 micrograms/mL or greater) C albicans vaginitis from 2000 to 2010 were enrolled. Patients completed a questionnaire pertaining to demographics, comorbidities, behavioral characteristics, exposure to antimicrobials and antifungals, fluconazole consumption in defined daily doses in the previous 6 months, management received, and outcomes. With patients not located, data were extracted from charts. Susceptibilities to antifungals were determined by broth microdilution. RESULTS: Twenty-five women with fluconazole-resistant recurrent C albicans vaginitis were identified, and 16 returned filled questionnaires. Study cohort consisted mainly of married, insured white women with more than 12 years of formal education and average or above average socioeconomic status. Median fluconazole MIC was 8 micrograms/mL (range 2-128 micrograms/mL). Risk factors for mycologic failure included increased fluconazole consumption (P=.03) with 16 of 25 women exposed to low-dose weekly fluconazole maintenance therapy. All patients were clinically controlled successfully, although treatment was difficult and often prolonged. CONCLUSION: Fluconazole-resistant C albicans vaginitis was previously considered rare. We report 25 cases over an 11-year period, indicating an emerging problem. All patients had fluconazole consumption in the previous 6 months. Management of fluconazole refractory disease is extremely difficult with limited options, and new therapeutic modalities are needed.