Assessment of mortality stratified by meropenem minimum inhibitory concentration in patients with Enterobacteriaceae bacteraemia: A patient-level analysis of published data.

In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered carbapenem breakpoints to reduce the proportion of 'susceptible' organisms that produced carbapenemases. Few studies have evaluated the effect of this change on clinical outcomes. This systematic review aimed to evaluate the effect of carbapenem MICs on 30-day mortality from pooled patient-level data from studies of patients treated with carbapenems across a range of meropenem MICs. PubMed was searched to March 2019 with the terms 'carbapenem', 'meropenem', 'imipenem', 'doripenem', 'ertapenem', 'susceptibility' and 'outcomes'. Studies were included in the analysis if patients had Enterobacteriaceae bacteraemia treated with a carbapenem for ≥48 h and mortality was reported. Studies were excluded if all isolates were either susceptible or resistant to meropenem based on CLSI 2010 breakpoints or if only carbapenemase-producing isolates were included. Authors were contacted for patient-level data. The primary outcome was 30-day mortality, with planned subset analyses of patients treated with meropenem, receiving active combination therapy, treated in the ICU or infected with Klebsiella pneumoniae. Of 157 articles identified, 4 met the inclusion criteria (115 eligible patients). The odds of mortality increased with each increasing meropenem MIC dilution (OR = 1.51, 95% CI 1.06-2.15) as a continuous variable. A similar increase in odds was observed in patients treated with meropenem, treated in the ICU, infected with K. pneumoniae or receiving no other active antimicrobials. Increasing meropenem MICs in Enterobacteriaceae were associated with increased mortality; however, more work is needed to define optimal clinical decision rules for infections within the susceptible range.

Use of High-Dose Oral Valacyclovir During an Intravenous Acyclovir Shortage: A Retrospective Analysis of Tolerability and Drug Shortage Management.

INTRODUCTION: In late 2011, a shortage of IV acyclovir led to the need to empirically substitute high-dose oral valacyclovir (HDVA) to conserve IV acyclovir for patients with confirmed herpes simplex virus (HSV) meningitis or encephalitis. This report describes the management of the most recent national IV acyclovir shortage by the Antimicrobial Stewardship Program (ASP) at Northwestern Memorial Hospital (NMH), Chicago, IL, USA, and the use of HDVA. Secondarily, we assessed the safety and tolerability of HDVA as an alternate to IV acyclovir during this shortage. METHODS: We report the step-wise management, restrictions, and guidelines implemented at NMH during a protracted IV acyclovir shortage. The assessment of HDVA was a retrospective, observational cohort study of hospitalized patients receiving HDVA between 1 January 2012 and 31 December 2013. Appropriate demographic and treatment variables were collected. The primary outcome was percentage of patients experiencing an adverse event. RESULTS: There were 15 adult patients included in the study on a median daily dose of HDVA of 3 g (IQR 2-8). There were four patients with microbiologically confirmed viral CNS infections (n = 1 HSV-1, n = 2 HSV-2, n = 1 VZV encephalitis) and eleven patients with unknown causative pathogens. Six (40%) patients experienced at least one adverse drug reaction (ADR) to HDVA (thrombocytopenia, 33.3%, n = 5; headache, 6.7%, n = 1; nausea, 6.7%, n = 1; rash, 6.7%, n = 1). One patient (6.7%) was readmitted within 30 days with a suspected non-CNS infection. There were no treatment discontinuations or symptomatic therapy necessary to treat any of the ADRs. CONCLUSIONS: The shortage of IV acyclovir was successfully managed by the ASP and HDVA appeared to be well tolerated when used as an alternative to IV acyclovir.

Use of organism identification by 16S ribosomal RNA polymerase chain reaction to shorten antimicrobial length of therapy.

BACKGROUND: Organism detection by 16S ribosomal RNA (rRNA) PCR followed by amplicon sequencing identification may help guide antimicrobial treatment in culture-negative patients. The objectives of this study were to assess the effect of a positive versus negative 16S rRNA PCR on antibiotic length of therapy (LOT) and rate of antibiotic discontinuation. METHODS: Patients with a sterile site, direct-specimen 16S rRNA PCR negative, and suspected active infection were matched 1:1 with 16S rRNA PCR positive patients based on specimen site and retrospectively evaluated. RESULTS: Ninety patients were included (n=45 positive and negative). 16S rRNA PCR negative patients had shorter median LOT (33days [IQR 8-46] versus 43days [IQR 29-51], P=0.02). Antibiotics were discontinued more frequently in 16S rRNA PCR negative patients (38% versus 4%, P<0.01). CONCLUSIONS: For culture-negative patients with suspected sterile site infection, a negative, direct-specimen 16S rRNA PCR may help discontinue antibiotics and decrease LOT.

Impact of body mass index on clinical outcomes in patients with gram-negative bacteria bloodstream infections.

INTRODUCTION: Excess body mass index (BMI) is associated with a higher risk of death in many disease states, yet less is known about the impact of higher BMIs on clinical outcomes of serious bacterial infections. We sought to quantify the risk of all-cause mortality and/or organ failure following Gram negative bacteria bloodstream infections (GNBSI) according to BMI. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients with confirmed GNBSI who received ≥48 h of active antimicrobial therapy. Composite and component patient outcomes, including hospital mortality and organ failure, were assessed as a function of BMI. Organ failure was defined using modified consensus Surviving Sepsis Campaign definitions. Multi-variate methods were used to control for baseline confounders. RESULTS: Seventy-six patients met our inclusion criteria, of whom 8 died (10.5%). The majority of GNBSI were Escherichia (41.6%) or Klebsiella species (23.3%). Patients with higher BMI more frequently developed cardiovascular failure (P = 0.032), respiratory failure (P < 0.001), renal failure (P = 0.003), and died (P = 0.009). Multivariate analyses demonstrated that higher BMIs were associated with a greater risk of death and/or organ failure (aOR 1.07, 95% CI 1.01-1.14), respiratory failure (aOR 1.10, 95% CI 1.03-1.17), and renal failure (aOR 1.08, 95% CI 1.01-1.14) after adjusting for relevant covariates. CONCLUSION: Higher BMIs in patients with GNBSIs were associated with a greater risk of a composite of all-cause mortality and organ failure.

Prediction of inventory sustainability during a drug shortage.

PURPOSE: A methodology for predicting how long the on-hand inventory of a given medication will last during a supply shortage is described; a practical example of application of the methodology is provided. METHODS: Single-site data on consumption of i.v. tobramycin over an eight-month evaluation period were collected using commercial software that tabulates barcode-assisted medication administration (BCMA) events; administered doses were standardized as 1200-mg "vial-equivalents" and summed over the review period. The total number of vial-equivalents consumed was divided by the number of "non-zero weeks of consumption" (i.e., weeks during which any tobramycin use occurred) to obtain a mean ± S.D. weekly consumption rate; this rate was multiplied by the total i.v. tobramycin on-hand supply (in vial-equivalents) to determine the mean number of potentially sustainable weeks of therapy in the event a shortage were to restrict the future supply of the drug. RESULTS: Overall, 99.6 vial-equivalents of i.v. tobramycin were used during the evaluation period. The mean ± S.D. number of vial-equivalents used per non-zero week of consumption was 3.11 ± 1.26. A manual count of pharmacy inventory revealed that 102.9 vial-equivalents were available at the time of analysis. The mean predicted duration of supply was 33 weeks (95% confidence interval, -126 to 192 weeks). CONCLUSION: Available BCMA data on tobramycin consumption over eight months were used to calculate the mean number of weeks the on-hand supply of the drug could be expected to last during a persistent drug shortage.

Tree-Based Models for Predicting Mortality in Gram-Negative Bacteremia: Avoid Putting the CART before the Horse.

Increasingly, infectious disease studies employ tree-based approaches, e.g., classification and regression tree modeling, to identify clinical thresholds. We present tree-based-model-derived thresholds along with their measures of uncertainty. We explored individual and pooled clinical cohorts of bacteremic patients to identify modified acute physiology and chronic health evaluation (II) (m-APACHE-II) score mortality thresholds using a tree-based approach. Predictive performance measures for each candidate threshold were calculated. Candidate thresholds were examined according to binary logistic regression probabilities of the primary outcome, correct classification predictive matrices, and receiver operating characteristic curves. Three individual cohorts comprising a total of 235 patients were studied. Within the pooled cohort, the mean (± standard deviation) m-APACHE-II score was 13.6 ± 5.3, with an in-hospital mortality of 16.6%. The probability of death was greater at higher m-APACHE II scores in only one of three cohorts (odds ratio for cohort 1 [OR1] = 1.15, 95% confidence interval [CI] = 0.99 to 1.34; OR2 = 1.04, 95% CI = 0.94 to 1.16; OR3 = 1.18, 95% CI = 1.02 to 1.38) and was greater at higher scores within the pooled cohort (OR4 = 1.11, 95% CI = 1.04 to 1.19). In contrast, tree-based models overcame power constraints and identified m-APACHE-II thresholds for mortality in two of three cohorts (P = 0.02, 0.1, and 0.008) and the pooled cohort (P = 0.001). Predictive performance at each threshold was highly variable among cohorts. The selection of any one predictive threshold value resulted in fixed sensitivity and specificity. Tree-based models increased power and identified threshold values from continuous predictor variables; however, sample size and data distributions influenced the identified thresholds. The provision of predictive matrices or graphical displays of predicted probabilities within infectious disease studies can improve the interpretation of tree-based model-derived thresholds.

Knowledge and attitudes of doctor of pharmacy students regarding the appropriate use of antimicrobials.

Pharmacists are key partners in antimicrobial stewardship efforts, yet their degree of education on and attitudes toward this topic during training are not well documented. An electronic survey measuring knowledge and attitudes regarding antimicrobial use and resistance was administered to graduating pharmacy students at 12 US schools of pharmacy. Of 1445 pharmacy students, 579 (40%) completed the survey. The vast majority (94%) believed that strong knowledge of antimicrobials was important for their pharmacy careers, and 89% desired more education on appropriate antimicrobial use. Most students (84%) considered their pharmacy education regarding antimicrobials useful or very useful, but there was significant variability on perceptions of preparation for most antimicrobial stewardship activities according to the students' school. The mean number of correct answers on a section of 11 knowledge questions was 5.8 (standard deviation 2.0; P value for score between schools <.001). On multivariable linear regression analysis, significant predictors of a higher knowledge score were pharmacy school attended, planned postgraduate training, completion of a clinical rotation in infectious diseases, perception of pharmacy school education as useful, use of resources to answer the knowledge questions, and use of Infectious Diseases Society of America guidelines and smartphone applications as frequent resources for learning about antimicrobials. Pharmacy students perceive antimicrobial stewardship to be an important healthcare issue and desire more education on the subject. Student perceptions of antimicrobial coursework and actual antimicrobial knowledge scores significantly varied by the school of pharmacy attended. Sharing of best practices among institutions may enhance the preparation of future pharmacists to contribute to effective antimicrobial stewardship.

Pathogenicity of clinical Acinetobacter baumannii isolates in a Galleria mellonella host model according to bla(OXA-40) gene and epidemiological outbreak status.

Clinical studies have suggested that blaOXA-40-positive Acinetobacter baumannii isolates are associated with poor patient outcomes; however, reasons for unfavorable outcomes are difficult to discern in clinical studies. The objective of this study was to assess the virulence of carbapenem-resistant A. baumannii according to blaOXA-40 and epidemiological outbreak status in a Galleria mellonella model. Eight isolates of A. baumannii were studied. Nonoutbreak isolates and blaOXA-40-negative isolates more rapidly killed infected G. mellonella (P < 0.01).

Clinical implications of antiretroviral drug interactions with warfarin: a case-control study.

OBJECTIVES: Warfarin, a frequently prescribed anticoagulant with a narrow therapeutic index, is susceptible to drug-drug interactions with antiretroviral therapy (ART). This study compared the warfarin maintenance dose (WMD) between patients receiving and not receiving ART and evaluated predictors of warfarin dosage among those on ART. METHODS: This was a case-control (1:2) study. Cases were HIV-infected patients receiving warfarin and protease inhibitor (PI)- and/or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Controls were randomly selected HIV-uninfected patients receiving warfarin. The WMD was compared between cases and controls and between cases on varying ART regimens. Bivariate comparisons were performed and a linear regression model was developed to identify predictors of WMD. RESULTS: We identified 18 case and 36 control patients eligible for inclusion. Cases were younger than controls (mean age: 45.8 versus 63.1 years, P < 0.01), more often male (72.2% versus 36.1%, P=0.02) and more likely to be African American (50.0% versus 22.2%, P=0.04). ART was classified as PI-based (n=9), NNRTI-based (n=7) and PI + NNRTI-based (n=2). The WMD (mean ±â€ŠSD) differed between cases and controls (8.6  ±  3.4 mg versus 5.1 ±â€Š1.5 mg, P < 0.01), but not ART regimens (PI: 8.8  ±  4.5 mg; NNRTI: 8.6   ±â€Š1.8 mg; PI + NNRTI: 7.3  ±  3.3 mg; P = 0.86). Race and ritonavir dose were independent predictors of WMD, predicting an increase of 3.9 mg (95% CI: 0.88-6.98, P = 0.02) if a patient was African American or 3.7 mg (95% CI: 0.53-6.89, P = 0.03) if the total daily ritonavir dose was 200 mg. CONCLUSIONS: The required WMD was significantly higher in patients receiving ART. Prompt dose titration to achieve a higher WMD with vigilant monitoring may be required due to these drug-drug interactions.

Evaluation of clinical outcomes in patients with bloodstream infections due to Gram-negative bacteria according to carbapenem MIC stratification.

Predictive modeling suggests that actual carbapenem MIC results are more predictive of clinical patient outcomes than categorical classification of the MIC as susceptible, intermediate, or resistant. Some have speculated that current CLSI guidelines' suggested thresholds are too high and that clinical success is more likely if the MIC value is ≤1 mg/liter for certain organisms. Patients treated with carbapenems and with positive blood cultures for Pseudomonas aeruginosa, Acinetobacter baumannii, or extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria were considered for evaluation in this clinical retrospective cohort study. Relevant patient demographics and microbiologic variables were collected, including carbapenem MIC. The primary objective was to define a risk-adjusted all-cause hospital mortality breakpoint for carbapenem MICs. Secondarily, we sought to determine if a similar breakpoint existed for indirect outcomes (e.g., time to mortality and length of stay [LOS] postinfection for survivors). Seventy-one patients met the criteria for study inclusion. Overall, 52 patients survived, and 19 died. Classification and regression tree (CART) analysis determined a split of organism MIC between 2 and 4 mg/liter and predicted differences in mortality (16.1% versus 76.9%; P < 0.01). Logistic regression controlling for confounders identified each imipenem MIC doubling dilution as increasing the probability of death 2-fold (adjusted odds ratio [aOR] 2.0; 95% confidence interval [CI], 1.3 to 3.2). Secondary outcomes were similar between groups. This study revealed that patients with organisms that had a MIC of ≥4 mg/liter had worse outcomes than patients whose isolates had a MIC of ≤2 mg/liter, even after adjustment for confounding variables. We recommend additional clinical studies to better understand the susceptibility breakpoint for carbapenems.

Successful treatment of extensively drug-resistant Acinetobacter baumannii peritoneal dialysis peritonitis with intraperitoneal polymyxin B and ampicillin-sulbactam.

OBJECTIVE: To describe a case of extensively drug-resistant (XDR) Acinetobacter baumannii peritoneal dialysis (PD)-associated peritonitis successfully treated with combination antibiotics, including intraperitoneal polymyxin B, with retention of the catheter. CASE SUMMARY: A 54-year-old woman with end-stage renal disease receiving chronic PD and recent antibiotic and hospital exposure presented with abdominal pain, nausea, and vomiting. She was found to have XDR A. baumannii PD peritonitis. Treatment was initiated with intravenous and intraperitoneal ampicillin-sulbactam, followed by the addition of intraperitoneal polymyxin B based on susceptibilities. The patient recovered without the need for catheter removal or switch to hemodialysis. DISCUSSION: The frequency of XDR A. baumannii as a nosocomial pathogen is increasing, and polymyxins are being used more often as part of combination therapy for infections caused by this organism. Neither XDR A. baumannii PD peritonitis nor the use of intraperitoneal polymyxin B has been well described. In our patient, intraperitoneal dosing of polymyxin B was determined based on limited published pharmacokinetic and pharmacodynamic data. CONCLUSIONS: A case of XDR A. baumannii PD peritonitis was successfully treated with combination antibiotic therapy, including intraperitoneal polymyxin B, without major complications.

Prospective approach to managing antimicrobial drug shortages.

Antimicrobial drug shortages continue to increase, with few new therapeutic options available. Nationally, proposals have been offered to alleviate drug shortages; however, these recommendations are unlikely to effect change in the near future. Thus, antimicrobial stewardship leaders in acute care hospitals must develop a prospective management strategy to lessen the impact of these shortages on patient care. Herein, we describe several resources available to aid professionals in antimicrobial stewardship and healthcare epidemiology to manage drug shortages. An effective approach should include prospectively tracking shortages and maximizing inventory by appropriately managing usage. Several tenets should underpin this management. Alternative agents should be rationally chosen before the inventory of the primary agent has reached zero, ethical considerations should be taken into account, and timely notification and communication with key stakeholders should occur throughout the prescribing and dispensing process.

The impact of anti-infective drug shortages on hospitals in the United States: trends and causes.

Anti-infective shortages pose significant logistical and clinical challenges to hospitals and may be considered a public health emergency. Anti-infectives often represent irreplaceable life-saving treatments. Furthermore, few new agents are available to treat increasingly prevalent multidrug-resistant pathogens. Frequent anti-infective shortages have substantially altered patient care and may lead to inferior patient outcomes. Because many of the shortages stem from problems with manufacturing and distribution, federal legislation has been introduced but not yet enacted to provide oversight for the adequate supply of critical medications. At the local level, hospitals should develop strategies to anticipate the impact and extent of shortages, to identify therapeutic alternatives, and to mitigate potential adverse outcomes. Here we describe the scope of recent anti-infective shortages in the United States and explore the reasons for inadequate drug supply.

Life-years gained with meropenem over ciprofloxacin in penicillin-allergic patients with gram-negative bacilli sepsis: results of a probabilistic model.

STUDY OBJECTIVE: To compare meropenem with ciprofloxacin for treatment of gram-negative bacilli sepsis in penicillin-allergic patients in the intensive care unit (ICU) to determine if increased anaphylaxis risk with meropenem precluded its use when weighed against risks of inactive therapy with ciprofloxacin. DESIGN: A decision model constructed from probability distributions from the literature and data from a local ICU antibiogram. A probabilistic sensitivity analysis was performed to evaluate uncertainty in variable estimates by using one-way analyses, two-way analyses, and Monte Carlo simulation. MEASUREMENTS AND MAIN RESULTS: Microbiologic activity of treatment, anaphylaxis according to treatment regimen, curability of infection according to patient morbidity status, risk of superinfection, and recovery from gram-negative bacilli sepsis were the variables modeled. Effectiveness was defined by long-term survival and was modeled as life-years (LYs) and quality-adjusted life-years (QALYs) gained according to treatment group. Base case results were the incremental differences between the average effectiveness of each strategy calculated from the Monte Carlo simulation. Mean LYs and QALYs gained with meropenem were 9.9 (95% confidence interval [CI] 8.9-10.8) and 5.9 (95% CI 4.8-6.7), respectively. Mean LYs and QALYs gained with ciprofloxacin were 8.9 (95% CI 8.1-9.6) and 5.3 (95% CI 4.4-6.3), respectively. The incremental difference in effectiveness-or average benefit expected by selecting meropenem over ciprofloxacin-was 1.0 LY (95% CI 0.3-1.7 LYs) and 0.6 QALY (95% CI 0.2-1.1 QALYs) favoring meropenem. CONCLUSION: Use of empiric meropenem over ciprofloxacin may be justified in patients in the ICU who are allergic to penicillin.

Impact of carbapenem resistance and receipt of active antimicrobial therapy on clinical outcomes of Acinetobacter baumannii bloodstream infections.

Nosocomial Acinetobacter baumannii bloodstream infections occur with significant prevalence and mortality. The relationship between carbapenem resistance in A. baumannii and patient outcomes remains unclear. A retrospective cohort study was conducted on patients with A. baumannii bacteremia. Outcomes, controlling for confounders, were compared for carbapenem-nonresistant A. baumannii (CNRAB) and carbapenem-resistant A. baumannii (CRAB). The primary outcome studied was all-cause hospital mortality, and the secondary endpoints evaluated were time to mortality, time to negative cultures, and length of stay postinfection for survivors. A total of 79 patients, 37 infected with CRAB and 42 with CNRAB, were studied. Hospital mortality was greater in the CRAB group as determined based on bivariate analysis (P < 0.01); however, this effect was nullified when controlling for relevant confounders with logistic regression and a Cox proportional-hazards model (P = 0.71 and 0.75, respectively). Values for time to mortality and time to negative cultures did not differ between the groups. The median number of days of stay postinfection for survivors was greater for the CRAB group than the CNRAB group (14 versus 6.5; P < 0.01). Patients who received active antimicrobial therapy were less likely to die (93.5% versus 74.2%; P = 0.02), regardless of carbapenem susceptibility classifications, and this result was robust in the multivariate model (P = 0.02). Trends existed for improved outcomes in patients receiving an active beta-lactam, and patients fared worse if they had received a polymyxin as an active agent. Patients with CRAB bloodstream infections were more chronically ill and had more comorbidities. Inactive therapy was more important than carbapenem susceptibility with respect to outcomes, was a strong predictor of death, and is potentially modifiable.

Impact of the FDA warning of potential ceftriaxone and calcium interactions on drug use policy in clinical practice.

OBJECTIVE: In September 2007, the FDA issued an alert recommending that ceftriaxone and calcium-containing solutions should not be administered to any patient within 48 h of each other. Due to the widespread use of ceftriaxone, significant concern was expressed by the greater healthcare community about the warning, which the FDA eventually retracted in April of 2009. We sought to quantify the impact of the warning on healthcare institutions. SETTING: A survey was administered to the membership of the Society of Infectious Diseases Pharmacists to quantify perceived changes in ceftriaxone use among healthcare institutions across the United States. METHOD: A survey of Infectious Diseases experts was conducted. Participants were queried for hospital policies/drug use statistics during two times: immediately after the FDA warning and approximately 13 months post warning (preceding the FDA retraction). MAIN OUTCOME MEASURE: Related changes in formulary, drug-use policy, and the number of employee hours that were devoted to addressing the FDA warning were assessed. RESULTS: Ninety-four surveys representing 94 hospital systems were included in the analysis. Approximately half (n = 49, 52%) of respondent institutions enacted at least one drug-use policy change based on the warning; one institution removed ceftriaxone from a clinical protocol. Institutions' final interpretations of the warning differed slightly from initial understanding of the warning, and there was an overall minor decrease in the perceived use of ceftriaxone. The majority of those surveyed (n = 70, 74%) estimated that their respective institutions devoted between 1 and 49 employee hours to address the warning. CONCLUSION: Hospitals with ID pharmacists had minimal changes to ceftriaxone use after the 2007 FDA warning. Specialized pharmacists may be uniquely situated to help hospitals interpret global recommendations locally.