Rachel M. Kenney

Vancomycin-Associated Renal Dysfunction: Where Are We Now?

Vancomycin has been in clinical use for over 60 years, during which time renal toxicity has been well documented. Multiple risk factors and outcomes are associated with vancomycin‐related nephrotoxicity. Risk factors include vancomycin exposure (trough levels 15 mg/L or higher, larger area under the curve, duration of therapy), host susceptibility to vancomycin (increased body weight, preexisting renal dysfunction, critical illness), and concurrent nephrotoxin therapy. Nephrotoxicity is associated with prolonged hospital stays, mortality, and the need for renal replacement therapy. To what degree vancomycin‐associated nephrotoxicity exacerbates these adverse clinical outcomes remains unclear. This article reviews the current evidence on vancomycin‐associated nephrotoxicity and explores future research directions with potential implications for improved patient safety.

Comparison of fosfomycin to ertapenem for outpatient or step-down therapy of extended-spectrum β-lactamase urinary tract infections

Extended-spectrum β-lactamase (ESBL) enzymes cause resistance to common β-lactam antibiotics and are associated with poor outcomes. Management of ESBL urinary tract infections (UTIs) is challenging given the limited treatment options available outside the hospital setting. In this study, the primary endpoint of UTI-related 30-day hospital re-admission or emergency department/clinic revisit rates was compared for fosfomycin and ertapenem outpatient ESBL UTI treatments. A retrospective cohort study was performed on patients with ESBL UTIs treated with outpatient fosfomycin or ertapenem from January 2010 to February 2015. Inclusion criteria were age ≥18 years, outpatient treatment with fosfomycin or ertapenem for symptomatic ESBL UTI, and positive urine cultures with microbiologically proven ESBL-producing bacteria. A non-inferiority margin of 0.15 was selected to detect a difference in the primary endpoint. Patient and infection characteristics were compared. A sensitivity analysis with propensity score matching was performed. In total, 178 patients were included (89 fosfomycin-treated and 89 ertapenem-treated). Ertapenem-treated patients received longer outpatient antibiotic treatment (10 days vs. 6 days; P <0.001). ESBL isolates identified were 149 Escherichia coli (83.7%), 26 Klebsiella spp. (14.6%) and 3 other (1.7%). Common dosage regimens were oral dose of 3 g fosfomycin every 72 h (62%), oral dose of 3 g fosfomycin every 48 h (23%) and intravenous dose of 1 g ertapenem daily (76%). The thirty-day re-admission/revisit rates for fosfomycin and ertapenem were 14.6% vs. 13.5% (1.1% difference; 97.5% CI, -0.11 to 0.13). Fosfomycin was non-inferior to ertapenem for treating outpatient ESBL UTIs and should be considered as appropriate step-down therapy for these infections.

Randomized Controlled Trial to Determine the Efficacy of Early Switch From Vancomycin to Vancomycin Alternatives as a Strategy to Prevent Nephrotoxicity in Patients With Multiple Risk Factors for Adverse Renal Outcomes (STOP-NT)

Background: Use of alternative antimicrobials to vancomycin is a potential strategy to reduce acute kidney injury (AKI) in high-risk patients, but current data do not support widespread adoption of this practice. Objective: To determine the efficacy of early switch to a nonnephrotoxic alternative for prevention of AKI in high-risk patients who receive vancomycin. Methods: This was an IRB-approved, prospective randomized controlled trial in a single, tertiary care academic medical center. Patients initially prescribed vancomycin between October 2011 to April 2013 with at least 2 risk factors for AKI were included. Treatment randomization was stratified by indication for therapy. Patients were randomized to continuation of dose-optimized vancomycin or early switch to an alternative antimicrobial agent. The primary end point was nephrotoxicity by consensus guideline definition adjudicated by blinded review; the secondary end point was AKI network–defined AKI. Results: A total of 103 patients were randomized; 100 were included in the modified intent-to-treat population, 51 in the vancomycin group and 49 in the alternative group. The incidence of nephrotoxicity was 6.1% in the alternative therapy arm and 9.8% in the vancomycin group (P = 0.72). The incidence of AKI was 32.7% in the alternative therapy group and 31.4% in the vancomycin group (P = 0.89). Conclusions: No significant difference in nephrotoxicity or AKI was detected among patients treated with alternative antimicrobials compared with vancomycin. The use of alternative antimicrobial therapy instead of vancomycin solely for the purpose of preventing AKI in high-risk patients does not appear to be warranted.

Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections.

ABSTRACT Vancomycin-resistant urinary tract infections are often challenging to treat. This retrospective cohort study compared outcomes between patients treated for vancomycin-resistant enterococcal urinary tract infection with an aminopenicillin and those treated with a non-β-lactam antibiotic. Inpatients treated with an enterococcus-active agent for their first symptomatic vancomycin-resistant enterococcal urinary tract infection between 1 January 2012 and 31 December 2013 were considered for inclusion. Patients with colonization, on hospice, or receiving comfort care only were excluded. The primary endpoint of clinical cure was defined as resolution of clinical symptoms, or symptom improvement to the extent that no additional antibacterial drug therapy was necessary, and lack of microbiologic persistence. Secondary endpoints of 30-day readmission or retreatment and 30-day all-cause mortality were also compared. A total of 316 urinary isolates were screened, and 61 patients with symptomatic urinary tract infection were included. Twenty (35%) of the 57 isolates tested were ampicillin susceptible. Thirty-one patients received an aminopenicillin, and 30 received a non-β-lactam. Rates of clinical cure for aminopenicillin versus non-β-lactam treatment were 26/31 (83.9%) and 22/30 (73.3%) (P = 0.315), respectively. Rates of 30-day readmission (6/31, or 19.4%, versus 9/30, or 30%, respectively; P = 0.334), 30-day retreatment (4/31, or 12.9%, versus 4/30, 13.3%, respectively; P = 0.960), and 30-day all-cause mortality (2/31, or 6.5%, versus 1/30, or 3.3%, respectively; P = 0.573) were also not significantly different between groups. Aminopenicillins may be a viable option for treating vancomycin-resistant urinary tract infection regardless of the organisms ampicillin susceptibility. Prospective validation with larger cohorts of patients should be considered.

The State of Antimicrobial Stewardship in Michigan: Results of a Statewide Survey on Antimicrobial Stewardship Efforts in Acute Care Hospitals.

Clinical Pharmacy Specialist, Infectious Diseases, St. Joseph Mercy Health System, Ann Arbor, Michigan; Chief Operations Officer, Michigan Pharmacists Association, Lansing Michigan; Pharmacy Specialist, Antimicrobial Stewardship, Henry Ford Hospital, Detroit, Michigan; Clinical Pharmacist Specialist, Infectious Diseases, Detroit Receiving Hospital, Detroit Medical Center, Detroit, Michigan; ¶Clinical Pharmacy Specialist in Infectious Diseases, Department of Pharmacy and Infectious Diseases, Munson Medical Center, Traverse City, Michigan; Antimicrobial Stewardship Pharmacist, The University of Toledo, Main and Health Science Campuses, Toledo, Ohio; Infectious Diseases Pharmacist, Baptist Health Louisville Pharmacy Department, Louisville, Kentucky; Clinical Pharmacist, Infectious Diseases, Sinai-Grace Hospital, Detroit Medical Center, Detroit, Michigan; Clinical Assistant Professor of Medicine, Wayne State University School of Medicine, Detroit, Michigan. Corresponding author: Curtis Collins, PharmD, MS, BCPS (AQ-ID), FASHP, Clinical Pharmacy Specialist, Infectious Diseases, St. Joseph Mercy Health System, 5301 East Huron River Drive, Ann Arbor, MI 48106; phone: 734-712-6023; e-mail: cdc008@yahoo.com To the Editor: Infections due to drug-resistant organisms are associated with considerable morbidity and mortality.1 While resistant gram-positive infections, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE), remain a significant threat, the rise of resistant gramnegative infections due to P. aeruginosa, A. baumannii, and carbapenem-resistant enterobacteriaceae (CRE) have led to scenarios where clinicians are forced into treatment with highly toxic, often older, and pharmacologically suboptimal treatment regimens with drugs such as polymyxins or tigecycline.2 Despite the Infectious Diseases Society of America’s (IDSA) 10x20 initiative that promotes the development of 10 novel antimicrobials by 2020, the antimicrobial pipeline remains relatively dry, with only a few agents currently in phase III trials and none of these with a novel mechanism of action.3 These data highlight the need for antimicrobial stewardship efforts aimed at promoting the optimal use of current agents in an effort to limit further development of drug resistance. In addition, antimicrobial use, both appropriate and inappropriate, is the number one driver of Clostridium difficile infection (CDI), which has been shown to be a significant complication of hospitalization, leading to increased length of stay, hospital costs, morbidities, and ultimately mortality.4 In 2007, the IDSA developed and published guidelines and recommendations for antimicrobial stewardship within institutions.5 In this document, the authors recommended 2 core methods for stewardship: prospective audit and feedback (which involves daily monitoring of target antimicrobials and direct feedback with the prescribing team) and formulary restriction and preauthorization (requiring approval, usually by infectious diseases [ID], or predetermined criteria to be met, prior to dispensing an antimicrobial).5 They also recommended additional supplemental methods including education, guidelines and pathway development, intravenous to oral switching, de-escalation, and dose optimization to complement the 2 core methods. The authors suggested that the core stewardship team should consist of an ID physician and an ID-trained pharmacist, with support and collaboration of a clinical microbiologist, information technology, and hospital administration.5 Although these recommendations are commendable, the applicability to a large majority of institutions remains questionable and poorly described.

Safety and efficacy of outpatient parenteral antibiotic therapy in an academic infectious disease clinic

Outpatient parenteral therapy (OPAT) has become a safe and effective modality for patients requiring intravenous or prolonged antimicrobial therapy since the 1970s. It is being increasingly utilized in various settings; however, studies evaluating the safety and efficacy of clinic‐based OPAT are limited. Since 2012, patients being considered for OPAT have required an infectious disease (ID) consultation at our institution. Candidates receiving once‐daily antimicrobials who were ineligible for home infusion or nursing home placement as determined by their insurance companies and those who preferred the clinic over nursing home or home infusion were referred to the ID clinic. This study assessed the safety and outcome of patients receiving OPAT in an academic inner‐city ID clinic in Detroit, Michigan.

Evaluation of the Use of Novel Biomarkers to Augment Antimicrobial Stewardship Program Activities

As antimicrobial stewardship increasingly receives worldwide attention for improving patient care by optimizing antimicrobial therapy, programs are evaluating new tools that may augment antimicrobial stewardship activities. Biomarkers are objective, accurate, and reproducible measures that provide information about medical conditions. A systematic literature search using PubMed/MEDLINE databases was performed to evaluate the use of novel biomarkers as additions to the antimicrobial stewardship armamentarium. Procalcitonin may help clinicians discriminate between bacterial and viral infections, help with antimicrobial discontinuation decisions, and predict mortality. β‐d‐glucan, Candida albicans germ tube antibody, and galactomannan are useful in suspected fungal infections and may reduce inappropriate antifungal use. Adrenomedullin and soluble triggering receptor on myeloid cells‐1 may be useful for mortality prediction and the determination of a need for empiric antibacterials. Although studies evaluating these biomarkers are promising, these biomarkers are not without limitations and should be used in combination with clinical signs, symptoms, or other biomarkers. For successful implementation of biomarker use, stewardship programs should consider the populations most likely to benefit, without using them indiscriminately in all patients. Antimicrobial stewardship programs should facilitate education of clinicians through institutional guidelines to ensure the appropriate use and interpretation of these biomarkers.

Microbiology Comment Nudge Improves Pneumonia Prescribing

Abstract Background Systematic and behavioral interventions are needed to improve antibiotic use for common conditions like pneumonia. Methods Single pretest, post-test quasi-experiment in a 4-hospital health system in metropolitan Detroit, Michigan. Hospitalized patients treated with anti-methicillin-resistant Staphylococcus aureus and antipseudomonal antibiotics for respiratory infections from August 1, 2015, through January 31, 2016, and August 1, 2016, through January 31, 2017, were eligible for inclusion. Beginning in May 2016, respiratory cultures with no dominant organism growth and no Pseudomonas sp. or Staphylococcus aureus were reported by the clinical microbiology laboratory as “commensal respiratory flora only: No S. aureus/MRSA [methicillin-resistant Staphylococcus aureus] or P. [Pseudomonas] aeruginosa.” Before intervention, these were reported as “commensal respiratory flora.” The primary end point was de-escalation or discontinuation of anti-methicillin-resistant Staphylococcus aureus or antipseudomonal therapy. Secondary clinical and safety outcomes included nephrotoxicity and in-hospital, all-cause mortality. Results Two hundred ten patients were included in the study. De-escalation/discontinuation was more commonly performed in the intervention group (39% vs 73%, P < .001). After adjusting for APACHE II and Charlson Comorbidity Index, the intervention comment was associated with a 5.5-fold increased odds of de-escalation (adjusted odds ratio, 5.5; 95% confidence interval, 2.8–10.7). Acute kidney injury was reduced in the intervention phase (31% vs 14%, P = .003). No difference in all-cause mortality was detected between the groups (30% vs 18%, P = .052). Conclusion A simple, behavioral nudge in microbiology reporting increased de-escalation and discontinuation of unnecessary broad-spectrum antibiotics. This highlights the importance of clear, persuasive communication of diagnostic testing in improving antibiotic prescribing behaviors.

Reply to "Urinary Tract Infections: Resistance Is Futile".

We thank Dr. Wenzler and Dr. Danziger ([1][1]) for their comments on our recent paper ([2][2]) and appreciate their insightful perspective on the use of aminopenicillins for selected urinary tract infections (UTIs) caused by vancomycin-resistant enterococci. As they point out, our data provide