Incidence of drug-resistant pathogens in community-acquired pneumonia at a safety net hospital.

The 2019 Infectious Diseases Society of America guideline for the management of community-acquired pneumonia (CAP) emphasizes the need for clinician to understand local epidemiological data to guide selection of appropriate treatment. Currently, the local distribution of causative pathogens and their associated resistance patterns in CAP is unknown. A retrospective observational study was performed of patients admitted to an 870-bed safety net hospital between March 2016 and March 2021 who received a diagnosis of CAP or healthcare-associated pneumonia within the first 48 hours of admission. The primary outcome was the incidence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (PsA) as determined by comparing the number of satisfactory sputum cultures or blood cultures with these drug-resistant organisms to the total number of reviewed patients. Secondary outcomes studied included risk factors associated with CAP caused by drug-resistant organisms, utilization of broad-spectrum antibiotics, appropriate antibiotic de-escalation within 72 hours, and treatment duration. In this 220-patient cohort, MRSA or PsA was isolated from three sputum cultures and no blood cultures. The local incidence of drug-resistant pathogens among the analyzed sample of CAP patients was 1.4% (n = 3/220). The overall incidence of CAP caused by MRSA or PsA among admitted patients is low at our safety-net county hospital. Future research is needed to identify local risk factors associated with the development of CAP caused by drug-resistant pathogens.IMPORTANCEThis study investigates the incidence of drug-resistant pathogens including methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa among community-acquired pneumonia (CAP) patients at a safety net hospital. Understanding local bacteria resistance patterns when treating CAP is essential and supported by evidence-based guidelines. Our findings empower other clinicians to investigate resistance patterns at their own institutions and identify methods to improve antibiotic use. This has the potential to reduce the unnecessary use of broad-spectrum antibiotic agents and combat the development of antibiotic resistance.

Combination eravacycline therapy for ventilator-associated pneumonia due to carbapenem-resistant Acinetobacter baumannii in patients with COVID-19: A case series.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia is associated with poor clinical outcomes and increased mortality. Clinical data regarding the optimal treatment of CRAB is limited, and combination therapy is often preferred. Eravacycline has demonstrated in-vitro activity against A. baumannii and has been considered for the treatment of pulmonary infections caused by CRAB. OBJECTIVE: The objective of this case series was to describe clinical outcomes associated with eravacycline when utilized as part of a combination regimen for the treatment of CRAB pneumonia at a county hospital. METHODS: A retrospective chart review was conducted from April 1, 2020, to October 1, 2020, which included hospitalized patients ≥18 years of age, diagnosed with coronavirus disease 2019 (COVID-19), with a sputum culture positive for CRAB, and receipt of at least one dose of eravacycline. The primary outcome studied was clinical resolution of CRAB pneumonia. A key secondary outcome was microbiological resolution. RESULTS: A total of 24 patients received combination eravacycline therapy for a median of 10.5 days. Overall, 17 (71%) patients demonstrated clinical resolution of CRAB pneumonia. Repeat sputum cultures post-treatment were collected in 17 (71%) patients, of which 12 (71%) achieved microbiological resolution. No adverse events attributable to eravacycline were identified. CONCLUSION: With limited viable salvage treatment options, combination eravacycline therapy showed favorable microbiological and clinical outcomes in patients with CRAB pneumonia. In light of this, eravacycline could be considered as a potential treatment option when designing CRAB pneumonia salvage therapy regimens.

Evaluation of Dalbavancin Use on Clinical Outcomes, Cost-Savings, and Adherence at a Large Safety Net Hospital.

Dalbavancin is a second-generation lipoglycopeptide antibiotic with activity against Gram-positive organisms. Dalbavancin is Food and Drug Administration (FDA)-approved for acute bacterial skin and soft tissue infections (ABSSTIs). There is a lack of substantial data on dalbavancin in more invasive infections, particularly in high-risk populations (patients with intravenous drug use and unstable living conditions). In this retrospective observational study, we reviewed all patients that received at least one dose of dalbavancin in an inpatient or outpatient setting at Parkland Hospital from February of 2019 to August of 2021. The demographics, type of infection, and rationale for dalbavancin were collected at the baseline. Clinical failure was measured by an avoidance of emergency department (ED) visits or hospital readmission at 30, 60, and 90 days. A separate analysis was conducted to estimate hospital, rehabilitation, or nursing facility days saved based on the projected length of treatment. 40 patients were included, and the majority were uninsured (85%), experiencing homelessness (60%), or had intravenous drug use (IDU) (57.5%). Indications for use included ABSSTIs (45%), bloodstream infection (67.5%), osteomyelitis (40%), infective endocarditis (10%), and septic arthritis (10%). Clinical failure was observed in 5 of the 40 patients (12.5%). Nonadherence to medical recommendations, a lack of source control, and ongoing IDU increased the risk of failure. Dalbavancin saved a total of 566 days of inpatient, rehabilitation, and nursing facility stays. Dalbavancin is a reasonable alternative to the standard of care in an at-risk population, offering decreased lengths of stays and cost savings. The uses of second-generation lipoglycopeptides are desirable alternatives to traditional outpatient parenteral antibiotic therapies for patients who otherwise would not qualify or for patients who desire less hospital contact in light of the COVID-19 pandemic. IMPORTANCE This study contributes additional experience to the literature of dalbavancin use in off-label indications, particularly for patients who do not qualify for outpatient parenteral antimicrobial therapy. The majority of the patient population were people who inject drugs and the uninsured. There is difficulty in tracking outcomes in this patient population, given their outpatient follow-up rates; however, we were able to track emergency room visits and readmissions throughout the majority of the local metroplex. The clinical use of dalbavancin at our institution also increased in the midst of the COVID-19 pandemic in an effort to preserve hospital resources and limit health care exposure. In addition, we are able to provide institution-specific cost-saving data with the use of dalbavancin.

A retrospective review of oral cephalosporins versus fluoroquinolones for the treatment of pyelonephritis.

BACKGROUND: The current Infectious Diseases Society of America guidelines for the treatment of acute uncomplicated pyelonephritis (AUP) advise caution when using oral beta-lactams due to concern for potentially inferior efficacy compared to fluoroquinolones (FQs) and trimethoprim-sulfamethoxazole; however, studies specifically evaluating the efficacy of oral cephalosporins (CPs) in AUP are limited. OBJECTIVE: To assess the safety and efficacy of oral CPs versus FQs for the treatment of AUP. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective, chart review study conducted at a single-center, tertiary care hospital. MEASUREMENTS: The primary endpoint was treatment failure within 30 days, defined as a change in antibiotic or return to ED or clinic due to persistent symptoms. Secondary endpoints included adverse drug reactions (ADRs) and C. difficile infection (CDI) within 30 days. RESULTS: Of the 343 patients included in the study, treatment failure occurred in 54/338 (16.0%) patients and was similar between oral CPs and FQs (35/229 [15.3%] vs. 19/109 [17.4%]). A higher percentage of treatment failures were observed for third generation (3GC) and first generation (1GC) CPs compared to second generation CPs (2GC) (3GC: 15/65 [23.4%]; 1GC: 11/49 [22.4%]; 2GC: 9/115 [7.8%]). Documented ADRs were low (6/343 [1.7%]) and no cases of CDI were documented. CONCLUSIONS: Oral CPs appear to be as safe and effective as FQs for the treatment of AUP. Fewer treatment failures were noted with 2GCs as compared to 3GCs and 1GCs.

Therapeutic Options for Coronavirus Disease 2019 (COVID-19): Where Are We Now?

PURPOSE OF REVIEW: Rapidly evolving treatment paradigms of coronavirus disease 2019 (COVID-19) introduce challenges for clinicians to keep up with the pace of published literature and to critically appraise the voluminous data produced. This review summarizes the clinical evidence from key studies examining the place of therapy of recommended drugs and management strategies for COVID-19. RECENT FINDINGS: The global magnitude and duration of the pandemic have resulted in a flurry of interventional treatment trials evaluating both novel and repurposed drugs targeting various aspects of the viral life cycle. Additionally, clinical observations have documented various stages or phases of COVID-19 and underscored the importance of timing for the efficacy of studied therapies. Since the start of the COVID-19 pandemic, many observational, retrospective, and randomized controlled studies have been conducted to guide management of COVID-19 using drug therapies and other management strategies. Large, randomized, or adaptive platform trials have proven the most informative to guide recommended treatments to-date. Antimicrobial stewardship programs can play a pivotal role in ensuring appropriate use of COVID-19 therapies based on evolving clinical data and limiting unnecessary antibiotics given low rates of co-infection. SUMMARY: Given the rapidly evolving medical literature and treatment paradigms, it is recommended to reference continuously updated, curated guidelines from national and international sources. While the drugs and management strategies mentioned in this review represent the current state of recommendations, many therapies are still under investigation to further define optimal COVID-19 treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11908-021-00769-8.

Optimizing the Management of Uncomplicated Gram-Negative Bloodstream Infections: Consensus Guidance Using a Modified Delphi Process.

BACKGROUND: Guidance on the recommended durations of antibiotic therapy, the use of oral antibiotic therapy, and the need for repeat blood cultures remain incomplete for gram-negative bloodstream infections. We convened a panel of infectious diseases specialists to develop a consensus definition of uncomplicated gram-negative bloodstream infections to assist clinicians with management decisions. METHODS: Panelists, who were all blinded to the identity of other members of the panel, used a modified Delphi technique to develop a list of statements describing preferred management approaches for uncomplicated gram-negative bloodstream infections. Panelists provided level of agreement and feedback on consensus statements generated and refined them from the first round of open-ended questions through 3 subsequent rounds. RESULTS: Thirteen infectious diseases specialists (7 physicians and 6 pharmacists) from across the United States participated in the consensus process. A definition of uncomplicated gram-negative bloodstream infection was developed. Considerations cited by panelists in determining if a bloodstream infection was uncomplicated included host immune status, response to therapy, organism identified, source of the bacteremia, and source control measures. For patients meeting this definition, panelists largely agreed that a duration of therapy of ~7 days, transitioning to oral antibiotic therapy, and forgoing repeat blood cultures, was reasonable. CONCLUSIONS: In the absence of professional guidelines for the management of uncomplicated gram-negative bloodstream infections, the consensus statements developed by a panel of infectious diseases specialists can provide guidance to practitioners for a common clinical scenario.

Efficacy and safety of eravacycline: A meta-analysis.

OBJECTIVES: This study was conducted to evaluate the efficacy and safety of eravacycline, a recently approved fluorocycline for treatment of complicated intra-abdominal infections (cIAIs). METHODS: PubMed, EMBASE and three trial registries were searched for randomised controlled trials (RCTs) comparing the efficacy and safety of eravacycline versus comparators. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using random-effects models. The study outcomes included clinical response, all-cause mortality and adverse events (AEs). RESULTS: Three RCTs (1128 patients) with cIAIs were included. There were no significant differences in clinical response in the modified intention-to-treat (ITT) (OR, 0.91, 95% CI 0.62-1.35; I2 = 0%), microbiological ITT (OR, 0.93, 95% CI 0.61-1.41; I2 = 0%) and clinically evaluable (OR, 0.98, 95% CI 0.55-1.75; I2 = 0%) populations or in all-cause mortality (OR, 1.18, 95% CI 0.16-8.94; I2 = 0%). Eravacycline was associated with significantly greater odds of total AEs (OR, 1.55, 95% CI 1.20-1.99; I2 = 0%) and nausea (OR, 5.29, 95% CI 1.77-15.78; I2 = 1.70%) but the increase in vomiting was non-significant (OR, 1.44, 95% CI 0.73-2.86; I2 = 1.70%). There were no significant differences in serious AEs or discontinuation due to AEs. CONCLUSION: This meta-analysis of RCTs found similar clinical efficacy and mortality for eravacycline compared with carbapenems for treatment of cIAIs. However, the odds of total AEs and specifically nausea was higher with eravacycline, while no significant differences were observed in vomiting (although numerically higher), serious AEs or discontinuation due to AEs.

Minimal impact of selective susceptibility reporting on the use of piperacillin-tazobactam for Escherichia coli and Klebsiella bacteremia.

Selective cascade reporting of antibiotic susceptibilities did not have a significant impact on de-escalation from piperacillin-tazobactam (PT), duration of PT use, length of stay, or rates of acute kidney injury and Clostridioides difficile infection in patients with positive monomicrobial blood cultures with either Escherichia coli or Klebsiella spp.

Decreased Outpatient Fluoroquinolone Prescribing Using a Multimodal Antimicrobial Stewardship Initiative.

BACKGROUND: Fluoroquinolones are antibiotics prescribed in the outpatient setting, though they have serious side effects. This study evaluates the impact of stewardship interventions on total and inappropriate prescribing of fluoroquinolones in outpatient settings in a large county hospital and health system. METHODS: In an effort to decrease inappropriate outpatient fluoroquinolone usage, a multimodal antimicrobial stewardship initiative was implemented in November 2016. Education regarding the risks, benefits, and appropriate uses of fluoroquinolones was provided to providers in different outpatient settings, Food and Drug Administration warnings were added to all oral fluoroquinolone orders, an outpatient order set for cystitis treatment was created, and fluoroquinolone susceptibilities were suppressed when appropriate. Charts from October 2016, 2017, and 2018 were retrospectively reviewed if the patient encounter occurred in primary care clinics, emergency departments, or urgent care centers within Parkland Health & Hospital System and a fluoroquinolone was prescribed. Inappropriate use was defined as a fluoroquinolone prescription for cystitis, bronchitis, or sinusitis in a patient without a history of Pseudomonas aeruginosa or multidrug-resistant organisms and without drug allergies that precluded use of other oral antibiotics. RESULTS: Total fluoroquinolone prescriptions per 1000 patient visits decreased significantly by 39% (P < .01), and inappropriate fluoroquinolone use decreased from 53% to 34% (P < .01). More than 90% of inappropriate fluoroquinolone prescriptions were given for cystitis, while bronchitis and sinusitis accounted for only 4.4% and 1.6% of inappropriate indications, respectively. CONCLUSION: A multimodal stewardship initiative appears to effectively reduce both total and inappropriate outpatient fluoroquinolone prescriptions.

A Multicenter Evaluation of Vancomycin-Associated Acute Kidney Injury in Hospitalized Patients with Acute Bacterial Skin and Skin Structure Infections.

BACKGROUND: We sought to determine the real-world incidence of and risk factors for vancomycin-associated acute kidney injury (V-AKI) in hospitalized adults with acute bacterial skin and skin structure infections (ABSSSI). METHODS: Retrospective, observational, cohort study at ten U.S. medical centers between 2015 and 2019. Hospitalized patients treated with vancomycin (≥ 72 h) for ABSSSI and ≥ one baseline AKI risk factor were eligible. Patients with end-stage kidney disease, on renal replacement therapy or AKI at baseline, were excluded. The primary outcome was V-AKI by the vancomycin guidelines criteria. RESULTS: In total, 415 patients were included. V-AKI occurred in 39 (9.4%) patients. Independent risk factors for V-AKI were: chronic alcohol abuse (aOR 4.710, 95% CI 1.929-11.499), no medical insurance (aOR 3.451, 95% CI 1.310-9.090), ICU residence (aOR 4.398, 95% CI 1.676-11.541), Gram-negative coverage (aOR 2.926, 95% CI 1.158-7.392) and vancomycin duration (aOR 1.143, 95% CI 1.037-1.260). Based on infection severity and comorbidities, 34.7% of patients were candidates for oral antibiotics at baseline and 39.3% had non-purulent cellulitis which could have been more appropriately treated with a beta-lactam. Patients with V-AKI had significantly longer hospital lengths of stay (9 vs. 6 days, p = 0.001), higher 30-day readmission rates (30.8 vs. 9.0%, p < 0.001) and increased all-cause 30-day mortality (5.1 vs. 0.3%, p = 0.024) CONCLUSIONS: V-AKI occurred in approximately one in ten ABSSSI patients and may be largely prevented by preferential use of oral antibiotics whenever possible, using beta-lactams for non-purulent cellulitis and limiting durations of vancomycin therapy.

Relationship Status between Vancomycin Loading Dose and Treatment Failure in Patients with MRSA Bacteremia: It's Complicated.

INTRODUCTION: A one-time vancomycin loading dose of 25-30 mg/kg is recommended in the current iteration of the vancomycin consensus guidelines in order to more rapidly achieve target serum concentrations and hasten clinical improvement. However, there are few clinical data to support this practice, and the extents of its benefits are largely unknown. METHODS: A multicenter, retrospective, cohort study was performed to assess the impact of a vancomycin loading dose (≥ 20 mg/kg) on clinical outcomes and rates of nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. The study matched patients in a 1:1 fashion based on age, Pitt bacteremia score, and bacteremia source. The primary outcome was composite treatment failure (30-day mortality, bacteremia duration ≥ 7 days after vancomycin initiation, persistent signs and symptoms of infection ≥ 7 days after vancomycin initiation, or switch to an alternative antimicrobial agent). Secondary outcomes included duration of bacteremia, length of stay post-bacteremia onset, and nephrotoxicity. RESULTS: A total of 316 patients with MRSA bacteremia were included. Median first doses in the loading dose and non-loading dose groups were 23.0 mg/kg and 14.3 mg/kg, respectively (P < 0.001). No difference was found in composite failure rates between the non-loading dose and loading dose groups (40.5% vs. 36.7%; P = 0.488) or in the incidence of nephrotoxicity (12.7% vs. 16.5%; P = 0.347). While multivariable regression modeling showed receipt of a vancomycin loading dose on a mg/kg basis was not significantly associated with composite failure [aOR 0.612, 95% CI (0.368-1.019)]; post hoc analyses demonstrated that initial doses ≥ 1750 mg were independently protective against failure [aOR 0.506, 95% CI (0.284-0.902)] without increasing the risk for nephrotoxicity [aOR 0.909, 95% CI (0.432-1.911)]. CONCLUSION: These findings suggest that initial vancomycin doses above a certain threshold may decrease clinical failures without increasing toxicity and that weight-based dosing might not be the optimal strategy.

Plazomicin: A Novel Aminoglycoside for the Treatment of Resistant Gram-Negative Bacterial Infections.

Plazomicin is a novel semisynthetic parenteral aminoglycoside that inhibits bacterial protein synthesis. It was approved by the United States Food and Drug Administration for use in adults with complicated urinary tract infections (cUTI), including pyelonephritis. Plazomicin displays potent in vitro activity against Enterobacteriaceae, including both extended-spectrum ß-lactamase-producing and carbapenem-resistant isolates. Plazomicin's enhanced Enterobacteriaceae activity is due to its stability to commonly encountered aminoglycoside-modifying enzymes that compromise the activity of traditional aminoglycosides. Plazomicin resistance in Enterobacteriaceae is via modification of the ribosomal binding site due to expression of 16S rRNA methyltransferases. Plazomicin does not display improved activity over traditional aminoglycosides against other problematic resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter baumannii. Plazomicin has been assessed in two phase III randomized controlled trials. The EPIC trial compared plazomicin and meropenem for the management of cUTI. In this trial, plazomicin demonstrated superiority in composite cure (81.7% vs 70.1%; difference 11.6%; 95% confidence interval [CI] 2.7-25.7) at the test-of-cure visit, which was driven by enhanced sustained microbiological eradication. The CARE trial compared plazomicin-based and colistin-based combinations in patients with serious infections due to carbapenem-resistant Enterobacteriaceae (CRE). In this analysis, plazomicin-based combinations were associated with numerically decreased mortality or serious disease-related complications when compared with colistin-based combinations (23.5% vs 50%, respectively; 90% CI -0.7 to 51.2). Furthermore, plazomicin was also associated with a lower incidence of nephrotoxicity than colistin. However, small sample sizes limit the interpretation of the findings in the CARE trial. Plazomicin is a novel aminoglycoside that offers clinicians an additional option for the management of CRE infections, with superior activity compared with traditional aminoglycosides and potentially improved efficacy and decreased toxicity compared with colistin.

Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia.

BACKGROUND: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. METHODS: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. RESULTS: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval -5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p=0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR)=1.2; 95% CI, 0.3-4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR)=5.4; 95% CI, 1.1-26.8). CONCLUSION: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections.

Morbidity, mortality, and management of methicillin-resistant S. aureus bacteremia in the USA: update on antibacterial choices and understanding.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with significant healthcare costs, morbidity, and mortality in the United States. Complications of MRSA bacteremia include infective endocarditis, osteomyelitis, and sepsis, all of which are difficult to treat. Time to effective therapy and antibacterial choice greatly affect patient outcomes. Vancomycin and daptomycin remain first-line therapies; however, reports of vancomycin-associated treatment failure and reduced daptomycin susceptibility highlight the need to define alternative strategies for MRSA bacteremia treatment. In addition, several patient- and pathogen-specific factors influence the outcomes of MRSA bacteremia. It is, therefore, critical to explore the interaction between host- and pathogen-specific factors and its effect on MRSA bacteremia pathogenesis and mortality. This review discusses the factors that drive the development of MRSA bacteremia and examines alternative treatment strategies.

Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins?

The polymyxins (colistin and polymyxin B) have emerged over the past 20 years as essential antibacterial agents that often are the only remaining active class against troublesome multidrug-resistant Gram-negative bacilli such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. The utility of this class is limited by its dose-dependent nephrotoxicity, which can occur in more than one-half of patients receiving therapy with either agent. Strategies are urgently needed to optimise the use of this class of agents to ensure optimal activity while minimising the treatment-limiting nephrotoxicity. This review will focus on risk factors for polymyxin-associated nephrotoxicity, potential strategies for limiting this exposure-dependent toxicity and, finally, unknowns and future research directions pertinent to this topic.

Ceftazidime/Avibactam: Who Says You Can't Teach an Old Drug New Tricks?

PURPOSE: Gram-negative resistance continues to rise with treatment options becoming more limited. Ceftazidime/avibactam was recently approved in the United States and Europe, which combines an established third-generation cephalosporin with a new, unique, non-ß-lactam ß-lactamase inhibitor. This review conducts a thorough examination of structure, pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical efficacy and safety/tolerability of ceftazidime/avibactam, as well as detailed future directions for the agent. METHODS: Pubmed and clinicaltrials.gov searches, as well as abstracts from the 2015 Interscience Conference on Antimicrobial Agents and Chemotherapy/International Society of Chemotherapy (ICAAC/ICC) and ID Week meetings and the 2016 American Society of Microbiology Microbe meeting, were conducted from January 2004 - September 2016. Relevant search terms included ceftazidime, ceftazidime/avibactam, avibactam, NXL104 and AVE1330A. The US package insert for ceftazidime/avibactam (02/2015) and European public assessment report (06/2016) were also reviewed. RESULTS: In vitro susceptibility for ceftazidime/avibactam displayed potent activity against many Enterobacteriaceae including extended-spectrum-ß-lactamase (ESBL) and carbapenemase-producing strains, as well as Pseudomonas aeruginosa. Phase II clinical trials utilized for approval demonstrated comparable safety and efficacy to imipenem/cilistatin for treatment of complicated urinary tract infections (70.4% vs. 71.4%) and combined with metronidazole compared to meropenem in complicated intra-abdominal infections (91.2% vs 93.4%). Phase III data displayed non-inferior efficacy of ceftazidime/avibactam compared to doripenem for complicated urinary tract infections (70.2% vs 66.2%) and combined with metronidazole compared to meropenem in complicated intra-abdominal infections (82.5% vs 84.9%), as well as comparable safety. Ceftazidime/avibactam was well-tolerated but does require renal adjustments. Additionally, 3 case series and a single case report have demonstrated the potential for ceftazidime/avibactam against multidrug resistant organisms for compassionate use or failure after previous therapy. CONCLUSION: By adding avibactam to ceftazidime, clinicians' antimicrobial armamentarium is expanded, potentially increasing the ability to combat multi-drug resistant gram-negative pathogens, particularly ESBL and carbapenemase-producing organisms, as well as Pseudomonas aeruginosa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Strategies for the safe use of colistin.

Colistin has re-emerged as an essential antibiotic for the treatment of carbapenem-resistant Gram-negative infections. Unfortunately, its utility is limited by high rates of nephrotoxicity, even at potentially therapeutic concentrations, and an overall lack of understanding on how to optimally administer the agent. In this review, recent advancements in the understanding of the safety and efficacy of colistin are discussed and strategies and suggestions on how to balance the two are described.