Opportunities for antimicrobial stewardship among carbapenem-treated patients in 18 North American hospitals.

Here we describe the characteristics of carbapenem use at 18 hospitals across North America. Adult inpatients treated with a carbapenem for ≥24 h were included in this multicentre, retrospective, cross-sectional study. Outcomes evaluated included classification of therapy as empirical or definitive, discharge disposition and 30-day re-admission. A total of 621 patients were included in this study. Of these, 467 patients (75.2%) received a carbapenem empirically, among whom negative cultures occurred in 313 (67.0%) and 93% were eligible for de-escalation of therapy. In-hospital mortality occurred in 72 patients (11.6%) and 549 patients (88.4%) were discharged. Of the 549 patients who were discharged, 349 patients (63.6%) went home and 30-day infection-related re-admission occurred in 95 patients (17.3%). This population represents a significant need for carbapenem stewardship. Institutional guidelines should focus on four common disease states (respiratory, genitourinary, intra-abdominal and bloodstream), and diagnostic stewardship should be employed to aid in rapid de-escalation of carbapenem therapy. Additional studies aiming to identify antimicrobial stewardship techniques that may help to optimise carbapenem therapy and increase education about the importance of utilising carbapenem-sparing regimens are required.

Trends in and Predictors of Carbapenem Consumption across North American Hospitals: Results from a Multicenter Survey by the MAD-ID Research Network.

We sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013. Consumption was tabulated as defined daily doses (DDD) or as days of therapy (DOT) per 1,000 patient days (PD). Multivariate mixed-effects models were explored, and final model goodness of fit was assessed by regressions of observed versus predicted values and residual distributions. A total of 20 acute-care hospitals responded. The centers treated adult patients (n = 19/20) and pediatric/neonatal patients (n = 17/20). The majority of the centers were nonprofit (n = 17/20) and not affiliated with medical/teaching institutions (n = 11/20). The median (interquartile range [IQR]) carbapenem consumption rates were 38.8 (17.4 to 95.7) DDD/1,000 PD and 29.7 (19.2 to 40.1) DOT/1,000 PD overall. Carbapenem consumption was well described by a multivariate linear mixed-effects model (fixed effects, R2 = 0.792; fixed plus random effects, R2 = 0.974). Carbapenem consumption increased by 1.91-fold/quarter from 48.6 DDD/1,000 PD (P = 0.004) and by 0.056-fold/quarter from 45.7 DOT/1,000 PD (P = 0.93) over the study period. Noncarbapenem consumption was independently related to increasing carbapenem consumption (beta = 0.31 for increasing noncarbapenem beta-lactam consumption; P < 0.001). Regular antibiogram publication and promotion of conversion from intravenous (i.v.) to oral (p.o.) administration independently affected carbapenem consumption rates. In the final model, 58.5% of the observed variance in consumption was attributable to between-hospital differences. Rates of carbapenem consumption across 20 North American hospitals differed greatly, and the observed differences were correlated with hospital-specific demographics. Additional studies focusing on the drivers of hospital-specific carbapenem consumption are needed to determine whether these rates are justifiable.

2018 Infectious Diseases Society of America Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial Therapy.

A panel of experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) [1]. This guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support.

2018 Infectious Diseases Society of America Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial Therapy.

A panel of experts was convened by the Infectious Diseases Society of America to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) [1]. This guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support.

In Vitro Activity of Ceftolozane/Tazobactam vs Nonfermenting, Gram-Negative Cystic Fibrosis Isolates.

Ceftolozane/tazobactam (C/T) was tested and compared against 93 nonfermenting, Gram-negative clinical isolates from cystic fibrosis specimens. Based on current breakpoints for intra-abdominal and urinary tract infections (which may not be appropriate for pulmonary infections), C/T was found to be the most active agent against P. aeruginosa (95.7% susceptible), followed by piperacillin/tazobactam (89.4% susceptible). For other Gram-negative pathogens included, C/T had varying activity.

Successful Implementation of an Antimicrobial Stewardship Program at an Academic Medical Center.

Background: Focus on antimicrobial use and infection prevention from accrediting or regulatory bodies such as the Joint Commission, as well as regulatory agencies such as the Centers for Medicare and Medicaid Services and the Centers for Disease Control, has highlighted the need for continuing development of antimicrobial stewardship programs at healthcare facilities across the country. Methods: Our institution utilized the 2007 Infectious Diseases Society of America and the Society for Healthcare Epidemiology guidelines to direct the evaluation of its antimicrobial use and develop a successful antimicrobial stewardship program. Three baseline evaluations were conducted. Retrospective chart reviews evaluating formulary restrictions for fluroquinolones and carbepenems, a dosing optimization program for meropenem, and the intravenous to oral conversion program for fluconazole and voriconazole were completed. Results: Approximately 40% of orders for levofloxacin were not supported with a clinical justification for nonformulary use in the patient chart. Forty-nine percent of orders written for meropenem did not follow the dose optimization program. Opportunity for fluconazole and voriconazole to be converted to oral therapy when appropriate was suggested. Conclusion: The baseline evaluations revealed the need for an antimicrobial stewardship program. This article outlines the process used to assess need, plan, implement, and evaluate the impact of an antimicrobial stewardship program.

Intravenous-only or Intravenous Transitioned to Oral Antimicrobials for Enterobacteriaceae-Associated Bacteremic Urinary Tract Infection.

OBJECTIVES: To characterize antibiotic regimens utilized for bacteremic Enterobacteriaceae urinary tract infections and assess treatment failure associated with intravenous-only compared to intravenous transitioned to oral antibiotic treatment. DESIGN: Retrospective cohort. SETTINGS: Tertiary care academic medical center. PATIENTS: 241 adult patients hospitalized between July 1, 2010, and June 30, 2015, with positive blood and urine cultures with the same Enterobacteriaceae pathogen. MAIN RESULTS: Hospital days on antibiotics as well as length of stay were less in the group treated with any oral antibiotics (intravenous/oral, median 5 [IQR 3-7] days vs intravenous-only antibiotics 6 [4-10] days, p<0.001; length of stay for intravenous/oral 4.6 [3.1-7.8] days vs intravenous-only 7.1 [4.0-17.5] days, p<0.001). No statistically significant difference was found in the composite outcome of treatment failure in patients who received intravenous-only antibiotics versus intravenous/oral antibiotics for the treatment of bacteremic urinary tract infections (intravenous-only 3.8% [95% CI: 1.0-9.4%] failure; intravenous/oral 8.2% [95% CI: 4.1-14.1%] failure; p=0.19). CONCLUSIONS: Intravenous transitioned to oral treatment (intravenous/oral) was associated with a shorter length of stay and fewer hospital antibiotic days compared with intravenous-only therapy. Transitioning from intravenous to oral antibiotic therapy is a viable treatment option to consider for patients with bacteremic Enterobacteriaceae urinary tract infection.

Impact of an Antimicrobial Stewardship Program on Antimicrobial Utilization, Bacterial Susceptibilities, and Financial Expenditures at an Academic Medical Center.

Background: Antimicrobial stewardship programs (ASPs) have the potential to improve patient outcomes, decrease microbial resistance, increase patient safety, and decrease costs. However, to justify the costs involved with providing an ASP, it is necessary to assess its impact in achieving these outcomes on an ongoing basis. Objective: The purpose of this study was to characterize the overall impact of the ASP at an Academic medical center. Methods: Quasi-experimental, before and after stewardship program implementation, retrospective analyses of quarterly antimicrobial utilization, bacterial susceptibilities, and antibiotic acquisition costs were utilized. Results: Mean stewardship-focused antibiotic utilization was 510.3 defined daily doses (DDD) per 1,000 patient days for the pre-ASP period and 426.4 DDD per 1,000 patient days for the ASP period (16.4% decrease; p < .001). Significant changes in Pseudomonas aeruginosa susceptibility to tobramycin (8% increase; p = .006) and piperacillin-tazobactam (8% decrease; p = .024) were noted. Changes in susceptibility of Staphylococcus aureus to methicillin (7% increase, p = .012) were also observed. ASP-focused antibiotic expenditures decreased from $4,028,068 in fiscal year (FY) 2010 to $2,135,173 in FY2013 (p = .01). Conclusions: ASP initiatives were associated with an observed reduction in stewardship-focused antibiotic utilization. Significant changes in susceptibilities of some bacteria were noted but did not seem to consistently reflect antibiotic utilization changes. Significant decreases in antimicrobial expenditures were observed. Observed outcomes are temporally related to shifts in antimicrobial selection through the initiation of stewardship program-driven antibiotic policy changes. These outcomes have been used to justify and expand our stewardship program moving forward.

Clinical pathway for moderate to severe acute bacterial skin and skin structure infections from a US perspective: a roundtable discussion.

This article was written with the aim to establish a consensus clinical pathway for long-acting lipoglycopeptide antibiotics such as oritavancin (Orbactiv®) and dalbavancin (Dalvance®) for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Seven infectious diseases pharmacy specialists from a variety of facilities across the United States (US) participated in a roundtable discussion to consider the use of newer single-dose long-acting lipoglycopeptides, and integrate them into clinical pathways for ABSSSI. They identified two ways of treating with these drugs: first, to facilitate discharge from the hospital by switching from initial therapy (e.g., with intravenous (IV) vancomycin) and second, to avoid hospital admission altogether, since the product can be administered in several outpatient settings of care including the emergency department (ED), observation unit (OU) or outpatient infusion center. The participants used existing literature on classification and treatment of ABSSSI and their experience in the clinical setting as bases for their discussion and came to a consensus on the considerations for patient inclusion and exclusion as well as a pathway for outpatient treatment with long-acting lipoglycopeptides. As a result of the discussion, we concluded that the current treatment paradigm for ABSSSI is ripe for re-evaluation and reconfiguration in order to more closely align with the changing healthcare landscape. Hospital stakeholders are constantly searching for new strategies that can improve quality of care while simultaneously reducing overall expenses. The availability of single-dose long-acting lipoglycopeptides is an opportunity to opt for lower-cost outpatient treatment of appropriate ABSSSI patients. This article proposes the inclusion and exclusion considerations, along with a consensus treatment pathway, that could provide a solid foundation for facilities to construct and adapt their own effective clinical pathways for ABSSSI.

Comparison of Linezolid and Vancomycin for Methicillin-Resistant Staphylococcus aureus Pneumonia: Institutional Implications.

OBJECTIVE: Recent studies suggesting clinical superiority of linezolid over vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia led to a change in our institution's clinical pathway/order form for hospital-acquired pneumonia, positioning linezolid as the preferred agent. Our objective was to assess the impact of this change within our institution. DESIGN: Retrospective electronic medical records review. METHODS: The analysis for this observational study included eligible patients admitted to our medical center between May 1, 2011, and August 31, 2014, with ICD-9 codes for MRSA and pneumonia. Included patients were at least 18 years of age and had vancomycin or linezolid initiated at least 2 days after admission and continued for at least 2 consecutive days. The primary end points were extent of antibiotic use before and after order form change and length of stay (LOS) and hospital charges in the two treatment groups. A secondary aim was to detect any gross discrepancies in patient outcomes such as treatment duration, mechanical ventilation duration, all-cause mortality rate, nephrotoxicity, and 30-day readmission between the two treatment groups. MEASUREMENTS AND MAIN RESULTS: Outcomes in 227 patients were assessed. Linezolid use increased 16.2% subsequent to the change in the order form. Although not statistically significant, the median hospital admission charge was $6200 lower in patients treated with linezolid compared with those treated with vancomycin ($25,900 vs $32,100). Hospital LOS was significantly associated with Charlson Comorbidity Index score (p<0.001), type of treatment (p=0.032), duration of treatment (p<0.001), mechanical ventilation (p<0.001), and intensive care unit admission (p<0.001). All-cause mortality favored linezolid treatment, and these patients were more likely to be discharged (shorter LOS). CONCLUSIONS: Although linezolid use increased markedly with this pathway/order form change, no negative institutional consequences or unfavorable patient outcomes were detected, justifying the change in policy from these perspectives.

Impact of a Stewardship-Initiated Restriction on Empirical Use of Ciprofloxacin on Nonsusceptibility of Escherichia coli Urinary Isolates to Ciprofloxacin.

STUDY OBJECTIVE: To evaluate the impact of a stewardship-initiated restriction on empirical use of ciprofloxacin on the nonsusceptibility of Escherichia coli urinary isolates to ciprofloxacin over time while controlling for the use of other key antibiotics with gram-negative activity. DESIGN: Retrospective single-center study. SETTING: Large tertiary and quaternary care academic medical center. ISOLATES: Of 3714 E. coli urinary isolates. MEASUREMENTS AND MAIN RESULTS: The susceptibilities of the E. coli urinary isolates to ciprofloxacin, ceftriaxone, cefepime, piperacillin-tazobactam, meropenem, trimethoprim-sulfamethoxazole, and nitrofurantoin obtained over a 7-year period (January 1, 2006-December 31, 2012) from adult inpatients were evaluated for potential relationships with antibiotic use over time by using multiple variable regression analysis. After introduction of the restriction on empirical use of ciprofloxacin in the first quarter of 2011, ciprofloxacin use declined from 141.1-39.8 defined daily doses/1000 patient-days, and the percentage of E. coli isolates that were not susceptible to ciprofloxacin decreased from 41.5-32.8%. With all antibiotics evaluated included in the model, no apparent relationships were found between the percentage of E. coli isolates nonsusceptible to ciprofloxacin and antibiotic use. However, when nonsignificant variables were eliminated (p>0.20), ciprofloxacin use was found to be positively associated with the percentage of E. coli isolates nonsusceptible to ciprofloxacin (p=0.037), whereas ceftriaxone use was negatively associated (p=0.045). CONCLUSION: The restriction and subsequent reduction of ciprofloxacin use was found to have a positive effect on the susceptibility of E. coli urinary isolates to ciprofloxacin.

Recommendations for the successful pursuit of scholarship by pharmacy practice faculty members.

Scholarship has long been a basic expectation of faculty members at institutions of higher learning in the United States and elsewhere. This expectation is no less assumed in academic pharmacy. A number of organizations have verbalized and enforced this precept over the years.(1-3) For example, this expectation is spoken to directly in the American Council for Pharmacy Education's Accreditation Standards and Guidelines.(4) This expectation is further emphasized in the draft document of the accreditation standards to be implemented in 2016, in Standard 20. Specifically, Element 20.2 states: "The college or school must create an environment that both requires and promotes scholarship, and must also develop mechanisms to assess both the quantity and quality of faculty scholarly productivity."(5) The successful pursuit of scholarship by clinical faculty members (those engaged in both clinical practice and teaching, without regard to tenure or clinical track status) is challenging. (6-10) Thus, faculty member job descriptions or models should be designed so clinical faculty members can successfully meet all academic job expectations, including productive and meaningful scholarship. In 2012, an AACP Section of Teachers of Pharmacy Practice task force was charged with examining this issue and providing recommendations for models for clinical faculty members that would allow the successful pursuit of scholarship. The task force gathered information relating to the current state of affairs at a number of colleges and reviewed relevant literature. This information, along with personal experiences and much discussion and contemplation, led to some general observations as well as specific recommendations. This paper reiterates the task force's observations and recommendations and provides further detail regarding our interpretation of the findings and basis for the eventual recommendations to the section.

Adverse reactions associated with systemic polymyxin therapy.

The systemic polymyxins, colistin and polymyxin B, are increasingly used for multidrug-resistant bacterial infections and have a long history of dose-limiting toxicity. This review summarizes the most recent available information about the mechanisms, incidence, risk factors, and minimization strategies for polymyxin toxicity. Nephrotoxicity is related to polymyxin exposure with both size of dose and length of therapy associated with frequency. Newer studies have questioned conventional thinking that the relative risk of nephrotoxicity is lower for colistin than polymyxin B, especially in light of evolving dosing practices. Neurotoxicities and hypersensitivity reactions are less common than nephrotoxicity. New techniques to minimize or avoid polymyxin toxicities are now emerging including a growing interest in clinical assays for therapeutic drug monitoring and the development of novel, less toxic agents (e.g., polymyxin derivatives) for the treatment of multidrug-resistant bacterial infections.

Lack of Change in Susceptibility of Pseudomonas aeruginosa in a Pediatric Hospital Despite Marked Changes in Antibiotic Utilization.

INTRODUCTION: It is assumed that a direct relationship exists between the extent of use of any given antibiotic or antibiotic class and the degree of susceptibility or resistance on the part of various bacteria to that antibiotic or class. METHODS: Pseudomonas aeruginosa susceptibility rates and utilization of key antipseudomonal antibiotics in a pediatric hospital, reflected as grams/1,000 patient days, were studied over a 7-year period. RESULTS: While the volume of use of a number of antibiotics changed dramatically over this time period, susceptibility of Pseudomonas to these same agents remained relatively stable. The use of aminoglycosides decreased 14.5% while that of piperacillin/tazobactam increased 92% over the period of observation while susceptibility generally varied by <10%. CONCLUSION: Contrary to popular belief, changes in antibiotic utilization patterns do not always result in changes in susceptibility thus emphasizing the importance of continual institutional monitoring of antibiotic use and susceptibility patterns.

Adherence to the 2009 consensus guidelines for vancomycin dosing and monitoring practices: a cross-sectional survey of U.S. hospitals.

STUDY OBJECTIVES: To describe the implementation of vancomycin dosing and monitoring practices recommended by the consensus guidelines in a diverse sample of hospitals, and to identify needs for quality improvement and research. DESIGN: Cross-sectional study using an online survey instrument. SETTING: Making a Difference in Infectious Diseases Pharmacotherapy (MAD-ID) Research Network. PARTICIPANTS: A total of 163 respondents from MAD-ID who work in antimicrobial stewardship and represent unique hospitals. MEASUREMENTS AND MAIN RESULTS: The survey population represented a wide range of patient populations (96% adult, 49% pediatric, and 23% long-term care) and settings (52% not-for-profit nonuniversity, 31% university based, and 11% for profit). Automatic consultation of pharmacy services for all vancomycin dosing was reported in 51% of the institutions. Among the dosing and monitoring practices endorsed by the consensus guidelines, participant institutions commonly followed these recommendations: use of trough concentrations without peak concentrations, maintenance of trough concentration higher than 10 mg/L, and target trough concentrations of 15-20 mg/L for complicated infections. In contrast, there was less consistent application of appropriate timing of trough concentrations, use of loading doses, and use of actual body weight. The remaining challenges and controversies surrounding vancomycin dosing are discussed. CONCLUSION: Despite the availability of consensus guideline recommendations, practices for dosing and monitoring of vancomycin are not universally applied. The findings of this survey highlight many opportunities for future research and quality improvement strategies.

Antimicrobial stewardship in the management of community-acquired pneumonia.

PURPOSE OF REVIEW: Antimicrobial stewardship can be applied to the management of community-acquired pneumonia (CAP) to optimize management while maintaining or improving the quality of patient outcomes. We discuss such applications, in general, and review the relevant recent literature. RECENT FINDINGS: Clinical pathways or care plans are a means to standardize care for a given disease state and thus improve or optimize the utilization of treatment modalities while at the same time maintaining or improving patient outcomes. Most recent publications describe the application of clinical pathways for the management of CAP in both pediatric and adult populations, reporting success in achieving compliance with national treatment guidelines. As a variation of clinical management pathways, audit tools have also been described that assist in determining the location and length of therapy and proper route of administration of antimicrobial agents with the aim of optimal resource utilization. Emerging rapid diagnostic tools allowing for early identification of pathogens and their antimicrobial susceptibility have great promise for early optimization of therapy for CAP. SUMMARY: There is a growing body of evidence that antimicrobial stewardship initiatives can be applied successfully and effectively to the management of CAP, benefiting both healthcare systems and patients. Such successful applications will likely grow as new techniques and technologies continue to evolve.

The Economic Impact of Starting, Stopping, and Restarting an Antibiotic Stewardship Program: A 14-Year Experience.

Regions Hospital started a multidisciplinary antibiotic stewardship program (ASP) in 1998. The program effectively shut down from 2002-2004 as key personnel departed and was then restarted but without the dedicated pharmacist and infectious diseases physician. Purchasing data (in dollars or dollars/patient/day) unadjusted for inflation served as a surrogate marker of antibiotic consumption. These data were reviewed monthly, quarterly, and yearly along with antibiotic susceptibility patterns on a semi-annual basis. Segmented regression analysis was use to compare restricted antibiotic purchases for performance periods of 1998-2001 (construction), 2002-2004 (de-construction), and 2005-2011 (reconstruction). After 4 years (1998-2001) of operation, a number of key participants of the ASP departed. For the following three years (2002-2004) the intensity and focus of the program floundered. This trend was averted when the program was revitalized in early 2005. The construction, deconstruction, and reconstruction of our ASP provided a unique opportunity to statistically examine the financial impact of our ASP or lack thereof in the same institution. We demonstrate a significant economic impact during ASP deconstruction and reconstruction.

Comparison of Hospitalwide and Custom Antibiograms for Clinical Isolates of Pseudomonas aeruginosa.

BACKGROUND: Hospital antibiograms, which are commonly used to determine empiric antibiotic therapy and as a tool in stewardship in a given institution, are open to bias when combining susceptibility results from various sources, hospital locations, and patient groups. METHODS: We assessed such differences, using Pseudomonas aeruginosa as a test case, with susceptibility data from 2008 through 2010 in our institution. Each year's data were analyzed separately. A variety of specific or subcategorical antibiograms were compared with each other as well as with versions including all tested isolates and those with results from inpatients and outpatients only. Statistical significance was determined at the .01 level using either chi-square or Fisher exact test, and clinical significance was defined as ≥10 percentage points. RESULTS: A variety of clinically significant differences were found that illustrated important differences within the intensive care unit environment and based on population, specifically adult versus pediatric. Concordance between statistically significant and clinically significant differences was poor. CONCLUSION: These results corroborate and extend previous similar observations and point to the potential importance of subanalyses in preparing the annual hospital antibiogram.

Stable susceptibility to aminoglycosides in an age of low level, institutional use.

INTRODUCTION: The use of aminoglycosides has decreased dramatically over several decades in the United States due to the introduction of safer Gram-negative agents. This study was conducted to assess possibly changing aminoglycoside susceptibility rates between 2006 and 2012 and in reference to 1992 use in the context of aminoglycoside use volume. METHODS: Quarterly adult use of amikacin, gentamicin and tobramycin were determined from the Medical University of South Carolina Medical Center, Charleston, South Carolina, USA, pharmacy drug use database and expressed as total aminoglycoside defined daily doses per 1,000 patient days for the years 1992 and 2006 through 2012. Annual susceptibility of Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae, for the years 1992, 2006, and 2008 through 2012 were retrieved from our hospital's clinical microbiology database (duplicate isolates were excluded). Quarterly and annualized aminoglycoside usage rates were compared to the other years of interest. Likewise, susceptibility rates of the target organisms to each aminoglycoside were also compared across the same timeframe. RESULTS: While total use of aminoglycosides decreased slightly from 1992 to 2006, it increased by about 40% between 2006 and 2008 and then stabilized. Changes in susceptibility rates between 1992 and 2006 were all ≤±9% with the exception of K. pneumoniae susceptibility to amikacin (-17%). Changes in susceptibility from 1992 to 2012 were also all ≤±9%. Tobramycin remained the most active versus P. aeruginosa (% susceptible = 90), while amikacin remained most active versus E. coli and K. pneumoniae (% susceptible = 98 and 98, respectively). CONCLUSION: With low level use of aminoglycosides in our institution over the past 2 decades, the susceptibility of key Gram-negative pathogens has remained relatively stable, preserving these agents as potential alternative therapies as resistance arises to other frequently used antibiotics.