Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals : A Retrospective Cohort Study.

BACKGROUND: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. OBJECTIVE: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). DESIGN: Retrospective cohort. SETTING: 619 U.S. hospitals. PARTICIPANTS: Adult inpatients. MEASUREMENTS: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. RESULTS: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. LIMITATION: Residual confounding. CONCLUSION: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration; NIH Intramural Research Program.

The role of new antimicrobials for Gram-negative infections in daily clinical practice.

PURPOSE OF REVIEW: To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field. RECENT FINDINGS: Novel agents, both belonging to ß-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future. SUMMARY: The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.

New Drugs 2019, part 4.

This article reviews nine drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.

A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis.

Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum ß-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.).

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model.

Plazomicin is a novel aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model. ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem, and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem, or tigecycline human-equivalent doses alone or in combinations of plazomicin-meropenem and plazomicin-tigecycline. Treatments were initiated at 1 h postinfection and continued for 24 h. Efficacy was assessed by determination of mouse survival through 96 h. Compared with the survival of the controls, plazomicin monotherapy produced a significant improvement in survival for all mice infected with the isolates (P < 0.05) and resulted in overall survival rates of 86% (n = 50) and 53.3% (n = 30) for mice infected with isolates with plazomicin MICs of ≤4 and ≥8 mg/liter, respectively (P < 0.05). The survival of the meropenem and tigecycline groups correlated well with susceptibilities of their respective isolates, with incremental increases in survival being observed at lower MIC values. For mice infected with isolate Klebsiella pneumoniae 561 (plazomicin, meropenem, and tigecycline MICs, 8, >32, and 2 mg/liter, respectively), combination therapies showed a significant reduction in mortality compared with that achieved with any monotherapy (P < 0.05). Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably, for mice infected with isolates with plazomicin MICs of ≤4 mg/liter. As evidenced by our current data, coadministration of meropenem or tigecycline could potentially lead to a further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MICs of ≤4 mg/liter, including carbapenem-resistant isolates.

Plazomicin is effective in a non-human primate pneumonic plague model.

The efficacy of plazomicin for pneumonic plague was evaluated in a non-human primate model. African Green monkeys challenged with a lethal aerosol of Yersinia pestis [median (range) of 98 (15-331) LD50s] received placebo (n=12) or 'humanized' dose regimens (6.25, 12.5 or 25mg/kg every 24h) of plazomicin (n=52) after the onset of fever for a duration of 5 or 10days. All animals treated with placebo died, while 36 plazomicin-treated animals survived through study end. The majority (33/36) were either in the 10-day (high-/mid-/low-dose) or 5-day high-dose groups. The findings suggest an exposure range of plazomicin for treatment of pneumonic/bacteremic Y. pestis infection in humans.

Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model.

BACKGROUND: Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells. METHODS: We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model. Plazomicin was administered in a humanized fashion (ie, administration of decrementing doses 5 times over 24 hours, mimicking a human daily administration profile). Pharmacokinetic profiling was performed in plasma and epithelial lining fluid. All samples were simultaneously analyzed with a population model. Mouse cohorts were treated for 24 hours; other cohorts treated with the same therapy were observed for another 24 hours after therapy cessation, allowing delineation of the therapeutic effect necessary to reduce the bacterial burden to a level below the half-saturation point. RESULTS: The mean bacterial burden (±SD) at which granulocyte-mediated kill was half saturable was 2.45 × 10(6) ± 6.84 × 10(5) colony-forming units of bacteria per gram of tissue (CFU/g). Higher levels of plazomicin exposure reduced the bacterial burden to <5 log10 CFU/g, allowing granulocytes to kill an additional 1.0-1.5 log CFU/g over the subsequent 24 hours. CONCLUSIONS: For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospital-acquired pneumonia), it is imperative to kill ≥2 log10 CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance.

In vitro activity of plazomicin against quinolone-resistant gram-negative bacteria isolated from catheter-associated urinary tract infections.

Quinolone resistance among uropathogens is an increasing concern. Plazomicin is a new aminoglycoside that shows promising results against resistant bacteria. However, no study has yet tested its effect specifically on quinolone-resistant organisms. This study aimed to evaluate the in vitro activity of plazomicin and comparator drugs against quinolone-resistant Gram-negative isolates of catheter-associated urinary tract infections (CAUTI). Plazomicin demonstrated high inhibiting activity against Enterobacteriaceae isolates (95.9% at MIC≤ 2 mg/L), with MIC50/90 was 1/2 mg/L. High MICs values were detected against non-Enterobacteriaceae isolates (MIC50/90, 4/32 mg/L). Plazomicin had susceptibility rate of 97.2% against Enterobacteriaceae isolates carrying aminoglycosides modifying enzymes (AME) genes, while other aminoglycosides, amikacin and gentamicin showed reduced activity (32.4% and 25.4%, respectively). In conclusion, plazomicin showed potent in vitro activity against quinolone-resistant Enterobacteriaceae causing CAUTI, regardless of the AME pattern.

Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Children.

Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes. Optimal treatment strategies for CRE infections continue to evolve. A lack of pediatric-specific comparative effectiveness data, uncertain pediatric dosing regimens for several agents, and a relative lack of new antibiotics with pediatric indications approved by the US Food and Drug Administration (FDA) collectively present unique challenges for children. In this review, we provide a framework for antibiotic treatment of CRE infections in children, highlighting relevant microbiologic considerations and summarizing available data related to the evaluation of FDA-approved antibiotics (as of September 2019) with CRE activity, including carbapenems, ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam, polymyxins, tigecycline, eravacycline, and plazomicin.

Plazomicin for the treatment of patients with complicated urinary tract infection.

In June 2018, the United States Food and Drug Administration (FDA) approved plazomicin, a novel neoglycoside, for the treatment of adults with complicated urinary tract infections who have limited or no alternative treatment options. This approval was based on substantial preclinical and clinical work, and marks an important advance in the treatment of multidrug-resistant bacterial pathogens. This manuscript reviews the in vivo and in vitro work that led to the approval of plazomicin and examines how the drug may be used in the years ahead to treat patients with aggressive and life-threatening infections.

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation.

Aminoglycosides are cidal inhibitors of bacterial protein synthesis that have been utilized for the treatment of serious bacterial infections for almost 80 years. There have been approximately 15 members of this class approved worldwide for the treatment of a variety of infections, many serious and life threatening. While aminoglycoside use declined due to the introduction of other antibiotic classes such as cephalosporins, fluoroquinolones, and carbapenems, there has been a resurgence of interest in the class as multidrug-resistant pathogens have spread globally. Furthermore, aminoglycosides are recommended as part of combination therapy for empiric treatment of certain difficult-to-treat infections. The development of semisynthetic aminoglycosides designed to overcome common aminoglycoside resistance mechanisms, and the shift to once-daily dosing, has spurred renewed interest in the class. Plazomicin is the first new aminoglycoside to be approved by the FDA in nearly 40 years, marking the successful start of a new campaign to rejuvenate the class.

Novel pharmacotherapy for the treatment of hospital-acquired and ventilator-associated pneumonia caused by resistant gram-negative bacteria.

INTRODUCTION: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP. AREAS COVERED: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed. EXPERT OPINION: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated.

Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options.

The increasing prevalence of infections due to multidrug-resistant (MDR) gram-negative bacteria constitutes a serious threat to global public health due to the limited treatment options available and the historically slow pace of development of new antimicrobial agents. Infections due to MDR strains are associated with increased morbidity and mortality and prolonged hospitalization, which translates to a significant burden on healthcare systems. In particular, MDR strains of Enterobacteriaceae (especially Klebsiella pneumoniae and Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii have emerged as particularly serious concerns. In the United States, MDR strains of these organisms have been reported from hospitals throughout the country and are not limited to a small subset of hospitals. Factors that have contributed to the persistence and spread of MDR gram-negative bacteria include the following: overuse of existing antimicrobial agents, which has led to the development of adaptive resistance mechanisms by bacteria; a lack of good antimicrobial stewardship such that use of multiple broad-spectrum agents has helped perpetuate the cycle of increasing resistance; and a lack of good infection control practices. The rising prevalence of infections due to MDR gram-negative bacteria presents a significant dilemma in selecting empiric antimicrobial therapy in seriously ill hospitalized patients. A prudent initial strategy is to initiate treatment with a broad-spectrum regimen pending the availability of microbiological results allowing for targeted or narrowing of therapy. Empiric therapy with newer agents that exhibit good activity against MDR gram-negative bacterial strains such as tigecycline, ceftolozane-tazobactam, ceftazidime-avibactam, and others in the development pipeline offer promising alternatives to existing agents.

Plazomicin: an investigational therapy for the treatment of urinary tract infections.

INTRODUCTION: Living in the ever-expanding era of multidrug-resistant (MDR), extensively drug-resistant (XDR), and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the approaching fear of the "End of Antibiotics." Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance. A newer aminoglycoside active against several MDR-XDR microorganisms is herein presented and discussed. AREAS COVERED: Herein, the authors present the currently available information on plazomicin. This includes the current knowledge concerning plazomicin's: mechanisms of action, in vitro activity and interactions, its pharmacokinetics, its clinical efficacy in complicated urinary tract infections (cUTIs) and acute pyelonephritis, and its toxicity issues. EXPERT OPINION: Plazomicin was developed to evade all clinically relevant aminoglycoside-modifying enzymes. Unfortunately, ribosomal enzymatic modification by ribosomal 16S-rRNA methyltransferases confers broad-spectrum high-level aminoglycoside resistance. Still, plazomicin demonstrates high activity against the Enterobacteriaceae including extended spectrum beta lactamase and most carbapenemase producers, as well as several of the non-fermenters. When compared to levofloxacin, the in vivo activity of plazomicin in complicated urinary tract infections (cUTIs) and in acute pyelonephritis in humans was very promising. Furthermore, regarding safety, no clinically significant effects on renal, vestibular, or cochlear function have been observed both at Phase I and II studies in humans, with mild to moderate adverse events being dose related. However, the authors believe that the real position of plazomicin in the MDR-XDR world will be revealed once pending Phase III studies are completed.

Aminoglycoside antibiotics in infectious diseases. An overview.

This article presents an overview of the aminoglycoside antibiotics used in clinical practice. Facts concerning the discovery and properties of the aminoglycosides are followed by information about spectrums of activity and mechanisms of action and resistance. Individual compounds are compared and proposals on the possibilities for their clinical use, both as single drugs and in combination with beta-lactam antibiotics, are made. The importance placed on measuring the serum concentrations of aminoglycoside antibiotics should serve as a remainder that this procedure is important, on one hand, to increase clinical efficacy and, on the other, to reduce the side effects of these antibiotics. Finally, the aminoglycosides are compared briefly with other antibacterial compounds, some of which are very new. There is no doubt that in the future the aminoglycosides will continue to occupy an important place in the treatment of severe infections, although newly developed agents appear to be effective complements.

Qualitative overview of randomized trials of aminoglycosides.

A qualitative overview was conducted of randomized clinical trials comparing two or more of the following aminoglycoside antibiotics--amikacin. gentamicin, netilmicin, sisomicin, and tobramycin--with respect to efficacy, nephrotoxicity, or auditory toxicity. Design features considered included number of participants in each treatment arm, proportion of randomized participants available for analysis, blinding of evaluators, and report of statistically significant results. The proportion of participants eligible for analysis was less than or equal to 75 percent for 66 percent of the comparisons regarding nephrotoxicity, 43 percent regarding efficacy, and 19 percent regarding auditory toxicity. Twenty-nine percent of the trials reported that evaluators were blinded to treatment group assignments. The results of most trials showed no significant differences, although sample sizes were, in general, smaller than necessary to detect moderate differences. Quantitative overviews may be a useful means of detecting real differences in risk that are not apparent from the results of several individual small trials.

Outbreak of amikacin-resistant Enterobacteriaceae in an intensive care nursery.

An outbreak of amikacin-resistant Enterobacteriaceae (KES) occurred in the Intensive Care Nursery (ICN) of the Louisville General Hospital from January 1978 through March 1978. Epidemic disease and an increased colonization rate in newborn infants due to amikacin-resistant microorganisms has not been documented previously. Three of the 11 neonates died. The organisms isolated were resistant to amikacin and two experimental aminoglycosides, sissomicin and netilmicin. The outbreak was contained following institution of several control measures, including pharyngeal inoculation of an experimental strain of alpha streptococcus in four infants.