Advancing New Antibacterial Drug Development for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia

Abstract Background New drug development for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) is critical. Challenges remain in the conduct of HABP/VABP trials, especially in the contexts of enrollment, endpoints, non-study antibacterial drug therapy, and antimicrobial resistance. Methods Four Phase 3 noninferiority trials (n=2,433 participants) submitted to the Food and Drug Administration after 2015 were analyzed for enrollment statistics, participant characteristics associated with 28-day all-cause mortality (ACM), microbiology, and receipt of non-study antibacterial drugs. All trials primarily enrolled patients with gram-negative bacterial infections. Results The mean trial length was 2.7 years and the mean recruitment rate was 0.17 participants/site/month. ACM at 28 days was 17.1% and was higher among participants diagnosed with ventilated HABP (31.9%) or VABP (19.0%) than non-ventilated HABP (9.9%). VABP participants tended to be younger, less likely to have chronic obstructive pulmonary disease, and more likely to have previously sustained an injury. Age, South American residence, diagnosis of ventilated HABP or VABP, and Acinetobacter baumannii infection were all associated with 28-day ACM in a multivariate logistic regression model. A. baumannii infection was most common in Eastern European and Asia/Pacific participants, and Eastern European isolates exhibited the highest levels of meropenem resistance. Concomitant non-study antibacterial drug therapy most commonly included beta-lactams and was initiated earliest in Western Europe. Conclusion This analysis of recent trials may assist in trial considerations for HABP/VABP development programs and promote needed antibacterial drug development for patients with serious infections.

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A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

Clinical Infectious Diseases ◽

10.1093/cid/ciab032 ◽

2021 ◽

Author(s):

Richard G Wunderink ◽

Antoine Roquilly ◽

Martin Croce ◽

Daniel Rodriguez Gonzalez ◽

Satoshi Fujimi ◽

...

Keyword(s):

Clinical Response ◽

Bacterial Pneumonia ◽

Double Blind Study ◽

Phase 3 ◽

Gram Positive ◽

Double Blind ◽

Intention To Treat ◽

The Difference ◽

Hospital Acquired ◽

Noninferiority Margin

Abstract Background Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. Methods In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. Results Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, –1.8%; 95% confidence interval [CI]: –8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, –7.6%; 97.5% CI: –15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. Conclusions Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. Clinical Trials Registration NCT02019420.

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MODERN APPROACHES TO TREATMENT OF PSEUDOMONAS AERUGINOSA VENTILATOR-ASSOCIATED PNEUMONIA (LITERATURE REVIEW)

Wiadomości Lekarskie ◽

10.36740/wlek201905130 ◽

2019 ◽

Vol 72 (5) ◽

pp. 892-896

Author(s):

Olha A. Poda ◽

Tetyana O. Kryuchko ◽

Inna N. Nesina ◽

Olha Ya. Tkachenko ◽

Nataliia V. Kuzmenko

Keyword(s):

Pseudomonas Aeruginosa ◽

Causative Agent ◽

Optimal Dose ◽

Correct Choice ◽

Antibacterial Drug ◽

Controversial Issues ◽

Ventilator Associated Pneumonia ◽

Scientific Investigations ◽

Multiresistant Strains ◽

Hospital Acquired

Introduction: Nowadays anti-microbial therapy of ventilator-associated pneumonia caused by is one of the most topical issue as a consequence of widespread multiresistant strains of causative agent and their biological peculiarity of actively formation of resistance to new antibacterial drugs. The aim is to describe modern approaches to therapy of ventilator-associated pneumonia causative agent of which is presented by Pseudomonas aureginosa . Materials and methods: An analysis and summing up of results of scientific investigations described in medical publications concerning the issues of therapy of ventilatorassociated pneumonia caused by Pseudomonas aureginosa was done. Conclusions: Despite the development of modern approaches to anti-microbial therapy of ventilator-associated pneumonia caused by Pseudomonas aeruginosa, which are also concerned with such controversial issues as correct choice of antibacterial drug, its optimal dose, and duration of this therapy, the problem of treatment of hospital-acquired infections of respiratory airways caused by Pseudomonas aeruginosa has been discussable yet and requires the further study.

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Randomized Trial of Ceftazidime-Avibactam vs Meropenem for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (REPROVE): Analyses per US FDA–Specified End Points

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz149 ◽

2019 ◽

Vol 6 (4) ◽

Cited By ~ 10

Author(s):

Antoni Torres ◽

Doug Rank ◽

David Melnick ◽

Ludmyla Rekeda ◽

Xiang Chen ◽

...

Keyword(s):

Randomized Trial ◽

Bacterial Pneumonia ◽

End Points ◽

Us Fda ◽

Hospital Acquired

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A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study)

Clinical Infectious Diseases ◽

10.1093/cid/ciaa803 ◽

2020 ◽

Cited By ~ 5

Author(s):

Ivan Titov ◽

Richard G Wunderink ◽

Antoine Roquilly ◽

Daniel Rodríguez Gonzalez ◽

Aileen David-Wang ◽

...

Keyword(s):

Clinical Response ◽

Bacterial Pneumonia ◽

Severe Renal Impairment ◽

Apache Ii Score ◽

Efficacy And Safety ◽

Double Blind ◽

Gram Negative ◽

Mitt Population ◽

All Cause Mortality ◽

Hospital Acquired

Abstract Background Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population. Results Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, −5.3% [95% confidence interval {CI}, −11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, −3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. Conclusions Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. Clinical Trials Registration NCT02493764.

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