Ceftazidime-Avibactam Therapy for Ceftazidime-Resistant Enterobacteriaceae and Pseudomonas Infections

22 May, 23

Introduction

Carbapenemase-producing pathogens pose a threat to the effectiveness of carbapenems in treating multidrug-resistant Gram-negative bacterial infections, new agents such as ceftazidime-avibactam is needed. While traditional clinical trials can provide valuable information about safety, tolerability, and efficacy, they may not be sufficient in assessing efficacy against resistant pathogens. Therefore, pathogen-directed studies are conducted to evaluate the effectiveness of ceftazidime-avibactam in treating drug-resistant infections.

Aim

To compare Ceftazidime-Avibactam with the best available therapy for the treatment of complicated urinary tract and intra-abdominal infections caused by ceftazidime-resistant Gram-negative pathogens.

Method

Study Design

Open-label, randomized phase 3 trial

Patient Profile

Age: 18-90 years old; both male and female

Diagnosis: Confirmed complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa

Treatment Strategy

Ceftazidime-avibactam treatment group:

Patients received 5-21 days of treatment with ceftazidime-avibactam (combination of 2000 mg ceftazidime + 500 mg avibactam).
Administered as 2-hour intravenous (IV) infusion every 8 hours.

Best available therapy:

Preferred therapy options for complicated urinary tract infection and complicated intra-abdominal infection were meropenem, imipenem, doripenem, colistin, and (for complicated intra-abdominal infection) tigecycline, administered intravenously

Endpoints

Primary Endpoints

Clinical response (cure, failure, or indeterminate) at the test-of-cure visit which was 7-10 days after last infusion of study therapy.

Clinical cure was defined as complete resolution of signs and symptoms of index infection

Secondary Endpoints

Clinical response at end of treatment and at follow-up visits 1 and 2
Clinical response at the test-of-cure visit by baseline gram-negative pathogen and entry diagnosis
Per-patient favorable microbiological response at end of treatment, test-of-cure visit and follow-up visits 1 and 2

Favorable microbiological response was defined as absence of causative pathogen from the site of infection

Safety Endpoints

Adverse events (AEs)
Serious AEs (SAEs)
Laboratory parameters including liver function tests

Results

333 patients were randomly assigned to two groups:

165 to ceftazidime-avibactam; 168 to best available therapy

Primary outcome was analyzed for:

154 patients in the ceftazidime-avibactam group; 148 patients in the best available therapy group

The proportion of patients with a clinical cure at the test-of-cure visit was similar between ceftazidime-avibactam and best available therapy groups. (Table 1)

Table 1. % of patients with a clinical cure

Patient Group / Condition	Clinical Cure at Test-of-Cure Visit (%)- Ceftazidime-Avibactam	Clinical Cure at Test-of-Cure Visit (%) - Best Available Therapy
Complicated Urinary Tract Infection	92% (132/144)	94% (129/137)
Acute Pyelonephritis	91% (52/57)	90% (63/70)
Complicated Intra-Abdominal Infection	80% (8/10)	55% (6/11)

Table 2. % of patients with favorable microbiological response at test-of-cure visit

Patient Group / Condition	Ceftazidime-Avibactam	Best Available Therapy
Complicated Urinary Tract Infection	82% (118/144)	64% (88/137)
Acute Pyelonephritis	88% (50/57)	70% (49/70)
Complicated Intra-Abdominal Infection	80% (8/10)	55% (6/11)

Adverse events occurred in 31% of patients in the ceftazidime-avibactam group and 39% of patients in the best available therapy group; most were mild or moderate in intensity.
Gastrointestinal disorders was the most commonly reported treatment-emergent adverse events in both groups.

Conclusions

The findings offer substantiation for the effectiveness of ceftazidime-avibactam as a viable substitution for carbapenems in treating patients diagnosed with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa infections.

Lancet Infect Dis. 2016; 16:661-73.