ZAVICEFTA (ceftazidime and avibactam) Clinical Efficacy and Tolerability

Clinical Efficacy

ZAVICEFTA: Proven efficacy for patients with cUTIs and cIAIs, investigated in 3 clinical trials: REPRISE, RECLAIM and RECAPTURE1-3

REPRISE: The first pathogen-directed clinical trial for ZAVICEFTA examining its efficacy against ceftazidime-resistant Gram-negative bacteria1

Effective against serious Gram-negative infections, including strains resistant to ceftazidime1

*Preferred best available therapy options for cUTI and cIAI were 5–21 days of treatment with meropenem, Imipenem, doripenem, colistin and (for cIAI) tigecycline, administered intravenously, but any therapy, including combination treatment, was permitted.

**Formal statistical comparison not performed; corresponding CIs for the efficacy of best available therapy were used to provide context for descriptive estimates of ceftazidime-avibactam efficacy.

†Patients in the mMITT population are defined as carrying a pathogen at the start of treatment and who received at least one dose of study drug.

RECLAIM: Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of cIAI2

As effective as a carbapenem when combined with metronidazole in hospitalised patients with Gram-negative cIAIs2

*The 2 combined studies were sized to provide 90% power for a 10% non-inferiority margin and thus 95% power for a 12.5 non-inferiority margin.
**Patients in the mMITT population are defined as carrying a pathogen at the start of treatment.
†In most cases microbiological outcomes (eradication) were presumed based on clinical outcome, since intra-abdominal cultures require an invasive procedure and were therefore only obtained if clinically indicated.

RECAPTURE: Ceftazidime-avibactam versus doripenem for the treatment of cUTI, including acute pyelonephritis3

As effective as a carbapenem in hospitalised patients with Gram-negative cUTIs3

*Non-inferiority of ceftazidime-avibactam vs doripenem was demonstrated for the FDA co-primary endpoints (prespecified margin of −10%), as well for the EMA primary endpoint (prespecified margin of −12.5%). The lower limit of the 2-sided 95% CI for the treatment difference for the EMA primary endpoint was also >0%, showing superiority of ceftazidime-avibactam at the 5% significance level.

**Patients in the mMITT population are defined as carrying a pathogen at the start of treatment and who received at least one dose of study drug.

Tolerability

ZAVICEFTA: A safety and tolerability profile consistent with a cephalosporin2

In Phase III clinical trials, the adverse-event profile of ZAVICEFTA was similar to that seen with either best available therapy, doripenem or meropenem1–3

•   Overall rates of any AE were low in the ZAVICEFTA and comparator arms1–4

•   Most common (>5%) AEs for ZAVICEFTA were positive Direct Coombs test, nausea and diarrhoea4

•   Nausea and diarrhea were  usually mild or moderate in intensity4

•   No new, significant or unexpected safety concerns were identified in Phase III clinical trials1–3

AEs in cIAI and cUTI

The following adverse reactions have been reported with ceftazidime alone and/or identified during the Phase 2 and Phase 3 trials with Zavicefta. Please see Product Information for full list of undesirable effects1.

*ZAVICEFTA use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the cross-matching of blood and/or may cause drug-induced immune haemolytic anaemia. While DAGT seroconversion in patients receiving ZAVICEFTA was very common in clinical studies (the estimated range of seroconversion across Phase III studies was 3.2% to 20.8% in patients with a negative Coombs test at baseline and at least one follow-up test), there was no evidence of haemolysis in patients who developed a positive DAGT on treatment. However, the possibility that haemolytic anaemia could occur in association with ZAVICEFTA treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with ZAVICEFTA should be investigated for this possibility.

Special warnings and precautions for use4

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8). In case of hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems.

Clostridium difficile-associated diarrhoea

Clostridium difficile-associated diarrhoea has been reported with ceftazidime/avibactam, and can range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta (see section 4.8). Discontinuation of therapy with Zavicefta and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Renal impairment

Ceftazidime and avibactam are eliminated via the kidneys, therefore, the dose should be reduced according to the degree of renal impairment (see section 4.2). Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment.

In patients with renal impairment, close monitoring of estimated creatinine clearance is advised. In some patients, the creatinine clearance estimated from serum creatinine can change quickly, especially early in the course of treatment for the infection.

Nephrotoxicity

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.

Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of haemolytic anaemia

Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the cross-matching of blood and/or may cause drug induced immune haemolytic anaemia (see section 4.8). While DAGT seroconversion in patients receiving Zavicefta was very common in clinical studies (the estimated range of seroconversion across Phase 3 studies was 3.2% to 20.8% in patients with a negative Coombs test at baseline and at least one follow-up test), there was no evidence of haemolysis in patients who developed a positive DAGT on treatment. However, the possibility that haemolytic anaemia could occur in association with Zavicefta treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Zavicefta should be investigated for this possibility.

Limitations of the clinical data

Clinical efficacy and safety studies of Zavicefta have been conducted in cIAI, cUTI and HAP (including VAP).

Complicated intra-abdominal infections

In two studies in patients with cIAI, the most common diagnosis (approximately 42%) was appendiceal perforation or peri-appendiceal abscess. Approximately 87% of patients had APACHE II scores of ≤ 10 and 4.0% had bacteraemia at baseline. Death occurred in 2.1% (18/857) of patients who received Zavicefta and metronidazole and in 1.4% (12/863) of patients who received meropenem.

Among a subgroup with baseline CrCL 30 to 50 mL/min death occurred in 16.7% (9/54) of patients who received Zavicefta and metronidazole and 6.8% (4/59) of patients who received meropenem. Patients with CrCL 30 to 50 mL/min received a lower dose of Zavicefta than is currently recommended for patients in this sub-group.

Complicated urinary tract infections

In two studies in patients with cUTI, 381/1091 (34.9%) patients were enrolled with cUTI without pyelonephritis while 710 (65.1%) were enrolled with acute pyelonephritis (mMITT population). A total of 81 cUTI patients (7.4%) had bacteraemia at baseline.

Hospital-acquired pneumonia, including ventilator-associated pneumonia

In a single study in patients with nosocomial pneumonia 280/808 (34.7%) had VAP and 40/808 (5.0%) were bacteraemic at baseline.

Patients with limited treatment options

The use of ceftazidime/avibactam to treat patients with infections due to Gram-negative aerobic pathogens who have limited treatment options is based on experience with ceftazidime alone and on analyses of the pharmacokinetic-pharmacodynamic relationship for ceftazidime/avibactam (see section 5.1).

Spectrum of activity of ceftazidime/avibactam

Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes (see sections 4.2 and 5.1). Additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process.

The inhibitory spectrum of avibactam includes many of the enzymes that inactivate ceftazidime, including Ambler class A β-lactamases and class C β-lactamases. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes (see section 5.1).

Non-susceptible organisms

Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. enterococci, fungi), which may require interruption of treatment or other appropriate measures.

Interference with laboratory tests

Ceftazidime may interfere with copper reduction methods (Benedict's, Fehling's, Clinitest) for detection of glycosuria leading to false positive results. Ceftazidime does not interfere with enzyme-based tests for glycosuria.

Controlled sodium diet

Each vial contains a total of 6.44 mmol of sodium (approximately 148 mg). This should be considered when administering Zavicefta to patients who are on a controlled sodium diet.

References

1. Carmeli Y, et al. Lancet Infect Dis 2016;16:661–73.

2. Mazuski JE, et al. Clin Infect Dis 2016;62:1380–9.

3. Wagenlehner FM, et al. Clin Infect Dis 2016;63:754–62.

4. ZAVICEFTA. Summary of product characteristics, 2018.