Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam.

An extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (PK) modeling and Monte Carlo simulations using clinical PK data supported modified ceftazidime-avibactam dosage adjustments for patients with moderate or severe renal impairment (comprising a 50% increase in total daily dose compared with the original dosage adjustments) to reduce the risk of subtherapeutic drug exposures in the event of rapidly improving renal function. The modified dosage adjustments were included in the ceftazidime-avibactam labeling information at the time of initial approval and were subsequently evaluated in the final phase 3 trial (in patients with HAP, including VAP), providing supportive data for the approved U.S. and European ceftazidime-avibactam dosage regimens across renal function categories. This review describes the analyses supporting the ceftazidime-avibactam dosage adjustments for renal impairment and discusses the wider implications and benefits of using modeling and simulation to support dosage regimen optimization based on emerging clinical evidence.

Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial.

BACKGROUND: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. METHODS: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. RESULTS: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.

Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme.

Objectives: This analysis evaluated the clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates pooled from the adult Phase III clinical trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) or nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). Methods: Baseline isolates from five Phase III randomized controlled trials of ceftazidime/avibactam versus predominantly carbapenem comparators in patients with cIAI (RECLAIM 1 and 2; NCT01499290 and RECLAIM 3; NCT01726023), cUTI (RECAPTURE 1 and 2; NCT01595438 and NCT01599806), NP including VAP (REPROVE; NCT01808092) and cIAI or cUTI caused by ceftazidime-non-susceptible Gram-negative pathogens (REPRISE; NCT01644643) were tested for MDR status and susceptibility to ceftazidime/avibactam and carbapenem-based comparators using CLSI broth microdilution methodology. Microbiological and clinical responses for patients with ≥1 MDR Enterobacteriaceae or P. aeruginosa isolate were assessed at the test-of-cure (TOC) visit. Results: In the pooled microbiologically modified ITT population, 1051 patients with MDR Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were identified. Favourable microbiological response rates at TOC for all MDR Enterobacteriaceae and MDR P. aeruginosa were 78.4% and 57.1%, respectively, for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators. The proportions of patients with ≥1 MDR isolate who were clinically cured at TOC were similar in the ceftazidime/avibactam (85.4%) and comparator (87.9%) arms. Conclusions: Ceftazidime/avibactam demonstrated similar clinical efficacy to predominantly carbapenem comparators against MDR Enterobacteriaceae and P. aeruginosa, and may be a suitable alternative to carbapenem-based therapies for cIAI, cUTI and NP/VAP caused by MDR Gram-negative pathogens.

In Vitro Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections.

The increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-ß-lactam-ß-lactamase inhibitor, restores the activity of ceftazidime against Ambler class A, C, and some class D ß-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa The in vitro activities of ceftazidime-avibactam versus comparators were evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; ClinicalTrials.gov identifier NCT01499290). Overall, in vitro activities were determined for 803 Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobic, and 255 anaerobic isolates obtained from 1,066 randomized patients at baseline. Susceptibility was determined by broth microdilution. The most commonly isolated Gram-negative, Gram-positive, and anaerobic pathogens were Escherichia coli (n = 549), Streptococcus anginosus (n = 130), and Bacteroides fragilis (n = 96), respectively. Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae, with an overall MIC90 of 0.25 mg/liter. In contrast, the MIC90 for ceftazidime alone was 32 mg/liter. The MIC90 value for ceftazidime-avibactam (4 mg/liter) was one dilution lower than that of ceftazidime alone (8 mg/liter) against isolates of Pseudomonas aeruginosa The ceftazidime-avibactam MIC90 for 109 ceftazidime-nonsusceptible Enterobacteriaceae isolates was 2 mg/liter, and the MIC range for 6 ceftazidime-nonsusceptible P. aeruginosa isolates was 8 to 32 mg/liter. The MIC90 values were within the range of susceptibility for the study drugs permitted per the protocol in the phase 3 study to provide coverage for aerobic Gram-positive and anaerobic pathogens. These findings demonstrate the in vitro activity of ceftazidime-avibactam against bacterial pathogens commonly observed in cIAI patients, including ceftazidime-nonsusceptible Enterobacteriaceae (This study has been registered at ClinicalTrials.gov under identifier NCT01499290.).

In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections.

Objectives: To evaluate the in vitro activity of ceftazidime/avibactam relative to comparator agents against Gram-negative isolates from a Phase 3 clinical trial programme for complicated urinary tract infections (RECAPTURE). Methods: The in vitro activity of ceftazidime/avibactam was evaluated against 840 Gram-negative pathogens isolated at baseline from 1033 randomized patients in two pivotal Phase 3 clinical trials for the treatment of complicated urinary tract infections. The trials were conducted in 160 institutions from 25 countries worldwide. Susceptibility testing was performed by broth microdilution at a central laboratory according to CLSI methodologies. Results: Overall, ceftazidime/avibactam showed significant activity against the Enterobacteriaceae and Pseudomonas aeruginosa with MIC 90 values of 0.5 and 8 mg/L, respectively. Against the most common Enterobacteriaceae, MIC 90 values were 0.25 mg/L for Escherichia coli , 1 mg/L for Klebsiella pneumoniae , 0.06 mg/L for Proteus mirabilis and 2 mg/L for Enterobacter cloacae . The ceftazidime/avibactam MIC 90 for 154 ceftazidime-non-susceptible isolates of Enterobacteriaceae was 1 mg/L and the ceftazidime/avibactam MIC 90 for 15 non-susceptible isolates of P. aeruginosa was 64 mg/L. There was a significant reduction in the ceftazidime/avibactam MIC relative to ceftazidime alone for most of the Enterobacteriaceae isolates. Conclusions: The ceftazidime/avibactam in vitro activity against these clinical urinary tract isolates demonstrates the potential utility of the drug in complicated urinary tract infections.

Huli oral health.

The Tari oral health study was conducted in 1985 and aimed to provide an oral health profile of a rural highlands community. The sample was selected from the database of the Tari Research Unit, Southern Highlands Province, Papua New Guinea and consisted of 815 Huli people aged from 3 to 64 years, in seven age groups, who were examined for oral health status and had completed an interview-questionnaire. A wide range of oral health status was seen, ranging from excellent to very poor. Dental caries and periodontal disease were common in the population. Oral habits such as smoking and betelnut chewing were associated with an increase in leukoplakia, which may lead to oral cancer in some people. Dental caries varied in prevalence and severity. Higher decayed, missing and filled teeth scores in the primary teeth of young children were associated with defective tooth formation (hypoplasia) linked to maternal and childhood illnesses and nutritional deficiencies. Older adults had the worst oral health, with the 45-64 year old group having a caries prevalence of 95% and a decayed, missing and filled teeth score of 14.7. Root surface caries, seen as a consequence of poor oral hygiene and gum recession, was the major site of caries attack in the older Hull. The public oral health services are unable to reach a large proportion of the rural population, and people continue to use traditional herbal and folk remedies. Many seek the skills of local tooth extractors who use six-inch nails with no anaesthetic.