Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults

Lodise, Thomas; O'Donnell, J. Nicholas; Balevic, Stephen J.; Liu, Xing; Gu, Kenan; George, Jomy; Raja, Shruti; Guptill, Jeffrey T.; Zaharoff, Smitha; Schwager, Nyssa; Fowler, Vance G.; Wall, Alison; Wiegand, Katherine; Chambers, Henry F.

doi:10.1128/aac.00936-22

Cited by 9 publications

(5 citation statements)

References 51 publications

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“…Also, without loading doses, there will be on average a longer time to achieve targets in the critical early phase of treatment. In addition, the safety (including transaminase liability) of ceftazidime-avibactam plus aztreonam is unknown, although transaminase elevations have been reported to be more frequent with combinations including 8 g/day of aztreonam compared to those including 6 g/day [47]. Overall, the 'off-label' use of combinations of ceftazidime-avibactam plus aztreonam might not provide adequate exposures for all patients across the range of pathogen susceptibilities.…”

Section: Discussionmentioning

confidence: 99%

Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for phase IIa and phase III evaluation

Das

Riccobene

Carrothers

et al. 2023

Preprint

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Purpose A series of iterative population pharmacokinetic (PK) modelling and probability of target attainment (PTA) analyses were undertaken to support dose optimization for aztreonam-avibactam, a combination antibiotic. Methods Joint PTA analyses (primary target: 60% fT>8 mg/L for aztreonam, 50% fT>2.5 mg/L for avibactam) explored the impact of patient variability, and evaluated loading doses and extended infusions, and adjustments for patients with moderate (estimated creatinine clearance [CrCL] >30 to ≤50 mL/min) and severe renal impairment (>15 to ≤30 mL/min). Achievement of >90% joint PTA, and the impact of differential renal clearance, were considerations in dose selection. Results Dose selection for phase I and phase IIa (Cohort 1) was based on PK models of avibactam in patients and of aztreonam in healthy volunteers with ‘patient-like’ assumptions. Simulations demonstrated that: 3-h and continuous infusions provide comparable PTA; with patient variability, avibactam dose is the main driver of joint PTA; loading doses support more rapid joint target attainment. Aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h was selected for initial phase IIa evaluation in patients with complicated intra-abdominal infection. Later PTA analyses using expanded PK models supported an increased avibactam dose (500/167 mg loading; 1500/500 q6h maintenance) and were also used to select doses for renal impairment. Conclusion Aztreonam-avibactam 3-h infusions administered q6h are necessary to optimize joint PTA. Aztreonam-avibactam 500/167 mg loading 30-min infusion followed by 1500/500 mg maintenance 3-h infusions q6h (for CrCL >50 mL/min) is undergoing phase III evaluation. Clinical trial registration: NCT01689207 (September 21, 2012); NCT02655419 (January 14, 2016); NCT03329092 (November 1, 2017); NCT03580044 (July 9, 2018)

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Section: Discussionmentioning

confidence: 99%

Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for phase IIa and phase III evaluation

Das

Riccobene

Carrothers

et al. 2023

Preprint

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“…Aztreonam, co-administered with CAZ/AVI, was studied in healthy subjects which resulted in reduced AZT clearance. Meanwhile, continuously infused AZT was associated with severe hepatic transaminase elevations [ 113 ].…”

Section: Antimicrobials In Phase 3 Clinical Trialsmentioning

confidence: 99%

Novel Antimicrobial Agents for Gram-Negative Pathogens

et al. 2023

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Gram-negative bacterial resistance to antimicrobials has had an exponential increase at a global level during the last decades and represent an everyday challenge, especially for the hospital practice of our era. Concerted efforts from the researchers and the industry have recently provided several novel promising antimicrobials, resilient to various bacterial resistance mechanisms. There are new antimicrobials that became commercially available during the last five years, namely, cefiderocol, imipenem-cilastatin-relebactam, eravacycline, omadacycline, and plazomicin. Furthermore, other agents are in advanced development, having reached phase 3 clinical trials, namely, aztreonam-avibactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulopenem, tebipenem, and benapenem. In this present review, we critically discuss the characteristics of the above-mentioned antimicrobials, their pharmacokinetic/pharmacodynamic properties and the current clinical data.

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“…Although hepatic aminotransferase elevations were observed in 40% of the volunteers, none had any clinical findings suggestive of acute liver failure. Furthermore, the results of the PK analyses revealed that ATM clearance may be reduced when it is used in combination with CZA, thus resulting in higher-than-anticipated plasma exposure profiles in patients with reduced renal function and possibly more exposure-related adverse effects [130 ▪ ]. Finally, limited but promising clinical data suggests that CZA-ATM may be used for Sma infections [84 ▪ ,131,132].…”

Section: Introductionmentioning

confidence: 99%

Treatment approaches for severe Stenotrophomonas maltophilia infections

Mojica,

Bonomo,

van Duin

2023

Current Opinion in Infectious Diseases

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Purpose of review Stenotrophomonas maltophilia is an emerged opportunistic pathogen. Intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Herein, we provide an update on the most recent literature on treatment options for severe S. maltophilia infections. Recent findings Trimethoprim-sulfamethoxazole (SXT) is recognized as the first-line therapy for S. maltophilia infections. However, its clinical use is based on good in vitro activity and favorable clinical outcomes, rather than on solid minimum inhibitory concentration (MIC) correlations with pharmacokinetic/pharmacodynamics (PK/PD) and/or clinical outcomes. The same is true for other treatment options like levofloxacin (LVX) and minocycline (MIN). Recent PK/PD studies question the current clinical breakpoints for SXT, LVX, and MIN. Based on this, the latest guidance issued by the Infectious Diseases Society of America (IDSA) recommends using these agents only as part of a combination therapy. Alternatively, novel therapeutic options such as cefiderocol (FDC) and ceftazidime-avibactam plus aztreonam (CZA-ATM) are suggested, based on limited but promising clinical data. Summary PK/PD data and controlled clinical studies are needed to optimize current treatment options. Presently, combination therapy of SXT, LVX, MIN, or FDC, or monotherapy with CZA-ATM are recommended therapeutic options for severe-to-moderate S. maltophilia infections.

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Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults

Cited by 9 publications

References 51 publications

Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for phase IIa and phase III evaluation

Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for phase IIa and phase III evaluation

Novel Antimicrobial Agents for Gram-Negative Pathogens

Treatment approaches for severe Stenotrophomonas maltophilia infections

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