Sulbactam and Durlobactam

See the table below for the recommended dosage of sulbactam/durlobactam in patients (18 years of age and older) based on renal function.

Adjustments to the dosing regimen are recommended for patients with creatinine clearance (CLcr) less than 45 mL/min. For patients undergoing intermittent hemodialysis (HD), start the dosing of sulbactam/durlobactam immediately after the completion of HD.

For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly.

Dosage of sulbactam and durlobactam in patients (18 years of age and older) based on renal function:

^* CLcr = creatinine clearance estimated by Cockcroft-Gault equation
^† For patients on hemodialysis, the dose should be administered after the dialysis session has ended.

Patients Receiving Continuous Renal Replacement Therapy (CRRT)

Limited information is available to provide a dosage recommendation in this setting and therapy should be guided by the patient’s clinical status. While on CRRT, a patient’s residual renal function may change, which may warrant a change in sulbactam/durlobactam dosage. Monitor renal function regularly and adjust the dosage of sulbactam/durlobactam accordingly as renal function may change during the course of therapy.

Concomitant administration with OAT1 inhibitors may increase plasma concentrations of sulbactam. Concomitant administration of OAT1 inhibitors (e.g., probenecid) with sulbactam/durlobactam is not recommended.

CLcr 130 mL/min or greater may be seen in seriously ill patients who are receiving intravenous fluid resuscitation. Dosage adjustment of sulbactam/durlobactam is required in patients with CLcr 130 mL/min or greater. Monitor renal function regularly and adjust the dosage of sulbactam/durlobactam accordingly as renal function may change during the course of therapy.

Dosage of sulbactam and durlobactam in patients (18 years of age and older): 1 g of sulbactam and 1 g of durlobactam 1 g every 4 hours.

Risk Summary

Sulbactam/durlobactam combination

There are no available data on the use of sulbactam/durlobactam in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Sulbactam

Available published data from case reports and case series with sulbactam use in combination with ampicillin during pregnancy over many decades have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. The published literature reports that sulbactam crosses the human placenta. Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of harm to the fetus due to sulbactam (see Data).

Durlobactam

There are no available data on the use of durlobactam in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Durlobactam administered to pregnant mice and rats during organogenesis, showed no drug-induced fetal malformations but an increased incidence of skeletal variations was observed in mice at 2- and 4-times the Maximum Recommended Human Dose (MRHD) (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Sulbactam:

Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of harm to the fetus due to sulbactam sodium/ampicillin sodium.

Durlobactam:

Daily administration of durlobactam at 400, 800, or 1600 mg/kg/day (administered as four doses per day) via subcutaneous injection to pregnant mice from gestation day (GD) 6 through 15 resulted in durlobactam-related, increased incidence of skeletal variations (unossified calcaneum) of the hindlimb and asymmetrical ossification of the sternebrae and supernumerary ribs at 800 and/or 1600 mg/kg, equivalent to 2- and 4-times the maximum recommended human dose based on area under the curve (AUC) comparisons. No adverse effects on mean body weight, reproductive performance, or cesarean section parameters were observed in any pregnant mice. IV infusion (2 hours/day) of durlobactam to pregnant female Sprague Dawley rats from GD 6 to weaning on Lactation Day 20 at a dose level of 300 or 1000 mg/kg/day was well tolerated with no adverse maternal effects in either group. Similarly, there was no adverse effect of maternal treatment in either group on embryo-fetal, perinatal or postnatal development up to 1000 mg/kg/day (approximately 4 times the MRHD based on AUC).

Risk Summary

There are no data on the presence of durlobactam in human or animal milk. Sulbactam is present in human milk in low concentrations. Published data report sulbactam in breastmilk at an estimated maximum daily infant dose of 560 mcg/kg/day (1% to 2% of adult weight-adjusted dose), assuming mean milk consumption of 200 mL/kg/day. There are no data on the effects of sulbactam/durlobactam combination, sulbactam, or durlobactam on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sulbactam/durlobactam and any potential adverse effects on the breastfed child from sulbactam/durlobactam or from the underlying maternal condition.

Carcinogenesis

Carcinogenicity studies with sulbactam/durlobactam have not been conducted.

Mutagenesis

Durlobactam was negative in genetic toxicology studies including the Salmonella typhimurium bacterial reverse mutation assay, in vivo and in vitro micronucleus assays, and the in vivo Pig-A assay in rats.

Genetic toxicology studies were not conducted with sulbactam or the combination of sulbactam-durlobactam.

Impairment of Fertility

No adverse effects on fertility, reproductive performance, fetal viability, growth, or postnatal development were observed in male and female rats, and female mice for durlobactam at intravenous doses up to 1000 mg/kg/day (approximately 4 times the MRHD based on AUC comparisons) and subcutaneous doses up to 1600 mg/kg/day, (equivalent to 4 times the MRHD based on AUC comparisons) respectively.

Clinical Trials Experience

Clinical trials are conducted under widely varying conditions, therefore adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of durlobactam with or without sulbactam was evaluated in 380 adult subjects across six phase 1 trials, one phase 2 trial in patients with complicated urinary tract infections (cUTIs) including acute pyelonephritis, and one phase 3 trial (also referred to as Trial 1) in adult patients with infections caused by Acinetobacter baumannii-calcoaceticus complex including hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and ventilated pneumonia (VP).

In the randomized, active-controlled portion of the phase 3 trial, 91 patients received 1 g sulbactam and 1 g durlobactam, or renally adjusted dose intravenously over 3 hours every 6 hours and 86 patients were treated with colistin 2.5 mg/kg (or renally adjusted dose) intravenously over 30 minutes every 12 hours after an initial loading dose of colistin 2.5 to 5 mg/kg. Both treatment arms also received 1 g imipenem/1 g cilastatin (or renally adjusted dose) intravenously every 6 hours as background therapy for potential HABP/VABP pathogens other than Acinetobacter baumannii-calcoaceticus complex. The mean duration of sulbactam/durlobactam therapy was 9 days versus 8 days for colistin.

Serious Adverse Reactions and Discontinuation of Treatment

Thirty-six patients (40%) in the sulbactam/durlobactam treatment group and 42 patients (49%) in the colistin treatment group experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 10/91 (11%) patients treated with sulbactam/durlobactam and in 14/86 (16%) patients treated with colistin. One patient treated with sulbactam/durlobactam developed anaphylactic shock which led to discontinuation of treatment.

Common Adverse Reactions

Adverse reactions were reported in 88% (80/91) of patients in the sulbactam/durlobactam treatment group and 94% (81/86) of patients in the colistin treatment group. The most common adverse reactions reported in >10% of patients treated with sulbactam/durlobactam were liver test abnormalities, diarrhea, anemia, and hypokalemia. Table 2 lists selected adverse reactions occurring at a frequency of >5% in Trial 1.

Table 2. Selected Adverse Reactions Occurring at a Frequency of >5% in Trial 1:

^* Liver test abnormalities includes the following adverse reactions: liver function test abnormal, hepatic function abnormal, increased transaminases, ALT increased, and AST increased; Acute kidney injury includes the following adverse reactions: renal impairment, blood Cr increased, toxic nephropathy, renal failure and acute kidney injury.