Author: [AUTHOR] Published on 8/11/2023 5:00:00 AM

FDA Approves XACDURO (Sulbactam and Durlobactam) for the Treatment of Pneumonia Caused by Certain Difficult-to-Treat Bacteria

On May 23, 2023, the US Food and Drug Administration (FDA) approved XACDURO (sulbactam for injection; durlobactam for injection), a new treatment for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex in patients 18 years of age and older. 

XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. To reduce the development of drug-resistant bacteria and maintain the effectiveness of XACDURO and other antibacterial drugs, XACDURO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

XACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. The approved recommended dosage of XACDURO is 1 g of sulbactam and 1 g of durlobactam every 6 hours administered by intravenous (IV) infusion over 3 hours in patients with creatinine clearance (CLcr) of 45 to 129 mL/min. Adjustments to the dosing regimen for XACDURO are recommended for patients with CLcr less than 45 mL/min and for patients with CLcr greater than or equal to 130 mL/min. The recommended duration of treatment with XACDURO is 7 to 14 days. The duration of therapy should be guided by the patient’s clinical status. Additional details regarding dosing adjustments can be found in the prescribing information below.

Additional information regarding dosage and administration as well as warnings and precautions about hypersensitivity reactions, Clostridioides difficile-Associated Diarrhea (CDAD), and the development of drug-resistant bacteria can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) 

MOA: XACDURO is a co-packaged product containing sulbactam, a beta-lactam antibacterial, and durlobactam, a beta lactamase inhibitor.

General PK: Sulbactam and durlobactam PK are similar following single- and multiple-dose administrations. The Cmax and AUC of sulbactam increase in proportion to dose (0.5 times the recommended single dose to 1 g single dose). Durlobactam demonstrated dose-proportional PK across the dose range studied (0.25 times the recommended single dose to 2 times the recommended single dose infused over 3 hours every 6 hours).

The PK properties of the components of XACDURO and the PK parameters of sulbactam and durlobactam are summarized in Table 1.

Table 1. PK Properties (Mean ± SD) of the Components of XACDURO

PK parameters	Sulbactam	Durlobactam
Cmax (μg/mL)*	32.4 ± 24.7	29.2 ± 13.2
AUC0-24 (h·μg/mL)*	515 ± 458	471 ± 240
Distribution
% Bound to human plasma protein	38%	10%
AUC0-6 ELF/plasma ratio	0.5	0.37
Vss (L)*	25.4 ± 11.3	30.3 ± 12.9
Metabolism	Minimally metabolized
Elimination
CL (L/h)*	11.6 ± 5.64	9.96 ± 3.11
T1/2 (h)*	2.15 ± 1.16	2.52 ± 0.77
Excretion
Major route of elimination	Renal
% excreted unchanged in urine	75% to 85%	78%

*PK parameters are presented at steady state (Day 3) in patients with normal renal function defined as creatinine clearance of greater than or equal to 90 mL/min and less than 130 mL/min at a dosage of 1 g sulbactam and 1 g durlobactam every 6 hours.

AUC_0-6 = area under the plasma concentration time curve from time of dosing to 6 hours post dose; AUC_0-24 = area under the plasma concentration time curve from time of dosing to 24 hours; CL = clearance; C_max = maximum concentration; ELF = epithelial lining fluid; SD = standard deviation, T_1/2 = terminal half-life; V_ss = volume of distribution at steady state

PD: For sulbactam, the percent time of dosing interval that unbound plasma concentrations of sulbactam exceed the minimum inhibitory concentration (MIC) of A. baumannii has been shown to be the best predictor of efficacy in animal and in vitro models of infection. For durlobactam, the ratio of the 24-hour unbound plasma durlobactam AUC to the sulbactam-durlobactam MIC (fAUC0–24/MIC) best predicts the activity in in vivo and in vitro models of infection.

Drug Interactions
Organic Anion Transporter 1 (OAT1) Inhibitors: Concomitant administration of OAT1 inhibitors (e.g., probenecid) with XACDURO is not recommended. Concomitant administration with OAT1 inhibitors may increase plasma concentrations of sulbactam. 

Use in Specific Populations
No clinically significant differences in the PK of sulbactam or durlobactam were observed based on age (18-91 years), gender, weight (35-150 kg), and race (White, Black, Asian, American Indian/Alaska Native, Other). Sulbactam and durlobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on XACDURO exposures.
Patients with Renal Impairment: In a single-dose trial evaluating the effect of renal impairment on the PK of sulbactam and durlobactam, dose normalized systemic exposures of sulbactam and durlobactam were higher at all levels of renal impairment compared to healthy subjects with CLcr greater than or equal to 90 mL/min. Adjustments to the XACDURO dosing regimen are required in patients with CLcr less than 45 mL/min as described in the full prescribing information linked below. 

• Patients Receiving Intermittent Hemodialysis (HD): In subjects with end stage renal disease (ESRD) on HD, the fraction of the dose removed by hemodialysis was 0.41 and 0.33 for sulbactam and durlobactam, respectively. In patients requiring HD, complete HD at the latest possible time before the start of XACDURO dosing. Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.
• 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 XACDURO dosage. Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.

CLcr 130 mL/min or greater may be seen in seriously ill patients who are receiving intravenous fluid resuscitation. Increased sulbactam and durlobactam clearance have been observed in patients with CLcr of 130 mL/min or greater. Dosage adjustment of XACDURO is required in patients with CLcr 130 mL/min or greater as described in the full prescribing information linked below. Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.

Lactation: There are no data on the presence of durlobactam in human or animal milk. Sulbactam is present in human milk in low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XACDURO and any potential adverse effects on the breastfed child from XACDURO or from the underlying maternal condition.  

Efficacy and Safety
Efficacy of XACDURO was demonstrated in a multicenter, active-controlled, investigator-unblinded, independent assessor-blinded, non-inferiority, phase 3 trial. The primary efficacy endpoint for the study was 28-day all-cause mortality in the patients who received any amount of study medication with a confirmed baseline infection with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence > 10%) were liver test abnormalities, diarrhea, anemia, and hypokalemia.

Visit the XACDURO (sulbactam and durlobactam) prescribing information page to learn more about XACDURO. 
Visit the Drugs@FDA Database for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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