Sulbactam; durlobactam is a co-packaged product for intravenous administration containing sulbactam, a beta-lactam antibacterial and beta-lactamase inhibitor, and durlobactam, a beta-lactamase inhibitor. The drug indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) due to susceptible isolates of Acinetobacter baumannii-calcoaceticus complex in adults. Alone, sulbactam is easily degraded by beta-lactamases found in Acinetobacter sp.; however, the addition of durlobactam protects sulbactam from beta-lactamase degradation and increases its activity. Approval was based on trials showing it to be non-inferior compared to colistin, in patients with confirmed carbapenem-resistant Acinetobacter baumannii. The most common adverse reactions reported included liver test abnormalities, diarrhea, anemia, and hypokalemia. Dosing frequency adjustments are recommended for creatine clearance less than 45 mL/minute or 130 mL/minute or more.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration whenever solution and container permit. The reconstituted solution ranges from clear, to light yellow to orange solution. Do not administer if sulbactam; durlobactam appears cloudy or contains particulates.
-Sulbactam; durlobactam is a co-packaged kit consisting of 1 single-dose sulbactam vial containing 1 g of sulbactam and 2 single-dose durlobactam vials each containing 0.5 g of durlobactam.
Intravenous Administration
Reconstitution
-Sulbactam
--Reconstitute each 1 g sulbactam vial with 5 mL of Sterile Water for Injection.
-Gently shake the vial to ensure the powder is dissolved. The reconstituted vial should be a clear, colorless to slightly yellow solution.
-Each reconstituted vial contains 1 g sulbactam/5 mL.
-Durlobactam
--Reconstitute each 0.5 g durlobactam vial with 2.5 mL of Sterile Water for Injection.
-Reconstitute both vials.
-Gently shake the vial to ensure the powder is dissolved. The reconstituted vial should be a clear, light yellow to orange solution.
-Each reconstituted vial contains 0.5 g durlobactam/2.5 mL.
-The reconstituted sulbactam and durlobactam solutions are NOT for direct injection and MUST be diluted prior to intravenous infusion.
-Storage: The sulbactam and durlobactam reconstituted solutions must be further diluted within 1 hour of reconstitution.
Dilution
-Prepare infusion dose by withdrawing 5 mL reconstituted sulbactam and a total of 5 mL from both reconstituted durlobactam vials (2.5 mL each).
-Add the withdrawn sulbactam and durlobactam volume to a 100 mL infusion bag of 0.9% Sodium Chloride for Injection, USP.
-Discard any unused portion remaining in the vials.
-Storage: Refrigerate the diluted solution at 2 to 8 degrees C (36 to 46 degrees F) solution prior to infusion. Administer diluted solution within 24 hours of reconstitution, inclusive of infusion time. Do not freeze.
Intermittent IV Infusion
-Sulbactam; durlobactam should be brought to room temperature (20 to 25 degrees C [68 to 77 degrees F]) prior to infusion.
-Compatibility of sulbactam; durlobactam with other drugs has not been established, do not mix with solutions containing other drugs.
-Administer via intravenous infusion over 3 hours.
During clinical trials, liver test abnormalities were reported in 19% of patients treated with sulbactam; durlobactam. Elevated hepatic enzymes were reported included, increased transaminases, increased ALT, and increased AST. Additionally, abnormal liver function tests and abnormal hepatic function were noted in patients treated with sulbactam; durlobactam.
Diarrhea (17%) and constipation (6%) were reported in patients treated with sulbactam; durlobactam during clinical trials.
Hypokalemia (12%) and arrhythmia exacerbation (9%) have been reported in patients treated with sulbactam; durlobactam during clinical trials.
Anemia (13%) and thrombocytopenia (6%) have been reported in patients treated with sulbactam; durlobactam during clinical trials.
During clinical trials, acute kidney injury was reported in 6% of patients treated with sulbactam; durlobactam. Acute kidney injury reports include renal impairment, increased serum creatinine, toxic nephropathy, and renal failure (unspecified).
Hypersensitivity was reported with sulbactam; durlobactam during clinical trials. One patient developed anaphylactic shock which led to discontinuation of sulbactam; durlobactam.
Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis have been reported with sulbactam; durlobactam. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.
Prior to initiating treatment with sulbactam; durlobactam, question patients regarding patients carbapenem hypersensitivity, penicillin hypersensitivity, cephalosporin hypersensitivity, or hypersensitivity to any other beta-lactam antibiotics. Serious and occasionally fatal hypersensitivity reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterials. Hypersensitivity was observed in patients treated with sulbactam; durlobactam in clinical trials. If an allergic reaction develops during treatment, discontinue sulbactam; durlobactam.
Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including sulbactam; durlobactam, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
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 has been reported in literature to cross human placenta. Available published data from case reports and case series with sulbactam used 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. In animal studies, no fetal harm was seen at ampicillin; sulbactam doses up to 10-times the human dose. In animal studies with durlobactam during organogenesis, fetal skeletal variations were observed at 2- and 4-times the maximum recommended human dose. No adverse effects on reproductive performance, mean body weight, or cesarean section parameters were noted.
There are no data on the effects of sulbactam; durlobactam on the effects of the breastfed infant or on milk production. There are no data on the presence of durlobactam in human milk. A low concentration of sulbactam is present in human milk at an estimated maximum daily infant dose of 560 mcg/kg/day, assuming mean milk consumption of 200 mL/kg/day. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for sulbactam; durlobactam and any potential adverse effects on the breastfed infant from sulbactam; durlobactam or the underlying maternal condition.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Acinetobacter baumannii
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of nosocomial pneumonia, including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), due to Acinetobacter baumannii:
NOTE: Sulbactam; durlobactam is not indicated for HAP/VAP caused by pathogens other than susceptible isolates of Acinetobacter baumannii.
Intravenous dosage:
Adults: 2 g (1 g sulbactam and 1 g durlobactam) administered over 3 hours IV every 6 hours for 7 days. The FDA-approved duration is 7 to 14 days.
Maximum Dosage Limits:
-Adults
8 g/day IV (4 g/day sulbactam and 4 g/day durlobactam); 12 g/day IV (6 g/day sulbactam and 6 g/day durlobactam) in patients with augmented renal clearance.
-Geriatric
8 g/day IV (4 g/day sulbactam and 4 g/day durlobactam); 12 g/day IV (6 g/day sulbactam and 6 g/day durlobactam) in patients with augmented renal clearance. -Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Dosage adjustments are not necessary in patients with impaired hepatic function.
Patients with Renal Impairment Dosing
CrCl 130 mL/minute or more: 2 g (1 g sulbactam and 1 g durlobactam) IV every 4 hours (augmented renal clearance).
CrCl 45 to 129 mL/minute: 2 g (1 g sulbactam and 1 g durlobactam) IV every 6 hours (no dosage adjustments needed).
CrCl 30 to 44 mL/minute: 2 g (1 g sulbactam and 1 g durlobactam) IV every 8 hours.
CrCl 15 to 29 mL/minute: 2 g (1 g sulbactam and 1 g durlobactam) IV every 12 hours
CrCl less than 15 mL/minute at initiation of therapy: 2 g (1 g sulbactam and 1 g durlobactam) IV every 12 hours for the first 3 doses, then 2 g (1 g sulbactam and 1 g durlobactam) every 24 hours.
CrCl declines to less than 15 mL/minute while taking sulbactam; durlobactam: 2 g (1 g sulbactam and 1 g durlobactam) every 24 hours.
Intermittent hemodialysis
For end-stage renal disease patients receiving intermittent hemodialysis at the initiation of therapy, 2 g (1 g sulbactam and 1 g durlobactam) IV every 12 hours for the first 3 doses, then 1 g (1 g sulbactam and 1 g durlobactam) every 24 hours. For patients receiving intermittent hemodialysis after starting sulbactam; durlobactam, 2 g (1 g sulbactam and 1 g durlobactam) every 24 hours. Both sulbactam and durlobactam are removed by hemodialysis; therefore, administer the dose after hemodialysis on hemodialysis days.
Continuous renal replacement therapy (CRRT)
NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered. Limited information is available to provide a dosage recommendation. Therapy should be guided by the patient's clinical status. While on CRRT, a patient's residual renal function may change. Regularly monitor renal function and adjust dosing accordingly.
*non-FDA-approved indication
Fexinidazole: (Moderate) Monitor for an increase in sulbactam-related adverse effects if concomitant use with fexinidazole is necessary. Concomitant use may increase sulbactam exposure. Sulbactam is an OAT1 substrate and fexinidazole is an OAT1 inhibitor.
Probenecid: (Moderate) Monitor for an increase in sulbactam-related adverse effects if concomitant use with probenecid is necessary. Concomitant use may increase sulbactam exposure. Sulbactam is an OAT1 substrate and probenecid is an OAT1 inhibitor.
Probenecid; Colchicine: (Moderate) Monitor for an increase in sulbactam-related adverse effects if concomitant use with probenecid is necessary. Concomitant use may increase sulbactam exposure. Sulbactam is an OAT1 substrate and probenecid is an OAT1 inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in sulbactam-related adverse effects if concomitant use with taurusodiol is necessary. Concomitant use may increase sulbactam exposure. Sulbactam is an OAT1 substrate and taurusodiol is an OAT1 inhibitor.
Sulbactam is a beta-lactam antibacterial and Ambler Class A serine beta-lactamase inhibitor of penicillin-binding proteins PB1 and PB3 in Acinetobacter baumannii-calcoaceticus (ABC). It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. PBPs are responsible for several steps in cell wall synthesis and are found in quantities of several hundred to several thousand molecules per bacterial cell. PBPs vary among different bacterial species. Thus, the intrinsic activity of sulbactam and other beta-lactams against a particular organism depends on their ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, sulbactam's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis and death. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.
Durlobactam is a diazabicyclooctane non-beta-lactam, beta-lactamase inhibitor. Durlobactam protects sulbactam from certain serine-beta-lactamases such as TEM-1, KPC-3, ADC-7, OXA-23, and OXA-24/40. The protective effects of durlobactam is achieved by the size and polarity of the drug, as well as the addition of a double bond to enhance reactivity. Durlobactam does not have antibacterial activity and its impact on Acinetobacter sp. minimum inhibitory concentrations (MIC) is minimal when used alone.
Sulbactam; durlobactam demonstrated in vitro activity against Acinetobacter baumannii isolated expressing serine beta-lactamase included in Ambler Class A (CTX-M-, TEM-, PER- and SHV-type extended spectrum beta-lactamases [ESBLs], KPC carbapenemase) Class C (ADC-type) and broad-spectrum activity against Class D (OXA-type) enzymes.
Sulbactam exhibits concentration-independent or time-dependent killing. The major pharmacodynamic parameter that determines efficacy is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T above the MIC). For durlobactam, the ratio of the 24-hour unbound plasma AUC to sulbactam; durlobactam MIC best predicts its activity.
The susceptibility interpretive criteria for sulbactam; durlobactam are delineated by pathogen. The MICs are defined for ABC susceptible at 4/4 mcg/mL or less, intermediate at 8/4 mcg/mL, and resistant at 16/4 mcg/mL or more.
Resistance to beta-lactams occurs as a result of decreased permeability, alterations of PBPs, and production of beta-lactamases. Sulbactam; durlobactam is not active against isolates that produce Ambler Class B metallo-beta-lactamases or have modification of active target sites of sulbactam (PBPs).
Sulbactam; durlobactam is administered intravenously.
-Sulbactam: Approximately 38% of circulating sulbactam is plasma protein bound. At steady state, the volume of distribution is 25.4 L (+/- 11.3L). Sulbactam has been reported to cross human placenta. Sulbactam undergoes minimal metabolism, and it is a substrate for renal organic anion transporters (OAT)1. Sulbactam is predicted to have active secretion and OAT1 may contribute to the elimination of the drug by actively removing it from the blood compartment. Sulbactam is renally eliminated with a clearance of 11.6 L/h (+/- 5.64 L/h), with 75% to 85% of a dose recovered in urine as unchanged drug. In patients with normal renal function, the elimination half-life is 2.15 hours (+/- 1.16 hours).
-Durlobactam: Approximately 10% of circulating durlobactam is plasma protein bound. At steady state, the volume of distribution is 30.3 L (+/- 12.9 L). Durlobactam undergoes minimal metabolism, and it is a substrate for renal organic anion transporters (OAT)1. Durlobactam is renally eliminated with a clearance of 9.96 L/h (+/- 3.11 L/h), with 78% of a dose recovered in urine as unchanged drug. In patients with normal renal function, the elimination half-life is 2.52 hours (+/- 0.77 hours).
Affected cytochrome P450 isoenzymes and drug transporters: OAT1
Sulbactam and durlobactam are substrates of OAT1. Inhibitors of this transporter may decrease the renal clearance of sulbactam, resulting in increased sulbactam plasma concentrations. Inhibition of OAT1 is not expected to affect durlobactam. In vitro, durlobactam does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. In vitro, durlobactam does not induce CYP1A2, CYP2B6, or CYP3A4. CYP450 activity with sulbactam is unknown. Neither sulbactam nor durlobactam inhibits P-gp, BCRP, OATP1B1, OAT1, OAT3, or OCT2. Sulbactam does not inhibit OATP1B3, OCT1, BSEP, MATE1, or MATE2-K.
-Route-Specific Pharmacokinetics
Intravenous Route
The pharmacokinetics of durlobactam and sulbactam remained similar following single and multiple dosing administrations.
-Sulbactam: The Cmax and AUC of sulbactam increase in proportion to the dose at 0.5 times the recommended dose to 1 g single dose. The steady-state Cmax of sulbactam is 32.4 mcg/mL (+/-24.7 mcg/mL) and the steady-state AUC from time of dosing to 24 hours is 515 hours x mcg/mL (+/- 458 hours x mcg/mL). The AUC of epithelial lining fluid to plasma ratio is 0.5.
-Durlobactam: Durlobactam demonstrated dose-proportional pharmacokinetics from 0.25 times the recommended single dose, to 2 times the recommended single dose. The steady-state Cmax of durlobactam is 29.2 mcg/mL (+/-13.2 mcg/mL) and the steady-state AUC from time of dosing to 24 hours is 471 hours x mcg/mL (+/- 240 hours x mcg/mL). The AUC of epithelial lining fluid to plasma ratio is 0.37.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of sulbactam; durlobactam are unknown. Neither drug undergoes substantial metabolism by the liver and are primarily cleared renally; thus, hepatic dysfunction is not expected to affect the pharmacokinetics of these drug.
Renal Impairment
-Sulbactam: Systemic exposures of sulbactam increased at all levels of renal impairment, compared to healthy patients with normal clearance. Compared to patients with a creatinine clearance (CrCl) of 90 mL/minute or higher, the AUC of patients with a GFR of 60 to 89 mL/minute/1.73 m2, 30 to 59 mL/minute/1.73 m2, and less than 30 mL/minute/1.73 m2, increased by 1.4, 2.0, and 4.3-fold, respectively. In patients with end stage renal disease and on hemodialysis, the fraction of the sulbactam dose removed by hemodialysis was 0.41.
-Durlobactam: Systemic exposures of durlobactam increased at all levels of renal impairment, compared to healthy patients with normal clearance. Compared to patients with a creatinine clearance (CrCl) of 90 mL/minute or higher, the AUC of patients with a GFR of 60 to 89 mL/minute/1.73 m2, 30 to 59 mL/minute/1.73 m2, and less than 30 mL/minute/1.73 m2, increased by 1.4, 1.9, and 3.7-fold, respectively. In patients with end stage renal disease and on hemodialysis, the fraction of the durlobactam dose removed by hemodialysis was 0.33.
Geriatric
The effect of age does not appear to affect the pharmacokinetics of sulbactam;durlobactam; however, clinical studies did not include a sufficient number of patients 65 and older to determine pharmacokinetic differences.
Gender Differences
Gender did not affect the pharmacokinetics of sulbactam; durlobactam.
Ethnic Differences
Race did not affect the pharmacokinetics of sulbactam;durlobactam.
Obesity
Body weight (35 to 150 kg) did not affect the pharmacokinetics of sulbactam; durlobactam.
Other
Augmented Renal Clearance
Increased sulbactam; durlobactam clearance has been observed in patients with CrCl of 130 mL/minute or greater. Increased CrCl may be observed in seriously ill patients or in those receiving IV fluid resuscitation.