Sulbactam: beta lactamase inhibitor in combination antibiotics
Sulbactam is a beta lactamase inhibitor with weak intrinsic antibacterial activity. It is used exclusively in fixed combinations with beta lactam antibiotics to preserve or restore activity against beta lactamase producing bacteria. Common combinations are ampicillin sulbactam (Unacid in Germany, Unasyn in the US), cefoperazone sulbactam (Sulperazon, mainly in Asia) and sultamicillin (an oral double ester of ampicillin and sulbactam).
In 2023 the combination sulbactam durlobactam (Xacduro) was approved for the treatment of severe infections by carbapenem resistant Acinetobacter baumannii, giving sulbactam a renewed role in reserve therapy.
Mechanism of action
Sulbactam is structurally a beta lactam with only weak antibacterial activity of its own. Its main effect is the irreversible inhibition of various beta lactamases that bacteria produce to inactivate penicillins and cephalosporins. By blocking these enzymes the partner beta lactam antibiotics (ampicillin or cefoperazone) are again protected from inactivation.
Sulbactam additionally has its own moderate activity against Acinetobacter baumannii by binding to PBP3 of this pathogen. This makes it a valuable component in the treatment of severe Acinetobacter infections, particularly in combination with durlobactam, a newer beta lactamase inhibitor with activity against many carbapenemases.
Sulbactam is mainly excreted renally. Its pharmacokinetics align well with ampicillin, which is why the fixed combination is clinically established.
Indications
- Ampicillin sulbactam (Unacid): intra abdominal infections, gynaecological infections, skin and soft tissue infections, pneumonia, septicaemia
- Cefoperazone sulbactam: nosocomial infections with gram negative pathogens, mainly used in Asia
- Sultamicillin oral: outpatient therapy of respiratory, skin and soft tissue infections, otitis media
- Sulbactam durlobactam (Xacduro): severe infections by carbapenem resistant Acinetobacter baumannii
- Off label high dose therapy: high dose sulbactam (up to 9 g per day) shows independent activity against Acinetobacter
Dosing and administration
Ampicillin sulbactam: 1.5 to 3 g (ampicillin 1 to 2 g plus sulbactam 0.5 to 1 g) intravenously every 6 to 8 hours, dose depending on severity.
Sultamicillin oral: 750 mg twice daily for adults.
Sulbactam durlobactam: specific protocols for the reserve indication.
Renal impairment: dose adjustment required because renal elimination dominates.
Intravenous administration is given as a short infusion over 15 to 30 minutes or as a bolus. Duration depends on indication and clinical course, generally 5 to 14 days.
Adverse effects
Common: diarrhoea, nausea, vomiting, rash, pruritus, local injection site irritation, eosinophilia.
Uncommon: allergic reactions, pseudomembranous colitis from Clostridioides difficile, raised liver transaminases, thrombocytopenia, leukopenia.
Rare and very rare: anaphylaxis, Stevens Johnson syndrome, hepatic reactions, seizures with high doses and impaired renal function, acute interstitial nephritis.
Important points:
- In penicillin allergy ampicillin sulbactam and sultamicillin are contraindicated
- In cephalosporin allergy cefoperazone sulbactam should be avoided
- Long or broad spectrum antibiotic therapy carries a risk of secondary infection with fungi or resistant pathogens
Interactions
- Probenecid: reduced renal excretion, higher plasma levels
- Allopurinol: increased risk of rash, particularly with ampicillin sulbactam
- Vitamin K antagonists: potentiation possible, INR monitoring
- Aminoglycosides: in vitro incompatibility, separate infusion lines required
- Methotrexate: reduced renal excretion of methotrexate, possible level rise
Special considerations
Pregnancy: acceptable for clear indications. Penicillins and sulbactam have a long safety record in pregnancy.
Breastfeeding: small amounts pass into milk, generally clinically acceptable.
Penicillin allergy: with documented allergy ampicillin sulbactam and sultamicillin are contraindicated.
Renal impairment: dose adjustment necessary. With severe impairment accumulation occurs and level monitoring may be warranted.
Cefoperazone sulbactam and alcohol: cefoperazone has an N methylthiotetrazole side chain that can cause disulfiram like reactions with alcohol. Patients should avoid alcohol during therapy and for several days afterwards.
Patient communication: sensible information about treatment duration, allergy history, possible adverse events such as diarrhoea and the need to seek medical advice if symptoms worsen.
Related substances
- Tazobactam, another beta lactamase inhibitor
- Aztreonam, monobactam antibiotic
- Imipenem, broad spectrum carbapenem
- Tigecycline, reserve antibiotic in MRSA and ESBL
- Mecillinam, amidinopenicillin in UTI
Frequently asked questions
What is a beta lactamase inhibitor?
Beta lactamases are enzymes that bacteria produce to inactivate penicillins and cephalosporins. Beta lactamase inhibitors such as sulbactam, tazobactam and clavulanic acid bind these enzymes and block them irreversibly. The partner antibiotic remains effective.
Why is sulbactam not used alone?
Sulbactam itself has only weak antibacterial activity. Only in combination with a beta lactam antibiotic does the full spectrum unfold. An exception is high dose therapy in Acinetobacter, where sulbactam shows independent activity.
What is sulbactam durlobactam?
A modern combination for treatment of severe infections by carbapenem resistant Acinetobacter baumannii. Durlobactam is a beta lactamase inhibitor with activity against many carbapenemases that potentiates sulbactam against this difficult to treat pathogen.
Which allergies should I be aware of?
With documented penicillin allergy ampicillin sulbactam and sultamicillin are not suitable. Cefoperazone sulbactam should be avoided in cephalosporin allergy. An allergy history before each therapy is mandatory.
Sources
- EMA European Medicines Agency
- BfArM German Federal Institute for Drugs and Medical Devices
- AWMF guidelines antibiotics and sepsis
- Gelbe Liste sulbactam monograph
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