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Ampicillin–Sulbactam

Katrina R. Viviano, DVM, PhD, DACVIM, DACVCP, University of Wisconsin–Madison

January 2017|Peer Reviewed

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Despite increasing bacterial resistance worldwide, penicillin-based antimicrobial agents remain one of the most important classes of antibiotics used in dogs, cats, and humans.¹

PHARMACOLOGY & CLINICAL APPLICATIONS

Ampicillin–sulbactam is a potentiated amino-penicillin that kills bacteria by blocking bacterial cell wall growth.2-4

For details, see Pharmacodynamics & Pharmacokinetics.

This combination agent is usually reserved for treating bacterial infections known to produce β-lactamase.

In humans, this agent is especially important in treating multidrug-resistant infections caused by Acinetobacter baumannii, an opportunistic gram-negative pathogen responsible for serious hospital-acquired infections.^2,5

In human medicine, increasing prevalence of bacterial resistance to ampicillin and amoxicillin–clavulanic acid has raised concerns.6-9

Use of ampicillin–sulbactam should be limited to cases in which a susceptible organism is strongly suspected or documented with susceptibility testing.
When presumptive treatment is initiated, performing a culture is strongly recommended.
- If the susceptibility of the isolated organism is resistant, ampicillin–sulbactam treatment should be discontinued.

In veterinary medicine, extralabel use is likewise indicated only when a susceptible organism is strongly suspected or documented.

Routine extralabel use not recommended

In dogs and cats, ampicillin–sulbactam may be a rational empiric choice or presumptive therapy for the following clinical situations involving specific suspected pathogens (see Spectrum of Activity):

Infections with penicillinase-producing anaerobes likely (eg, GI compromise)^10,11
Single therapy for penetrating skin injuries associated with cat bites, puncture wounds, and foreign bodies¹²
Combination therapy for systemic infection (eg, cholangitis, aspiration pneumonia, septicemia)^13-16
Susceptible infections during hospitalization, with de-escalation to amoxicillin–clavulanic acid because of its similar spectrum of activity or to amoxicillin when clinical need for β-lactamase inhibition has been ruled out^17,18
Presumptive use in animals in which an infectious agent (eg, Leptospira spp) is suspected in association with acute kidney injury and/or hepatopathy¹⁹
- Pending results of urine culture and leptospirosis testing (eg, urine PCR, serology)
- Clears leptospiremic phase of leptospirosis
  - Patients with confirmed leptospirosis should be transitioned to doxycycline.

SPECTRUM OF ACTIVITY^3,4

Susceptible gram-positive aerobes include Staphylococcus spp, Streptococcus spp, Enterococcus faecalis, and Actinomyces spp
- Ineffective against methicillin-resistant Staphylococcus spp
Susceptible gram-negative aerobes including β-lactamase–producing bacteria (ie, Escherichia coli, Pasteurella spp, Klebsiella spp, Proteus spp) and Salmonella spp
Ineffective against bacterial strains containing type 1 β-lactamases, including Citrobacter spp, Enterobacter spp, Serratia spp, and Pseudomonas spp
Also considered ineffective against Pseudomonas aeruginosa because of drug impermeability or drug efflux
Susceptible anaerobes including Clostridium spp, Bacteroides spp, Prevotella spp, Fusobacterium spp, Peptostreptococcus spp, and Propionibacterium spp

In the United States, extralabel use of ampicillin– sulbactam in dogs and cats is limited to parenteral administration as extrapolated from human formulation.

Extralabel doses (based on ampicillin component) as recommended³
- For empiric therapy in critically ill dogs and cats: extralabel dosage, 15-30 mg/kg IV q6-8h³
  - For systemic infections, use in combination with a parenteral drug with gram-negative activity (eg, aminoglycoside, fluoroquinolone).
- For infections susceptible to amoxicillin–clavulanic acid in patients unable to receive oral medication: extralabel dosage, 10-20 mg/kg IV or IM q8h³
Available as a 2:1 ratio of ampicillin to sulbactam for parenteral administration in vials as crystalline powder for reconstitution²⁰
- 1.5 g (1 g ampicillin sodium, 0.5 g sulbactam sodium)
- 3 g (2 g ampicillin sodium, 1 g sulbactam sodium)
- 15 g (10 g ampicillin sodium, 5 g sulbactam sodium)
Reconstituted ampicillin–sulbactam stability is concentration- and temperature-dependent.²⁰
- Concentration commonly used for IV administration is 30 mg/mL (20 mg/mL ampicillin, 10 mg/mL sulbactam; initially reconstituted in a small volume of sterile water to dissolve crystalline powder, followed by further dilution with 0.9% NaCl for final concentration for injection, which is stable at 4°C for 72 hours).²⁰
- Administer IV slowly, over ≈15 to 20 minutes.
- Aminopenicillins are eliminated by the kidneys (including a significant portion excreted via tubular secretion).²¹
  - In some human patients with altered glomerular filtration rates due to renal azotemia, consideration should be given for dose adjustment.^21,22
  - Although no known data are available for veterinary patients, some animals with severe renal dysfunction may require dose reduction.

PHARMACODYNAMICS & PHARMACOKINETICS

Ampicillin–sulbactam is a potentiated (ie, β-lactamase inhibitor) aminopenicillin with bactericidal and time-dependent activity.23

For antibacterial drugs with time-dependent activity, bactericidal activity depends on the duration of drug exposure above the minimum inhibitory concentration (MIC).
- Because bacterial killing is time-dependent, clinical success, especially in the treatment of gram-negative infections, depends on retaining drug concentrations above the MICs during the entire dosing interval.

Ampicillin is a semisynthetic penicillin (ie, β-lactam antibiotic) that effectively kills bacteria by disrupting the bacterial cell wall.2-4

Bacterial cell wall synthesis is inhibited through penicillin-binding proteins and by disrupting cell wall integrity via inhibition of the transpeptidation reaction responsible for bacterial cell wall cross-linking.

Sulbactam is a semisynthetic β-lactamase inhibitor that irreversibly binds and inactivates a variety of β-lactamases.2-4

Used in combination with β-lactam antimicrobials to target bacterial strains that would otherwise be resistant to nonpotentiated β-lactam antibiotics
Alone, sulbactam has weak antibacterial activity.

As an aminopenicillin, this combination has a short elimination half-life (healthy humans, 1 hour),21 resulting in need for frequent administration.

Overall, ampicillin–sulbactam is a relatively polar or hydrophilic drug combination.

In humans, drug concentrations are achieved in tissue (eg, bone, muscle, skin) and body fluids (eg, sputum, peritoneal fluid).^1,5

ADVERSE EVENTS & PRECAUTIONS

Adverse reactions include3,4,12

Thrombophlebitis or allergic reactions (IV)
Seizures (rapid IV infusion)
Pain at injection site (IM)

Other possible side effects include vomiting and diarrhea.

Hepatocellular cholestasis has been reported in association with administration of ampicillin–sulbactam in humans^24,25; this has not been reported in veterinary patients.
Pregnancy and lactation
- Penicillins are known to cross the placenta; however, ampicillin has been suggested as probably safe (class A) during pregnancy in dogs and cats, based on lack of toxicity or teratogenicity identified in other species.^26,27
- Little is known about the safety of sulbactam during pregnancy and whether it crosses the placenta.
- Breast milk concentrations of ampicillin and sulbactam are considered low, and both antimicrobial agents are considered compatible with breastfeeding in humans.³

MIC = minimum inhibitory concentration, PCR = polymerase chain reaction

References and Author Information

References

Lode HM. Rational antibiotic therapy and the position of ampicillin/sulbactam. Int J Antimicrob Agents. 2008;32(1):10-28.
Betrosian AP, Douzinas EE. Ampicillin–sulbactam: an update on the use of parenteral and oral forms in bacterial infections. Expert Opin Drug Metab Toxicol. 2009;5(9):1099-1112.
Plumb D. Amoxicillin sodium–sulbactam sodium. In: Plumb D, ed. Plumb’s Veterinary Drugs, digital ed. Tulsa, OK: Brief Media; 2015; monograph peer reviewed October 2015. Accessed September 2016.
Riviere JE, Papich MG. β-lactam antibiotics: penicillins, cephalosporins, and related drugs. In: Riviere JE, Papich MG, eds. Veterinary Pharmacology and Therapeutics. 9th ed. Ames, IA: Wiley-Blackwell; 2009:865-876.
Toussaint KA, Gallagher JC. β-lactam/β-lactamase inhibitor combinations: from then to now. Ann Pharmacother. 2015;49(1):86-98.
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Thungrat K, Price SB, Carpenter DM, Boothe DM. Antimicrobial susceptibility patterns of clinical Escherichia coli isolates from dogs and cats in the United States: January 2008 through January 2013. Vet Microbiol. 2015;179(3-4):287-295.
Unterer S, Lechner E, Mueller RS, et al. Prospective study of bacteremia in acute diarrhea syndromes in dogs. Vet Rec. 2015;176(12):309.
Wiest R, Rath HC. Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol. 2003;17(3):397-425.
Greene CE, Calpin J. Antimicrobial drug formulary: ampicillin sulbactam (appendix). In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. St Louis, MO: Saunders; 2012:1217.
Dear JD. Bacterial pneumonia in dogs and cats. Vet Clin North Am Small Anim Pract. 2014;44(1):143-159.
Dickinson AE, Summers JF, Wignal J, Boag AK, Keir I. Impact of appropriate empirical antimicrobial therapy on outcome of dogs with septic peritonitis. J Vet Emerg Crit Care (San Antonio). 2015;25(1):152-159.
Goggs RAN, Boag AK. Aspiration pneumonitis and pneumonia. In: Silverstein DC, Hopper K, eds. Small Animal Critical Care Medicine. 2nd ed. St Louis, MO: Saunders; 2015:130.
Wagner KA, Hartmann FA, Trepanier LA. Bacterial culture results from liver, gallbladder, or bile in 248 dogs and cats evaluated for hepatobiliary disease: 1998-2003. J Vet Intern Med. 2007;21(3):417-424.
Roy J, Messier S, Labrecque O, Cox WR. Clinical and in vitro efficacy of amoxicillin against bacteria associated with feline skin wounds and abscesses. Can Vet J. 2007;48(6):607-611.
Tabah A, Cotta MO, Garnacho-Montero J, et al. A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis. 2016;62(8):1009-1017.
Greene CE, Sykes JE, Moore GE, Goldstein RE, Schultz RD. Leptospirosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. St Louis, MO: Saunders; 2011:431-447.
AuroMedica Pharma, Dayton NJ; ampicillin and sulbactam for injection USP [package insert]; NDC# 55150-116-20, 55150-117-00, 5515-118-99. Updated 2014.
Adnan S, Paterson DL, Lipman J, Roberts JA. Ampicillin/sulbactam: its potential use in treating infections in critically ill patients. Int J Antimicrob Agents. 2013;42(5):384-389.
Lorenzen JM, Broll M, Kaever V, et al. Pharmacokinetics of ampicillin/sulbactam in critically ill patients with acute kidney injury undergoing extended dialysis. Clin J Am Soc Nephrol. 2012;7(3):385-390.
Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am. 2009;23(4):791-815, vii.
Köklü S, Köksal AS, Asil M, Kiyici H, Çoban S, Arhan M. Probable sulbactam/ampicillin-associated prolonged cholestasis. Ann Pharmacother. 2004;38:2055-2058.
See TT, Lee SP. Cholestasis associated with ampicillin/sulbactam therapy: a case report. J Intern Med Taiwan. 2006;17(2):87-90.
Root Kustritz MV. What drugs are unsafe to use during pregnancy in bitches? In: Root Kustritz MV. Clinical Canine and Feline Reproduction: Evidence-Based Answers. Ames, IA: Wiley-Blackwell; 2010:101-103.
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