Antibiotic Adjuvant

Antibiotic Adjuvants

Antibiotic adjuvants are pharmacological agents administered alongside antibiotics to enhance their efficacy. They function either by altering the pharmacokinetics (PK) of the antibiotic to boost plasma levels or by inhibiting bacterial resistance mechanisms (Pharmacodynamics/PD).

Pharmacokinetic Enhancers

These agents block the metabolism or excretion of antibiotics, maintaining higher serum concentrations for longer durations.

Agent Mechanism EM Clinical Utility
Probenecid OAT Inhibition: Inhibits organic anion transporters (OAT1 and OAT3) in the proximal renal tubule. This competitively blocks the renal tubular secretion of organic acids, specifically beta-lactams (penicillins/cephalosporins), prolonging their half-life.[1]
  • Gonorrhea: Historically used as a 1g oral single dose adjunct with Penicillin or Amoxicillin to maintain bactericidal levels longer.[2]
  • Neurosyphilis: Boosts CSF penetration of penicillin in outpatient/procaine regimens where IV access is difficult.[3]
  • Serum Boost: Increases antibiotic trough concentrations by >200% for severe infections (e.g., endocarditis) or prevention of rapid elimination.[1]
Cilastatin Dehydropeptidase Inhibition: Inhibits renal dehydropeptidase I, an enzyme found in the renal brush border that degrades Imipenem; it has no intrinsic antibacterial activity.[4]
  • Nephroprotection: Prevents the formulation of nephrotoxic metabolites of Imipenem formed during renal metabolism.
  • Mandatory Co-administration: Always formulated as Imipenem/Cilastatin (Primaxin).[4]

Probenecid Specifics

Dosing
  • Standard Adjuvant: 500 mg PO QID.
  • Gonorrhea protocol: 1 g PO single dose associated with oral beta-lactams.
Contraindications
  • Renal Failure: Ineffective if CrCl < 30 mL/min (drug cannot reach site of action in the tubule).[1]
  • Pediatrics: Generally contraindicated in children < 2 years old due to immature renal transport systems.
  • Acute Gout: Paradoxically, do not initiate during an acute gouty flare (mobilization of urate stores can exacerbate symptoms), despite it being a gout medication.
Interactions

Beta-Lactamase Inhibitors

While technically distinct chemical structures, these "suicide inhibitors" generally have negligible antibacterial activity alone and are used strictly as adjuvants to overcome enzymatic resistance.

Agent Combined With EM Clinical Utility
Clavulanate Amoxicillin (Augmentin) Oral coverage for polymicrobial infections (e.g., animal bites, Sinusitis, mild Diverticulitis). Extends spectrum against S. aureus (MSSA), H. influenzae, and Bacteroides.[6]
Sulbactam Ampicillin (Unasyn) IV coverage for Aspiration pneumonia and pneumonitis and intra-abdominal sepsis. *Uniquely has intrinsic activity against Acinetobacter on its own.*[7]
Tazobactam Piperacillin (Zosyn) Broad-spectrum agent for Sepsis, Pseudomonas, and nosocomial infections in the ED. Chemically a penicillanic acid sulfone.[6]
Avibactam Ceftazidime (Avycaz) Non-beta-lactam scaffold inhibitor. Reserved for Carbapenem-Resistant Enterobacteriaceae (CRE) or MDR Pseudomonas. Consult ID before use.[8]

Synergistic Adjuvants

Agents used to attack a bacteria from a second angle (mechanism of action) to clear difficult infections.

  • Aminoglycosides (e.g., Gentamicin):
    • Used as an adjuvant with Ampicillin or Vancomycin for Endocarditis.
    • Mechanism: Cell wall synthesis inhibitors (beta-lactams) allow the aminoglycoside to penetrate the cell wall and disrupt protein synthesis (ribosomal lethal effect).[9]
  • Rifampin:
    • Used as an adjuvant for Prosthetic joint infections.
    • Mechanism: Able to penetrate adherence biofilms on hardware that other antibiotics cannot reach; acts on RNA polymerase.[10]

References

  1. ↑ 1.0 1.1 1.2 Cunningham RF, Brouhard BH, Travis LB. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet. 1981;6(2):135-51. PubMed Abstract
  2. ↑ Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. PubMed Abstract
  3. ↑ Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals. Clin Infect Dis. 2000;30(3):540-4. PubMed Abstract
  4. ↑ 4.0 4.1 Birnbaum J, Kahan FM, Kropp H, MacDonald JS. Carbapenems, a new class of antibiotics. Discovery and development of imipenem/cilastatin. Am J Med. 1985;78(6A):3-21. PubMed Abstract
  5. ↑ Kyriazis AP, Kyriazis MA, Burke MD. Interaction of antibiotics with the renal organic anion and cation transporters. Expert Opin Drug Metab Toxicol. 2013;9(2):163-7. PubMed Abstract
  6. ↑ 6.0 6.1 Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201. PubMed Abstract
  7. ↑ Levin AS, Levy CE, Manrique AE, Medeiros EA, Costa SF. Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam. Int J Antimicrob Agents. 2003;21(1):58-62. PubMed Abstract
  8. ↑ van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016;63(2):234-41. PubMed Abstract
  9. ↑ Davis BD. Mechanism of bactericidal action of aminoglycosides. Microbiol Rev. 1987;51(3):341-50. PubMed Abstract
  10. ↑ Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645-54. PubMed Abstract
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