Amoxicillin and Clavulanic Acid: An oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor clavulanic acid.

INDICATIONS^1-2:

Amoxy-Clav are indicated for the treatment of patients with community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase−producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae, or methicillin-susceptible S. aureus) and S. pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs = 2 mcg/mL).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and other antibacterial drugs, amoxicillin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

DOSAGE^1,7:

Amoxicillin should be taken at the start of a meal to enhance its absorption and to minimize the potential for gastrointestinal intolerance. Absorption of the amoxicillin component is decreased when it is taken on an empty stomach.

MICROBIOLOGY^1,5:

Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Aerobic Gram-Positive Microorganisms:
Streptococcus pneumoniae (including isolates with penicillin MICs ≤ 2 mcg/mL)
Staphylococcus aureus (including β-lactamase–producing isolates

Note: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Aerobic Gram-negative Microorganisms:
Haemophilus influenzae (including β-lactamase–producing isolates)
Moraxella catarrhalis (including β-lactamase–producing isolates)
Haemophilus parainfluenzae (including β-lactamase–producing isolates)
Klebsiella pneumoniae (all known isolates are β-lactamase–producing)

Note: S. pyogenes, P. magnus, and P. micros do not produce β-lactamase, and therefore, are susceptible to amoxicillin alone.

The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the safety and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms:
Streptococcus pyogenes

Anaerobic Microorganisms:
Bacteroides fragilis (including β-lactamase–producing isolates)
Fusobacterium nucleatum (including β-lactamase–producing isolates)
Peptostreptococcus magnus
Peptostreptococcus micros

NOTE: S. pyogenes, P. magnus, and P. micros do not produce β-lactamase, and therefore, are susceptible to amoxicillin alone. Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to S. pyogenes.

IN-VITRO AND IN-VIVO SUMMARY / CLINICAL TRIAL SUMMARY⁶:

Acute Bacterial Sinusitis:

Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either amoxicillin/clavulanic acid 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17-28) visit. The combined clinical and radiological responses were 83.7% for amoxicillin/clavulanic acid and 84.3% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference = -9.4, 8.3). The clinical response rates at the test of cure were 87.0% and 88.6%, respectively.

The other 2 trials were non-comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of amoxicillin/clavulanic acid (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. At test of cure, the clinical success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1% (per protocol populations).

Patients with acute bacterial sinusitis due to S. pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open-label non-comparative clinical trials. Microbiologic eradication rates for key pathogens in these studies are shown in table 1:

• n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
• Confidence limits calculated using exact probabilities.
• S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.
• Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL.
  

Community-Acquired Pneumonia:

Four randomized, controlled, double-blind clinical studies and one non-comparative study were conducted in adults with community-acquired pneumonia (CAP). In comparative studies, 904 patients received amoxicillin/clavulanic acid at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received amoxicillin/clavulanic acid 2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86.3% to 94.7% in clinically evaluable patients who received amoxicillin/clavulanic acid; in the non-comparative study, the clinical success rate was 85.6%. Data on the efficacy of amoxicillin/clavulanic acid in the treatment of community-acquired pneumonia due to S. pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled clinical studies and the 1 non-comparative study. The majority of these cases were accrued from the non-comparative study.

• n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
• Confidence limits calculated using exact probabilities.
• S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.
• Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent-To-Treat group only.

ADVERSE EVENTS^1-4:

The majority of side effects observed were of a mild and transient nature. The most frequently reported adverse effects which were suspected or probably drug-related were diarrhea (14.5%), vaginal mycosis (3.3%) nausea (2.1%), and loose stools (1.6%).

Other adverse effects that are common for the ampicillin group of antibiotics and may occur during use of amoxicillin are: GI effects like diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudo-membranous colitis; Hypersensitivity reactions like skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions; A moderate rise in AST (SGOT) and/or ALT (SGPT), interstitial nephritis and hematuria; CNS effects like agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, headache, insomnia.

WARNINGS / PRECAUTIONS^{1-4, 6-7}:

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

Prolonged use may result in fungal or bacterial super infection, including C. difficile-associated diarrhea (CDAD) and pseudo-membranous colitis; CDAD has been observed >2 months post antibiotic treatment.

While amoxicillin/clavulanate potassium combination possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable if therapy is for longer than the drug is approved for administration.

DRUG INTERACTIONS^1-4:

Allopurinol: The concurrent administration of allopurinol may increase the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone.

BCG Vaccine: Antibiotics may diminish the therapeutic effect of BCG.

Fusidic Acid: May diminish the therapeutic effect of Penicillins.

Methotrexate: Penicillins may decrease the excretion of Methotrexate.

Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation.

Oral Contraceptives: In common with other broad-spectrum antibiotics, amoxicillin may reduce the efficacy of oral contraceptives.

Probenecid: decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid cannot be recommended.

Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins.

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.

REFERENCES:

1. Prescribing information for amoxicillin and clavulanic acid.
2. Drug information from Wolters Kluwer Health, Inc.
3. American Society of Health-System Pharmacists
4. British National Formulary (54th edition). September 2007
5. Donowitz, G. R. and Mandell, G. L. Beta-Lactam Antibiotics, N. Engl. J. Med., 1988, 318(7):419-26 and 318(8):490-500.
6. Todd, P. A. and Benfield, P. Amoxicillin/Clavulanic Acid: An Update of its Antibacterial Activity, Pharmacokinetic Properties, and Therapeutic Use, Drugs, 1990, 39(2):264-307.
7. Reed, M. D. Clinical Pharmacokinetics of Amoxicillin and Clavulanate, Pediatr. Infect. Dis. J., 1996, 15(10):949-54.