Amoxycillin Injectable: A Review of its Antibacterial Spectrum, Pharmacokinetics and Therapeutic Use

Summary

Synopsis: Amoxycillin¹, an acid stable semisynthetic penicillin shown to be effective against a wide range of infections when given orally, is now available for intramuscular and intravenous injection. Amoxycillin has an antibacterial spectrum and level of activity essentially the same as for ampicillin. Amoxycillin has been shown to have more rapid and complete bactericidal action than ampicillin against E. coli in vitro and in animal models of infection, but the clinical importance of this difference has not yet been determined. Amoxycillin is present in therapeutic amounts in the cerebrospinal fluid of meningitis patients given the drug intravenously and parenteral amoxycillin has been successfully used in the treatment of meningitis, and in urinary tract infections, septicaemia, upper and lower respiratory tract infections and a variety of other infections caused by Gram-negative and Gram-positive aerobic bacteria. However, the extent of experience is limited compared with ampicillin, and thus further studies are needed to more clearly delineate its relative therapeutic role.

Parenteral amoxycillin is generally well tolerated. Pain at the site of intramuscular injection occurs in about one-third of patients, but can be minimised by the use of lignocaine or procaine hydrochloride.

Antibacterial Activity: The antibacterial spectrum and level of activity of amoxycillin in vitro is essentially the same as for ampicillin. However, amoxycillin has been shown to have a more rapid and complete bactericidal action than ampicillin, in vivo in animals and in vitro against Escherichia coli. Amoxycillin is active at low concentrations against Staphylococcus aureus and epidermidis (non-penicillinase producing), Streptococcus pyogenes, Diplococcus pneumoniae and Streptococcus viridans and many strains of Streptococcus faecalis, but is generally slightly less active than the newer cephalosporins, cephaloridine or clindamycin against staphylococci. Amoxycillin is also active at therapeutic concentrations against Escherichia coli, Salmonella species and many strains of Proteus mirabilis. Most strains of indole-positive Proteus sp., Klebsiella sp., Serratia sp. and Enterobacter sp. are resistant, while all strains of Pseudomonas sp. are resistant.

A combination of amoxycillin and an aminoglycoside is synergistic against Streptococcus faecalis provided that the particular strain of S. faecalis is sensitive to the aminoglycoside.

Pharmacokinetics: Peak plasma concentrations and the plasma level profile after intramuscular injection of amoxycillin are dose-related and similar to that after oral administration of an equivalent dosage. Bioavailability is also similar after oral or intramuscular administration. The peak plasma concentration after intravenous injection varies according to the rapidity of the injection but when given by bolus injection (over 3 to 30 seconds) it is 6 to 12 times that attained after the same dose given intramuscularly. A plasma concentration of 5μg/ml is exceeded for about 3 hours after intramuscular and 1 hour after intravenous injection of 500mg amoxycillin, in patients with normal renal function, but levels remain elevated for much longer in marked renal impairment. After intravenous administration amoxycillin is present at therapeutic concentrations in the cerebrospinal fluid of patients with meningitis. Amoxycillin is about 17% bound to human serum protein. After intravenous, intramuscular or oral administration, amoxycillin is excreted in the urine as unchanged amoxycillin and as inactive penicilloic acid, which accounts for about 20% of a parenteral dose. About 75% of an intramuscular dose and 78% of an intravenous dose of amoxycillin is recovered in the urine as unchanged drug within the first 6 hours after administration in patients with normal renal function. The elimination half-life is similar after either intravenous, intramuscular or oral administration and is 0.94 to 1.24 hours. Half-life is prolonged and urinary recovery decreased in patients with renal impairment and in the newborn.

Therapeutic Trials: Although the efficacy of oral amoxycillin for several infections is well documented, there are relatively few published papers on its parenteral use. Nevertheless, published and unpublished data available suggest that amoxycillin administered by the intramuscular and intravenous routes is effective in infections of the urinary and respiratory tracts, and in meningitis and septicaemia caused by a variety of susceptible organisms. Parenteral amoxycillin has been successful in eradicating the original pathogen in about 85% of urinary tract infections caused by Gram-positive or Gram-negative bacteria including those in patients with underlying urinary tract abnormalities. At a dosage of 500mg 8-hourly, intramuscular or intravenous amoxycillin has achieved clinical and/or bacteriological responses in 87 to 100% of patients with bronchopneumonia, acute bronchitis or exacerbations of chronic bronchitis although many cases were not proven to be of bacterial origin. The response and relapse rates compared with other drugs or with oral amoxycillin have not been studied. Children aged 2 months to 11 years with lower respiratory tract infection have been successfully treated with intravenous amoxycillin 40 to 100mg/kg daily in 3 or 4 divided doses.

Available data on the use of intravenous amoxycillin in paediatric patients with meningitis caused mainly by H. influenzae (non-β-lactamase strains) meningococci and S. pneumoniae indicate that amoxycillin 200 to 400mg/kg daily is clinically effective in about 85% of patients. Bacteria have been eradicated from the CSF in all instances where such data were given. There are no studies directly comparing amoxycillin with established regimens although a retrospective comparison suggests that amoxycillin may be comparable with chloramphenicol plus penicillin. It has yet to be determined whether or not amoxycillin has any advantages over other agents in the treatment of meningitis. The inclusion of chloramphenicol in the initial treatment regimen in two series of patients prevents the determination of the contribution of amoxycillin to the resolution of the infection in these patients. Parenteral amoxycillin has also been used successfully in the treatment of various other infections including typhoid fever, peritonitis, septicaemia, otitis media, pelvic and subphrenic infections, wound infections and postoperative intra-abdominal infections due mainly to susceptible Gram-negative bacteria, and has been used in combination with clindamycin or metronidazole in anaerobic wound infections.

Side Effects: Parenteral amoxycillin has generally been well tolerated, with pain at the site of intramuscular injection and skin rash being the most frequently reported adverse effects. Although the incidence of pain on injection has varied between studies, overall, moderate pain has occurred in about one-third of patients but can be minimised by the use of lignocaine or procaine hydrochloride. Phlebitis has seldom occurred during intravenous administration.

Dosage: For the treatment of moderately severe infections the usual dosage is 500mg intramuscularly 8-hourly or more frequently if necessary. For more severe infections 1g 6-hourly should be given by intravenous injection (over 3 to 4 minutes) or by intravenous infusion (over a period of 30 to 60 minutes). In children up to 10 years of age the recommended dosage is 50 to 100mg/kg daily in divided doses. Dosages of 200 to 400mg/kg/day have been used in the treatment of children with meningitis.