Penicillins: Drug-Drug Interactions

Allopurinol

The risk of rashes caused by aminopenicillins does not seem to be increased by parallel treatment with allopurinol, as had been suggested before.

However, aminopenicillins can still cause rash on their own, and many patients receiving allopurinol have comorbid conditions that may predispose them to hypersensitivity reactions. Careful clinical observation remains important when these agents are used together.

Aminoglycosides

High doses of parenteral penicillin can inactivate aminoglycosides. In patients receiving low doses of aminoglycosides because of reduced renal function this can be clinically important. Parenteral administration of these drugs in neonatal dosages does not seem to produce relevant inactivation, and so temporal separation of the infusions is not required. Piperacillin protected against aminoglycoside nephrotoxicity without reducing its blood concentration; this was possibly a protective effect of co-administered mineral salts.

When higher aminoglycoside doses are necessary, or when renal function is impaired, coordinated dosing and monitoring of serum drug levels and kidney function can help reduce the risk of underdosing or toxicity.

Cyclosporine

In a study in lung transplant recipients, cyclosporine nephrotoxicity was potentiated by nafcillin.

Because cyclosporine has a narrow therapeutic index and transplant patients often receive multiple nephrotoxic agents, clinicians should monitor serum creatinine and adjust immunosuppressant or antibiotic therapy if renal function worsens.

Methotrexate

Beta-lactams are weak organic acids that compete with the renal tubular secretion of methotrexate and its metabolites and reduce their clearance, leading to methotrexate toxicity. Consecutive aplastic crises have been described, particularly in patients with impaired renal clearance. In contrast, co-administration of flucloxacillin in another study produced a significant but not clinically important reduction in methotrexate AUC.

The more basic interactions between piperacillin and methotrexate and its major metabolite 7-hydroxymethotrexate have been studied in rabbits. The interaction was mainly caused by reduced renal clearance of both methotrexate and its metabolite.

The authors concluded that renal function in patients taking this combination should be monitored, with adequate fluid intake, especially in elderly patients, because dehydration may accelerate the occurrence of toxicity.

In practice, frequent assessment of kidney function, blood counts, and clinical status can help detect early signs of methotrexate accumulation, particularly in patients already at risk for nephrotoxicity or marrow suppression.

Phenytoin

Competitive albumin binding of drugs with high serum protein affinity can increase pharmacologically active unbound concentrations and enhance the metabolism of low clearance drugs. In vitro data suggest a significant increase in unbound phenytoin concentration by high doses of oxacillin, especially with hypoalbuminemia or uremia.

Because total phenytoin levels may underestimate exposure when protein binding is altered, consideration of free drug levels and clinical monitoring for neurologic toxicity are advisable if high dose oxacillin is used in patients receiving phenytoin.

Interference with Diagnostic Tests

Pseudoproteinuria

Patients who take penicillin G or ureidopenicillin derivatives in doses over 5 g/day develop pseudoproteinuria. Proteinuria should be evaluated by a bromphenol blue test (Albustix) or after urine dialysis.

Recognition of this effect is important to avoid misinterpreting benign test interference as evidence of intrinsic kidney disease.

17-ketosteroids

High-dosage penicillin produces abnormally high concentrations of 17-ketogenic steroids in the blood and high concentrations of 17-ketosteroid in the urine.

When endocrine evaluation is needed, clinicians should take recent or ongoing high dose penicillin therapy into account, as it can complicate the interpretation of steroid measurements.