Dosing

Dosing: Adult
Note: Dose and duration of therapy can vary depending on infecting organism, severity of infection, and clinical response of patient. Treat severe staphylococcal infections for at least 14 days; endocarditis and osteomyelitis require an extended duration of therapy for 4-6 weeks. The intravenous route should be used for severe infections.
Susceptible infections:
I.M., I.V.: 250-500 mg every 6 hours (manufacturer recommended maximum adult dose: 6 g/day)
Dosing recommendations of World Health Organization unless otherwise noted:
Arthritis (septic), methicillin-sensitive Staphylococcus aureus (MSSA) (unlabeled dosing): I.M., I.V.: 2 g every 6 hours for 2-3 weeks;
Endocarditis (MSSA) (unlabeled dosing): I.V.:
Native valve: 2 g every 4 hours for 6 weeks; may give with gentamicin for initial 5 days (Choudri, 2000)
Prosthetic valve: 2 g every 4 hours for 6 weeks; give with gentamicin for 2 weeks and rifampin for 6 weeks (Choudri, 2000)
Uncomplicated endocarditis in I.V. drug users: 2 g every 4 hours for 4 weeks and gentamicin for initial 5 days or 2 g every 4 hours and gentamicin both given for 2 weeks total (Choudri, 2000)
Osteomyelitis (MSSA) (unlabeled dosing): I.M., I.V.: 2 g every 6 hours for 4-6 weeks (preferred) or for a minimum of 14 days, followed by 1 g every 6 hours orally to complete 4-6 weeks of therapy
Pneumonia (MSSA) (unlabeled dosing): I.M., I.V.: 1-2 g every 6 hours for 10-14 days

Dosing: Pediatric
Note: Dose and duration of therapy can vary depending on infecting organism, severity of infection, and clinical response of patient. Treat severe staphylococcal infections for at least 14 days; endocarditis and osteomyelitis require an extended duration of therapy for 4-6 weeks. The intravenous route should be used for severe infections.
Susceptible infections:
I.M., I.V.:
Children ≤20 kg: 25-50 mg/kg/day in divided doses every 6 hours; up to 200 mg/kg/day has been used in some studies for severe infections (Nunn, 2007; St. John, 1981)
Children >20 kg: Refer to adult dosing.
Dosing recommendations of World Health Organization unless otherwise noted:
Arthritis (septic), methicillin-sensitive Staphylococcus aureus (MSSA) (unlabeled dosing):
Children 2 months to 5 years: I.M., I.V.: 25-50 mg/kg (maximum: 2 g) every 4-6 hours given with ceftriaxone until clinical improvement, followed by oral therapy: 12.5 mg/kg (maximum: 500 mg) every 6 hours; total duration of therapy 2-3 weeks
Children >5 years: I.M., I.V.: 25-50 mg/kg (maximum: 2 g) every 4-6 hours (maximum daily dose: 12 g/day) until clinical improvement, followed by oral therapy: 25 mg/kg (maximum: 500 mg) every 6 hours; total duration of therapy 2-3 weeks
Endocarditis (MSSA) (unlabeled dosing): I.V.: 50 mg/kg (maximum: 2 g) every 4 hours for 6 weeks; give with gentamicin for initial 7 days
Osteomyelitis (MSSA) (unlabeled dosing):
Children 2 months to 5 years: I.M., I.V.: 25-50 mg/kg (maximum: 2 g) every 4-6 hours given with ceftriaxone until clinical improvement, followed by oral therapy: 12.5 mg/kg (maximum: 500 mg) every 6 hours; total duration of therapy 3-4 weeks
Children >5 years: I.M., I.V.: 25-50 mg/kg (maximum: 2 g) every 4-6 hours (maximum daily dose: 12 g/day) until clinical improvement, followed by oral therapy: 25 mg/kg (maximum: 500 mg) every 6 hours; total duration of therapy 3-4 weeks
Pneumonia (MSSA) (unlabeled dosing):
Children >5 years: I.M., I.V.: 50 mg/kg (maximum: 2 g) every 6 hours for 10-14 days

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment
No dosage adjustment necessary.

Use

Treatment of bacterial infections including endocarditis, pneumonia, bone and joint infections, skin and soft-tissue infections, and sepsis that are caused by susceptible strains of penicillinase-producing staphylococci.
Note: Exhibits good activity against Staphylococcus aureus; has activity against many streptococci, but is less active than penicillin and is generally not used in clinical practice to treat streptococcal infections.

Adverse Reactions

Frequency not defined.
Cardiovascular: Hypotension
Central nervous system: Confusion, fever, lethargy, seizure (high doses and/or renal failure)
Dermatologic: Pruritus, rash, urticaria
Gastrointestinal: Abdominal pain, black or hairy tongue, diarrhea, flatulence, nausea, oral candidiasis, pseudomembranous colitis, stomatitis, vomiting
Hematologic: Agranulocytosis, bone marrow depression, eosinophilia, granulocytopenia, hemolytic anemia, leukopenia, neutropenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased, ALT increased, AST increased, hepatotoxicity
Local: Thrombophlebitis
Neuromuscular & skeletal: Arthralgia, myalgia, myoclonus
Renal: Hematuria, interstitial nephritis, proteinuria, renal insufficiency, renal tubular damage
Respiratory: Bronchospasm, laryngeal edema, laryngospasm, sneezing, wheezing
Miscellaneous: Anaphylaxis, angioedema, allergic reaction, serum sickness-like reaction

Contraindications

Hypersensitivity to cloxacillin, other penicillins, cephalosporins, or any component of the formulation

Warnings / Precautions Drug

Concerns related to adverse effects:
• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients.
• CNS effects: Although not reported with cloxacillin, the transport of penicillins across the blood brain barrier may be enhanced by inflamed meninges or during cardiopulmonary bypass. An increased risk of myoclonia, seizures, or reduced consciousness may be observed in these patients (particularly those with renal failure).
• Hematologic effects: Penicillin use has been associated with hematologic disorders (eg, agranulocytosis, neutropenia, thrombocytopenia) believed to be a hypersensitivity phenomena. Reactions are most often reversible upon discontinuing therapy.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment; rate of elimination is reduced.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; high serum levels, particularly in the presence of renal impairment, may increase risk for seizures
Special populations:
• Neonates: May have decreased renal clearance of cloxacillin; frequent evaluation of serum levels and of clinical status for adverse effects as well as frequent dosage adjustments may be necessary in this patient population;

Interactions

BCG: Antibiotics may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Fusidic Acid: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Methotrexate: Penicillins may decrease the excretion of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 24 hours after cessation of antibacterial agents. Risk D: Consider therapy modification

Pregnancy

Pregnancy Implications
Cloxacillin crosses the placenta and distributes into fetal tissue. In general, penicillins as a class are considered safe for use during pregnancy.

Lactation

Enters breast milk/use caution
Dietary Considerations
Should be taken 1 hour before or 2 hours after meals with water.

Mechanism of Action

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Pharmacodynamics / Kinetics

Distribution: Widely to most body fluids and bone; penetration into cells, into eye, and across normal meninges is poor; crosses placenta; enters breast milk; inflammation increases amount that crosses blood-brain barrier
Protein binding: ~94% (primarily albumin)
Metabolism: Extensively hepatic to active and inactive metabolites
Half-life elimination: 0.5-1.5 hours; prolonged with renal impairment and in neonates
Excretion: Urine and feces