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 to 6 weeks. The intravenous route should be used for severe infections.
Usual dosage range:
Oral: 250 to 500 mg every 6 hours; may increase dose for serious infections (maximum dose: 6 g/day).
IM, IV: 1 to 2 g every 4 to 6 hours (Bai 2015; Chauhan 2004; ESC [Habib 2015]; Euba 2009; WHO 2001).
Bloodstream infection due to methicillin-susceptible S. aureus: IV: 2 g every 4 to 6 hours (Bai 2015; Burdet 2018; WHO 2001); treat uncomplicated S. aureus bacteremia for ≥14 days starting from day of first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (IDSA [Mermel 2009]).
Endocarditis due to methicillin-susceptible staphylococci:
Native valve: IV: 12 g/day in 4 to 6 divided doses for 4 to 6 weeks (ESC [Habib 2015]).
Prosthetic valve: IV: 12 g/day in 4 to 6 divided doses for ≥6 weeks, in combination with rifampin and gentamicin (ESC [Habib 2015]).
Osteomyelitis due to methicillin-susceptible S. aureus: IV: 2 g every 4 hours for ≥6 weeks (Euba 2009).
Skin and soft tissue infections:
Localized purulent skin lesions, impetigo: Oral: 250 to 500 mg every 6 hours for 5 to 7 days (WHO 2001).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
There are no dosage adjustments provided in the manufacturer’s labeling.
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 to 6 weeks. The intravenous route should be used for severe infections.
Susceptible infections (manufacturer’s labeling):
Oral:
Children ≤20 kg: 25 to 50 mg/kg/day in divided doses every 6 hours
Children and Adolescents >20 kg: Refer to adult dosing.
IM, IV:
Children ≤20 kg: 25 to 50 mg/kg/day in divided doses every 6 hours. Note: Doses up to 50 mg/kg/dose every 4 to 6 hours or 200 mg/kg to 300 mg/kg/day in divided doses have been recommended by others (Nunn 2007; St. John 1981) (also see indication-specific dosing).
Children and Adolescents >20 kg: Refer to adult dosing.
Dosing recommendations of World Health Organization (WHO) unless otherwise noted:
Arthritis (septic) (off-label dosing) (WHO 2001): Empiric therapy: Infants ≥2 months, Children, and Adolescents: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 6 hours with concomitant ceftriaxone
Methicillin-sensitive Staphylococcus aureus (MSSA):
Infants ≥2 months and Children ≤5 years: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours with concomitant ceftriaxone for 4 to 6 days or until clinical improvement, followed by oral cloxacillin 12.5 mg/kg/dose (maximum: 500 mg/dose) every 6 hours; total duration of therapy 2 to 3 weeks
Children >5 years and Adolescents: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours (maximum daily dose: 12 g/day) for 4 to 6 days or until clinical improvement, followed by oral cloxacillin 25 mg/kg/dose (maximum: 500 mg/dose) every 6 hours; total duration of therapy 2 to 3 weeks
Endocarditis (MSSA) (off-label dosing) (WHO 2001): Children and Adolescents: IV: 50 mg/kg/dose (maximum: 2 g/dose) every 4 hours for 6 weeks; with concomitant gentamicin for initial 7 days
Osteomyelitis (off-label dosing) (WHO 2001):
Haemophilus influenza or unknown pathogen: Infants ≥2 months and Children ≤5 years: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours with concomitant ceftriaxone for 4 to 6 days or until clinical improvement, followed by oral therapy with amoxicillin/clavulanate; total duration of therapy 3 to 4 weeks
MSSA:
Infants ≥2 months and Children ≤5 years: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours with concomitant ceftriaxone for 4 to 6 days until clinical improvement, followed by oral cloxacillin 12.5 mg/kg/dose (maximum: 500 mg/dose) every 6 hours; total duration of therapy 3 to 4 weeks
Children >5 years and Adolescents: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours (maximum daily dose: 12 g/day) for 4 to 6 days until clinical improvement, followed by oral cloxacillin 25 mg/kg/dose (maximum: 500 mg/dose) every 6 hours; total duration of therapy 3 to 4 weeks
Salmonella spp: Infants ≥2 months and Children ≤5 years: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours with concomitant ceftriaxone for 4 to 6 days or until clinical improvement, followed by oral therapy with sulfamethoxazole/trimethoprim or amoxicillin or ciprofloxacin; total duration of therapy 6 weeks.
Pneumonia (MSSA) (off-label dosing) (WHO 2001):
Infants ≥2 months and Children ≤5 years: Oral: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 6 hours for at least 3 weeks with concomitant gentamicin
Children >5 years and Adolescents: IM, IV: 50 mg/kg/dose (maximum: 2 g/dose) every 6 hours for 10 to 14 days
Pneumonia (nosocomial) (off-label dosing) (WHO 2001): Empiric therapy: Children and Adolescents: IV: 50 mg/kg/dose (maximum: 2 g/dose) every 6 hours with concomitant gentamicin for 7 days (add vancomycin for 10 to 14 days if in a hospital with a high prevalence of MRSA)
Septicemia (off-label dosing) (WHO 2001): Empiric therapy:
Infants ≥2 months to 5 years: IV: 50 mg/kg/dose (maximum: 2 g/dose) every 4 to 6 hours with concomitant ceftriaxone
Children >5 years and Adolescents: IV: 2 g every 4 to 6 hours with concomitant gentamicin
Skin and soft tissue infections (off-label dosing) (WHO 2001): Empiric therapy:
Contaminated soft tissue injuries: Children and Adolescents: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 6 hours for 5 to 10 days with concomitant gentamicin and metronidazole; with clinical improvement, may switch to oral cloxacillin 12.5 to 25 mg/kg/dose (maximum: 500 mg) every 6 hours
Localized purulent skin lesions, impetigo: Children and Adolescents: Oral: 12.5 to 25 mg/kg/dose (maximum: 500 mg/dose) every 6 hours for 5 to 7 days
Pyomyositis: Children and Adolescents: IM, IV: 25 to 50 mg/kg/dose (maximum: 2 g/dose) every 6 hours for 5 to 10 days; with clinical improvement, may switch to oral cloxacillin 12.5 to 25 mg/kg/dose (maximum: 500 mg/dose) every 6 hours
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
There are no dosage adjustments provided in the manufacturer’s labeling.
Refer to adult dosing.
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 250 mg, 500 mg
Solution Reconstituted, Injection:
Generic: 500 mg (1 ea); 1 g (1 ea); 2 g (1 ea); 10 g (1 ea)
Suspension Reconstituted, Oral:
Generic: 125 mg/5 mL (60 mL, 100 mL, 200 mL)
Not available in the US
Oral: Administer with water 1 hour before or 2 hours after meals.
IV:
IV push: Administer slowly over 2 to 4 minutes.
IV infusion: Administer over 30 to 40 minutes.
Parenteral:
IM: Administer into large muscle mass.
IV push: Administer slowly over 2 to 4 minutes.
IV infusion: Administer over 30 to 40 minutes.
Oral: Administer 1 to 2 hours before meals.
Oral solution: Shake well. Administer liquid with an accurate measuring device; do not use a household teaspoon (under- or overdosage may occur).
Note: Not approved in the United States.
Bacterial infections: Treatment of bacterial infections (eg, bloodstream infection, endocarditis, pneumonia, bone and joint infections, skin and soft-tissue infections) caused by susceptible strains of penicillinase-producing staphylococci.
Limitations of use: Exhibits good activity against Staphylococcus aureus; has activity against many streptococci, but is less active than penicillin. Not effective against methicillin-resistant staphylococci.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined. Adverse effects may be reported as class effects rather than specific to cloxacillin.
Cardiovascular: Hypotension, thrombophlebitis
Central nervous system: Confusion, lethargy, myoclonus, seizure (high doses and/or renal failure), twitching
Dermatologic: Pruritus, skin rash, urticaria
Gastrointestinal: Abdominal pain, diarrhea, epigastric distress, flatulence, hairy tongue, loose stools, melanoglossia, nausea, oral candidiasis, pseudomembranous colitis, stomatitis, vomiting
Genitourinary: Hematuria, proteinuria
Hematologic & oncologic: Agranulocytosis, anemia, bone marrow depression, eosinophilia, granulocytopenia, hemolytic anemia, immune thrombocytopenia, leukopenia, neutropenia, thrombocytopenia
Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased serum AST, hepatotoxicity
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction (immediate and delayed)
Immunologic: Serum sickness-like reaction
Neuromuscular & skeletal: Laryngospasm
Renal: Interstitial nephritis, renal insufficiency, renal tubular disease
Respiratory: Bronchospasm, laryngeal edema, sneezing, wheezing
Miscellaneous: Fever
Hypersensitivity to cloxacillin, other penicillins, cephalosporins, or any component of the formulation
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.
None known.
Acemetacin: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Risk C: Monitor therapy
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Methotrexate: Penicillins may increase the serum concentration 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
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Tetracyclines: May diminish the therapeutic effect of Penicillins. Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Cloxacillin may diminish the anticoagulant effect of Vitamin K Antagonists. Cloxacillin may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Food decreases cloxacillin absorption; serum levels are reduced by ~50%. Management: Administer with water on an empty stomach 1 hour before or 2 hours after meals.
Penicillin class antibiotics cross the placenta in varying degrees. Cloxacillin is highly protein bound which may influence fetal exposure (Nau 1987).
As a class, penicillin antibiotics are widely used in pregnant women. Based on available data, penicillin antibiotics are generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Damkier 2019; Lamont 2014; Muanda 2017a; Muanda 2017b).
Cloxacillin is present in breast milk.
Concentrations of penicillin class antibiotics in breast milk are limited (Nau 1987). Following a single dose of cloxacillin 500 mg IM to 2 or 3 women 5 to 7 days postpartum, breast milk concentrations were ≤0.4 mcg/mL over a 6-hour period, with the highest concentrations observed 4 to 6 hours after the maternal dose. In contrast, the highest maternal serum concentration (3.7 mcg/mL) was found 1 hour after the dose, decreasing to ≤0.3 mcg/mL 6 hours after the dose (Matsuda 1984).
A prospective cohort study evaluated the outcomes of breastfed infants whose mothers were taking various medications. Among 10 mother-infant pairs with reported cloxacillin exposure (dose, duration, relationship to breastfeeding not provided), diarrhea was reported in 2 infants (Ito 1993).
In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea. Cloxacillin is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).
Observe for signs and symptoms of anaphylaxis during first dose; CBC with differential (prior to initiating therapy and weekly thereafter), periodic urinalysis, BUN, creatinine, hepatic function
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.
Absorption: Oral: ~50%; reduced by food
Distribution: Widely to most body fluids and bone; penetration into cells, into eye, and across normal meninges is poor; inflammation increases amount that crosses blood-brain barrier
Protein binding: ~94% (primarily albumin)
Metabolism: Hepatic to active and inactive metabolites
Half-life elimination: 0.5 to 1.5 hours; prolonged with renal impairment and in neonates
Time to peak, serum: Oral: ~1 hour
Excretion: Urine and feces
