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Cloxacillin

Pronunciation

Pronunciation

(kloks a SIL in)

Index Terms

  • Cloxacillin Sodium

Pharmacologic Category

  • Antibiotic, Penicillin

Pharmacology

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

Metabolism

Hepatic to active and inactive metabolites

Excretion

Urine and feces

Time to Peak

Oral: Serum: ~1 hour

Half-Life Elimination

0.5 to 1.5 hours; prolonged with renal impairment and in neonates

Protein Binding

~94% (primarily albumin)

Use: Labeled Indications

Note: Not approved in the US

Bacterial infections: 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.

Limitations of use: 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. Not effective against methicillin-resistant staphylococci.

Contraindications

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

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 to 6 weeks. The intravenous route should be used for severe infections.

Susceptible infections (manufacturer’s labeling):

Oral: 250 to 500 mg every 6 hours (maximum adult dose: 6 g/day)

IM: 250 to 500 mg every 6 hours (maximum adult dose: 6 g/day). Note: Doses up to 2 g every 4 to 6 hours or 8 to 12 g/day in divided doses have been recommended by others (see indication-specific dosing).

IV: 250 to 500 mg every 6 hours (maximum adult dose 6 g/day). Note: Doses up to 2 g every 4 to 6 hours or 8 to 12 g/day in divided doses have been recommended by others (see indication-specific dosing).

Dosing recommendations of World Health Organization (WHO) unless otherwise noted:

Arthritis (septic) (off-label dosing) (WHO 2001): Empiric therapy: Adults: IM, IV: 2 g every 6 hours with concomitant ceftriaxone

Methicillin-sensitive Staphylococcus aureus (MSSA): IM, IV: 2 g every 6 hours for 2 to 3 weeks; Note: Cloxacillin oral therapy of 1 g every 6 hours may be used to complete therapy if parenteral therapy is discontinued prior to 2 to 3 week duration

Endocarditis (MSSA) (off-label dosing): IV:

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 IV 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) (off-label dosing) (WHO 2001): IM, IV: 2 g every 6 hours for 4 to 6 weeks (preferred) or for a minimum of 14 days, followed by 1 g every 6 hours orally to complete 4 to 6 weeks of therapy

Pneumonia (MSSA) (off-label dosing) (WHO 2001): IM, IV: 1 to 2 g every 6 hours for 10 to 14 days

Pneumonia (nosocomial) (off-label dosing) (WHO 2001): Empiric therapy: IV: 1 to 2 g 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: 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: IM, IV: 2 g every 6 hours for 5 to 10 days with concomitant gentamicin and metronidazole; with clinical improvement, may switch to oral cloxacillin 500 mg every 6 hours

Localized purulent skin lesions, impetigo: Oral: 250 to 500 mg every 6 hours for 5 to 7 days

Pyomyositis: IM, IV: 2 g every 6 hours for 5 to 10 days; with clinical improvement, may switch to oral cloxacillin 500 mg every 6 hours

Dosing: Geriatric

Refer to adult dosing.

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 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

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

IM injection: Reconstitute vial with appropriate volume of SWFI to make a final concentration of 125 mg/mL or 250 mg/mL

IV injection: Reconstitute vial with appropriate volume of SWFI to make a final concentration of 50 mg/mL or 100 mg/mL

IV infusion: Reconstitute vial with appropriate volume of SWFI to make a concentration of 250 mg/mL, followed by further dilution in a compatible solution.

Powder for oral solution:

60 mL bottle: Reconstitute by adding 42 mL of sterile water to make a final concentration of 125 mg/5 mL.

100 mL bottle: Reconstitute by adding 70 mL of sterile water to make a final concentration of 125 mg/5 mL.

200 mL bottle: Reconstitute by adding 140 mL of sterile water to make a final concentration of 125 mg/5 mL.

Administration

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

Compatibility

Solutions: Stable in NS, D5W, LR

Y-site administration: Incompatible with pantoprazole, vancomycin.

Compatibility in syringe: Incompatible with erythromycin, gentamicin, pantoprazole, polymyxin B.

Storage

Capsule: Store at room temperature not exceeding 25˚C (77˚F).

Powder for injection: Store at controlled room temperature 15°C to 30°C (59°F to 86°F). Upon reconstitution the resulting solution is stable for up to 24 hours at controlled room temperature not exceeding 25˚C (77˚F) or up to 48 hours under refrigeration 2°C to 8°C (36°F to 46°F).

IV infusion: Note: After reconstitution of powder with appropriate volume of sterile water for injection, the manufacturer suggests further dilution to concentrations of 1 to 2 mg/mL in a compatible solution (eg, D5W, NS); solutions are stable for up to 12 hours at controlled room temperature.

Powder for oral solution: Prior to mixing, store powder at room temperature not exceeding 25˚C (77˚F). Refrigerate oral solution after reconstitution; discard after 14 days.

Drug Interactions

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. 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. Monitor therapy

Probenecid: May increase the serum concentration of Penicillins. Management: Avoid the routine use of penicillins and probenecid, but this combination may be used advantageously in select cases with careful monitoring. Monitor for toxic effects of penicillins if probenecid is initiated or the dose is increased. Consider therapy modification

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. Consider therapy modification

Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. 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 3 days after cessation of antibacterial agents. 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. Monitor therapy

Test Interactions

May interfere with urinary glucose tests using cupric sulfate (Benedict's solution, Clinitest); may inactivate aminoglycosides in vitro; false-positive urine and serum proteins; false-positive in uric acid, urinary steroids

Adverse Reactions

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

Warnings/Precautions

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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Monitoring Parameters

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

Pregnancy Considerations

Cloxacillin crosses the placenta and distributes into fetal tissue

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain or gas. Have patient report immediately to prescriber sneezing, severe nausea, severe vomiting, severe diarrhea, bruising, bleeding, seizures, or vaginitis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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