Cloxacillin

J01C - Beta-lactam antibacterials, penicillins ATC J01CF02 Small molecule approved 1974 Oral Natural product

🧬 Cross-allergy: Penicillins

JFDA label: Cloxadar 250 Caps

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.

Indications

Approved

Bacterial infections

Class profile

gramStatus	Gram+
spectrumBreadth	Narrow
atypicalCoverage	No
isBactericidal	1
moaCategory	Cell wall synthesis inhibitor (beta-lactam, penicillinase-stable)
pdIndex	Time-dependent
postAntibioticEffect	None
mrsaCoverage	0
resistanceMechanisms	PBP2a mutation (mecA gene),Hyperproduction of PBP2a

Contraindications

Source: Lexicomp

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

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Not Known Hypotension · thrombophlebitis

Nervous system disorders (5)

Not Known Confusion · lethargy · myoclonus · seizure (high doses and/or renal failure) · twitching

Hepatobiliary disorders (4)

Not Known hepatotoxicity · Increased serum alkaline phosphatase · increased serum ALT · increased serum AST

Renal and urinary disorders (5)

Not Known Hematuria · Interstitial nephritis · proteinuria · renal insufficiency · renal tubular disease

Blood and lymphatic system disorders (10)

Not Known Agranulocytosis · anemia · bone marrow depression · eosinophilia · granulocytopenia · hemolytic anemia · immune thrombocytopenia · leukopenia · neutropenia · thrombocytopenia

Immune system disorders (4)

Not Known Anaphylaxis · angioedema · hypersensitivity reaction (immediate and delayed) · Serum sickness-like reaction

Gastrointestinal disorders (12)

Not Known Abdominal pain · diarrhea · epigastric distress · flatulence · hairy tongue · loose stools · melanoglossia · nausea · oral candidiasis · pseudomembranous colitis · stomatitis · vomiting

Skin and subcutaneous tissue disorders (3)

Not Known Pruritus · skin rash · urticaria

Musculoskeletal and connective tissue disorders (1)

Not Known Laryngospasm

General disorders and administration site conditions (1)

Not Known Fever

Respiratory, thoracic and mediastinal disorders (4)

Not Known Bronchospasm · laryngeal edema · sneezing · wheezing

Dosing

Source: Lexicomp

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

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 Childr

Refer to adult dosing.

No dosage adjustment necessary.

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

Warnings & Precautions

Source: Lexicomp

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.

Pregnancy & Lactation

Pregnancy

Cloxacillin crosses the placenta and distributes into fetal tissue

Lactation

Cloxacillin is excreted into breast milk

Monitoring

Efficacy	Culture and susceptibility testing; clinical resolution (temperature, WBC, CRP, procalcitonin)
Toxicity	Renal function (dose adjustment in renal impairment); hepatic function for hepatically cleared agents; signs of C. difficile infection (diarrhoea)
Clinical pearl	Culture results guide de-escalation to narrower-spectrum therapy. Review antibiotic appropriateness at 48–72 h (antimicrobial stewardship).
Counseling	Complete the full course. Report persistent diarrhoea, rash, or lack of improvement after 48–72 h.

Chemistry & Properties

Formula	C19H18ClN3O5S
Molecular weight	435.89 g/mol
IUPAC name	(2S,5R,6R)-6-[[3-(2-chlorophenyl)-5-methyl-1,2-oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
CAS	61-72-3
PubChem CID	6098
InChIKey	`LQOLIRLGBULYKD-JKIFEVAISA-N`
logP	2.55 (XLogP 2.4)
Polar surface area	112.74 Å²
H-bond acceptors / donors	6 / 2
Drug-likeness (QED)	0.71
Lipinski violations	0

SMILES

Cc1onc(-c2ccccc2Cl)c1C(=O)N[C@@H]1C(=O)N2[C@@H]1SC(C)(C)[C@@H]2C(=O)O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.212 h
Volume of distribution	0.123 L/kg
Protein binding	95.1%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)PEPT1 (Inhibitor)PEPT2 (Inhibitor)OAT3 (Substrate)P-gp (Substrate)

Drug–drug interactions (17, DDInter)

Interacting drug	Severity	Management
Methotrexate	major
Balsalazide	moderate
Chloramphenicol	moderate
Demeclocycline	moderate
Doxycycline	moderate
Ethinylestradiol	moderate
Iodide I-123	moderate
Iodide I-131	moderate
Minocycline	moderate
Mycophenolic acid	moderate
Pemetrexed	moderate
Picosulfuric acid	moderate
Proguanil	moderate
Tetracycline	moderate
Warfarin	moderate
Clarithromycin	minor
Erythromycin	minor

Registered Products (10)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cloxadar 250 Caps	Capsule 250 mg	16 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	1.600
PENCLODAR 500 CAPS.	Capsule 250 mg, 250 mg	16 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	2.340
Ultracloxam	Tablet 250 mg, 250 mg	2x8's	The Arab Pharmaceutical Manufactruing Co.	2.600
PENCLODAR 500 CAPS.	Capsule 250 mg, 250 mg	20 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	2.810
MONOCLOX VIAL	Vial 250 mg	10 vial	Khoury Drug Store	6.740
MONOCLOX VIAL	Vial 500 mg	10	Al Hilal Drug Store	10.310
Ultraxin Vials	Vial 250 mg	500	The Arab Pharmaceutical Manufactruing Co.	38.220
Cloxadar 250 Caps	Capsule 250 mg	500 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	40.000
PENCLODAR 500 CAPS.	Capsule 250 mg, 250 mg	500 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	57.610
Cloxa	Vial 500 mg	1 vial	ÙØ³ØªÙØ¯Ø¹ Ø£Ø¯ÙÙØ© Ø§ÙÙÙÙÙÙÙ	—