Penicillinase resistant penicillins

Definition
Penicillinase-resistant penicillins—also known as anti-staphylococcal penicillins—are a specific subclass of beta-lactam antibiotics developed to combat Staphylococcus aureus and other bacteria that produce penicillinase, a type of beta-lactamase enzyme. These penicillins resist degradation by staphylococcal beta-lactamase enzymes through structural modifications of the penicillin molecule, particularly in the R-group side chain, enabling them to maintain bactericidal activity against susceptible strains.

They are particularly effective against methicillin-sensitive Staphylococcus aureus (MSSA) and Streptococcus species, but they lack activity against methicillin-resistant Staphylococcus aureus (MRSA) and most Gram-negative organisms.

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1. Mechanism of Action

Like all beta-lactam antibiotics, penicillinase-resistant penicillins bind to penicillin-binding proteins (PBPs) located on the inner membrane of bacterial cell walls. This binding inhibits transpeptidation, a key step in peptidoglycan cross-linking, ultimately compromising bacterial cell wall integrity, leading to cell lysis and death.

Their resistance to penicillinase is achieved through bulky side chains that prevent beta-lactamase enzymes from hydrolyzing the beta-lactam ring.

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2. Generic and Brand Names

Generic Name	Brand Names	Route of Administration
Cloxacillin	Cloxapen, Orbenin	Oral, IV
Dicloxacillin	Dynapen, Pathocil	Oral
Flucloxacillin	Floxapen, Staphylex	Oral, IV
Nafcillin	Nafcil, Unipen	IV
Oxacillin	Bactocill	IV
Methicillin	(Discontinued due to toxicity)	Historical reference

Methicillin was the prototype of this group but is no longer in clinical use due to high rates of interstitial nephritis. The term MRSA still refers to methicillin-resistant strains resistant to all drugs in this class.

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3. Spectrum of Activity

Pathogen Group	Activity
Gram-positive cocci	Excellent activity against MSSA, Streptococcus spp.
Gram-negative organisms	Minimal to none
Anaerobes	Not active
MRSA	Not active (MRSA expresses PBP2a, reducing binding)

4. Indications

Penicillinase-resistant penicillins are primarily indicated in infections caused by penicillinase-producing Gram-positive bacteria, especially MSSA. Common clinical indications include:

• Skin and soft tissue infections (SSTIs)

• Bone and joint infections (osteomyelitis)

• Endocarditis

• Pneumonia (especially in healthcare-associated infections)

• Septic arthritis

• Post-surgical wound infections

• Bacteremia and sepsis due to MSSA

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5. Dosage and Administration

Drug	Typical Adult Dosage	Route/Frequency
Cloxacillin	250–500 mg every 6 hours	Oral/IV
Dicloxacillin	125–500 mg every 6 hours	Oral
Flucloxacillin	250–500 mg every 6 hours	Oral/IV
Nafcillin	1–2 g IV every 4–6 hours	IV
Oxacillin	1–2 g IV every 4–6 hours	IV

Pediatric doses are weight-based and should be adjusted for renal or hepatic impairment when necessary.

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6. Pharmacokinetics

Parameter	Details
Absorption (oral)	Dicloxacillin and flucloxacillin: moderate; best on empty stomach
Distribution	Well distributed; penetrates bone and synovial fluid
CNS penetration	Limited unless meninges are inflamed
Protein binding	High (~90%)
Metabolism	Nafcillin undergoes hepatic metabolism
Excretion	Primarily renal (except nafcillin: mainly biliary)
Half-life	Short (~0.5–1.5 hours) requiring multiple daily dosing

7. Adverse Effects

System	Common Effects	Serious Effects
GI	Nausea, diarrhea (less than amoxicillin)	Hepatitis (especially with flucloxacillin)
Allergic	Rash, urticaria	Anaphylaxis, angioedema
Renal	Rare interstitial nephritis (notably methicillin, nafcillin)
Hepatic	Cholestatic jaundice (flucloxacillin)	Hepatitis
Hematologic	Neutropenia (rare, usually with prolonged use)	Thrombocytopenia

Flucloxacillin-associated cholestatic jaundice may occur weeks after treatment ends and is more common in elderly patients.

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8. Contraindications and Precautions

Condition	Consideration
Penicillin allergy	Contraindicated; risk of anaphylaxis
Cholestatic hepatitis history	Avoid flucloxacillin
Severe renal impairment	Dose adjustment needed (except nafcillin)
Hepatic impairment	Caution with flucloxacillin, nafcillin

9. Drug Interactions

Drug/Class	Interaction and Clinical Impact
Warfarin	Possible increase in INR (monitor coagulation parameters)
Methotrexate	Reduced clearance, increased toxicity risk
Allopurinol	May increase risk of rash
Oral contraceptives	May reduce efficacy (controversial, but caution advised)
Probenecid	Inhibits renal excretion, increases penicillin levels

10. Clinical Considerations

• Flucloxacillin and dicloxacillin are more stable in acidic environments and better tolerated orally than cloxacillin.

• Nafcillin is excreted primarily via the liver, making it preferred in renal impairment.

• Empiric treatment for suspected MSSA infections often includes anti-staphylococcal penicillins.

• Methicillin-sensitive strains of Staphylococcus aureus are defined based on susceptibility to nafcillin or oxacillin.

• MRSA strains are resistant to all penicillinase-resistant penicillins due to the mecA gene encoding altered PBP2a.

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11. Resistance Patterns

Mechanism of Resistance	Effect
Beta-lactamase (penicillinase)	Inhibited by drug design
Altered PBPs (mecA gene)	Causes MRSA; penicillinase-resistant penicillins fail
Efflux pumps, biofilms	Contribute to resistance in certain S. aureus populations

The primary resistance issue is MRSA, which is not susceptible to any penicillin, including penicillinase-resistant ones. Alternative therapies for MRSA include:

• Vancomycin

• Linezolid

• Daptomycin

• Clindamycin (if susceptible)

• TMP/SMX

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12. Formulations and Availability

Formulation Type	Drugs Available
Oral Capsules	Flucloxacillin, Dicloxacillin, Cloxacillin
Intravenous Solutions	Nafcillin, Oxacillin, Flucloxacillin
Intramuscular Injections	Limited use; rarely preferred due to pain
Pediatric Suspensions	Dicloxacillin, Flucloxacillin

13. Use in Special Populations

Population	Recommendation
Pregnancy	Generally safe; Category B
Children	Commonly used; doses adjusted by weight
Renal Impairment	Dose adjustment may be needed for some (except nafcillin)
Hepatic Impairment	Monitor LFTs with flucloxacillin, avoid if prior hepatotoxicity

14. Comparison with Other Beta-Lactams

Feature	Penicillinase-Resistant Penicillins	Aminopenicillins	Cephalosporins (1st gen)
MSSA Activity	Strong	Weak	Moderate
MRSA Activity	None	None	None
Gram-negative Coverage	Minimal	Moderate	Moderate
Oral Availability	Good (flucloxacillin, dicloxacillin)	Good	Good
Beta-lactamase Stability	Stable (against staph penicillinase)	Unstable	Stable

15. Clinical Pearls

• First-line for confirmed MSSA infections

• Flucloxacillin is favored in UK, Australia, whereas nafcillin/oxacillin are more common in US

• Do not use for infections caused by MRSA or Gram-negative organisms

• Optimal dosing frequency is every 6 hours due to short half-life

• Monitor LFTs during long courses of flucloxacillin therapy

• Take oral forms on an empty stomach to maximize absorption