What antibiotic should be used for a patient currently on cephalexin (Keflex) with an isolate resistant to oxacillin and fluoroquinolones but susceptible to clindamycin, erythromycin, gentamicin, tetracycline, trimethoprim‑sulfamethoxazole, and vancomycin?

Antibiotic Selection for Oxacillin-Resistant Staphylococcal Infection

Switch immediately to vancomycin 15-20 mg/kg IV every 8-12 hours, as this patient has an oxacillin-resistant (methicillin-resistant) staphylococcal isolate that requires MRSA-active therapy; cephalexin (Keflex) is ineffective against MRSA and must be discontinued. 1

Interpretation of Susceptibility Results

Your patient's isolate demonstrates:

• Oxacillin resistance (R, NR) – This defines the organism as methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase-negative staphylococci (CoNS), rendering all beta-lactams (including cephalexin) ineffective 1, 2
• Fluoroquinolone resistance – Ciprofloxacin (R, MIC ≥8) and moxifloxacin (R, MIC 2) are not treatment options 1
• Levofloxacin intermediate (I, MIC 4) – Unreliable for therapy 1

First-Line Treatment Algorithm

Intravenous Therapy (Preferred for Serious Infections)

Vancomycin remains the gold standard for oxacillin-resistant staphylococcal infections:

• Dosing: 15-20 mg/kg IV every 8-12 hours, targeting trough concentrations of 15-20 mg/L 1
• Evidence: Class I, Level of Evidence B for prosthetic valve endocarditis; A-I evidence for complicated skin infections 1
• Duration: Minimum 6 weeks for prosthetic valve endocarditis; 7-14 days for complicated skin/soft tissue infections 1

Alternative IV Agents (If Vancomycin Cannot Be Used)

• Linezolid 600 mg IV twice daily (A-I evidence) 1
• Daptomycin 4-6 mg/kg IV once daily (A-I evidence; use 6 mg/kg for bacteremia) 1
• Teicoplanin (if vancomycin-allergic) 1

Oral Treatment Options (For Less Severe Infections After Clinical Improvement)

Your susceptibility panel shows several oral options:

Preferred Oral Agents

• Trimethoprim-sulfamethoxazole (S, MIC ≤10): 1-2 double-strength tablets (160/800 mg) twice daily 1, 3
• Clindamycin (S, MIC ≤0.25): 300-450 mg every 6 hours – Use only if local MRSA clindamycin resistance is <10% 1, 3
• Tetracycline (S, MIC ≤1): Doxycycline 100 mg twice daily is preferred over tetracycline 1, 3

Critical Caveat for Oral Therapy

Never use trimethoprim-sulfamethoxazole or doxycycline as monotherapy for typical cellulitis without adding a beta-lactam, because they lack reliable activity against beta-hemolytic streptococci. However, in your case with a documented oxacillin-resistant staphylococcal isolate, monotherapy with these agents is appropriate after source control. 3

Combination Therapy for Prosthetic Material or Endocarditis

If this infection involves prosthetic material (prosthetic valve, joint, or device):

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS rifampin 300-450 mg orally twice daily for minimum 6 weeks 1
• Add gentamicin (if susceptible) for the first 2 weeks only 1
• Rifampin must always be combined with another agent because resistance emerges rapidly with monotherapy 1

Why Cephalexin (Keflex) Failed

Cephalexin has zero activity against oxacillin-resistant staphylococci:

• Oxacillin resistance is mediated by the mecA gene, which produces an altered penicillin-binding protein (PBP2a) that confers resistance to all beta-lactams, including cephalosporins 2, 4
• Your isolate's oxacillin MIC of "NR" (not reported, but resistant) confirms this mechanism 2
• Continuing cephalexin guarantees treatment failure 2

Agents to Avoid Based on Your Susceptibility Panel

Do not use the following despite in vitro susceptibility:

• Erythromycin (S, MIC ≤0.25) – High resistance rates (65-90%) in MRSA populations make this unreliable despite reported susceptibility 4, 5
• Gentamicin (S, MIC ≤0.5) – Should only be used in combination with vancomycin for endocarditis or prosthetic infections, never as monotherapy 1
• Levofloxacin (I, MIC 4) – Intermediate susceptibility is unreliable; fluoroquinolone resistance is common in MRSA (40-95%) 4, 6

Clinical Decision Algorithm

Step 1: Determine infection severity and site

• Bacteremia, endocarditis, prosthetic infection, or severe cellulitis → Start vancomycin IV immediately 1
• Uncomplicated skin infection with documented MRSA → Oral options acceptable after drainage/debridement 1, 3

Step 2: Add rifampin if prosthetic material is involved

• Vancomycin PLUS rifampin 300-450 mg twice daily for 6 weeks minimum 1
• Add gentamicin for first 2 weeks if susceptible 1

Step 3: Transition to oral therapy (if appropriate)

• Once clinically improved (afebrile, resolving erythema/warmth) → Switch to oral trimethoprim-sulfamethoxazole or clindamycin 1, 3
• Total duration: 5 days for uncomplicated cellulitis; 7-14 days for complicated infections; 6 weeks for prosthetic infections 1, 3

Step 4: Monitor for treatment failure

• Reassess within 24-48 hours – If no improvement, consider vancomycin MIC creep (MIC >1.0 µg/ml associated with higher mortality) 6
• Obtain repeat cultures if bacteremic or prosthetic infection to detect resistance emergence 1

Common Pitfalls to Avoid

• Do not continue cephalexin – It has zero activity against your oxacillin-resistant isolate 2
• Do not use fluoroquinolones – Your isolate is resistant to ciprofloxacin and moxifloxacin, and levofloxacin is only intermediate 4
• Do not use rifampin alone – Resistance develops within days of monotherapy 1
• Do not use erythromycin despite susceptibility – MRSA populations have high macrolide resistance rates 4
• Do not delay vancomycin if infection is severe – Mortality increases with delayed appropriate therapy 6