What empiric broad‑spectrum antibiotics, dosing, renal adjustments, MRSA coverage, and duration are recommended for an adult with a serious undifferentiated infection (e.g., severe community‑acquired pneumonia, intra‑abdominal sepsis, complicated urinary‑tract infection, healthcare‑associated infection, or sepsis of unknown source) and risk factors for resistant organisms?

Empiric Broad-Spectrum Antibiotics for Serious Undifferentiated Infections in Adults

For adults with serious undifferentiated infections and risk factors for resistant organisms, initiate empiric therapy immediately with a broad-spectrum carbapenem (meropenem 1-2g IV q8h) or piperacillin-tazobactam (4.5g IV q6h) PLUS vancomycin (15 mg/kg IV q8-12h, target trough 15-20 mg/mL) or linezolid (600 mg IV q12h) for MRSA coverage, with antimicrobials administered within one hour of recognition. 1, 2

Immediate Antibiotic Administration

• Antimicrobials must be initiated within one hour of recognizing sepsis or septic shock, as this is a strong recommendation with moderate quality evidence from the Surviving Sepsis Campaign. 1
• The one-hour window applies to both sepsis and septic shock presentations, representing a critical time-sensitive intervention. 1

Core Empiric Regimen Selection

Gram-Negative and Anaerobic Coverage

Primary options for broad-spectrum coverage include:

• Carbapenems: Meropenem (1-2g IV q8h), imipenem/cilastatin (500mg-1g IV q6-8h), or doripenem are preferred for healthcare-associated infections with suspected multidrug-resistant organisms. 1
• Piperacillin-tazobactam (4.5g IV q6h) or ticarcillin/clavulanate provide extended-range penicillin/β-lactamase inhibitor coverage. 1
• Third-generation cephalosporins (ceftriaxone 2g IV q24h or cefotaxime 2g IV q8h) can be used as part of multidrug regimens, particularly when combined with other agents. 1

MRSA Coverage: Critical Risk Stratification

Add empiric MRSA coverage if ANY of the following risk factors are present:

• Prior intravenous antibiotic use within 90 days 2
• Hospitalization in a unit where ≥20% of S. aureus isolates are methicillin-resistant 2
• High risk of mortality (requiring ventilatory support or septic shock) 2
• Healthcare-associated infection with severe sepsis 1, 2

MRSA-active agents:

• Vancomycin 15 mg/kg IV q8-12h (target trough 15-20 mg/mL) is first-line. 2
• Linezolid 600 mg IV q12h may be preferred for pneumonia due to superior lung penetration. 2
• Both agents have high-quality evidence supporting their use. 2

Atypical Pathogen Coverage

For severe community-acquired pneumonia or undifferentiated respiratory infections:

• Add a macrolide (azithromycin 500mg IV q24h or clarithromycin) OR a respiratory fluoroquinolone (levofloxacin 750mg IV q24h or moxifloxacin 400mg IV q24h) to β-lactam therapy. 1
• Empiric atypical coverage reduces clinical failure rates in hospitalized CAP patients (RR 0.851,95% CI 0.732-0.99). 3
• For Legionella risk, levofloxacin or moxifloxacin are preferred over macrolides. 1

Site-Specific Considerations

Intra-Abdominal Sepsis

• Ceftazidime/avibactam 2.5g IV q8h plus metronidazole 500mg IV q6h for carbapenem-resistant Enterobacterales (CRE). 1
• Imipenem/cilastatin/relebactam 1.25g IV q6h provides alternative coverage. 1
• Ertapenem may be used for extended-spectrum β-lactamase (ESBL) producers without Pseudomonas risk. 1

Complicated Urinary Tract Infections

Healthcare-associated or nosocomial UTI with sepsis:

• Meropenem plus teicoplanin or vancomycin for multidrug-resistant organisms. 1
• For community-acquired UTI with sepsis: third-generation cephalosporin or piperacillin-tazobactam. 1

Pneumonia (Severe Community-Acquired or Healthcare-Associated)

Without Pseudomonas risk:

• Non-antipseudomonal cephalosporin III (ceftriaxone or cefotaxime) plus macrolide OR moxifloxacin/levofloxacin ± cephalosporin. 1

With Pseudomonas risk factors (prior antibiotics, structural lung disease, prolonged hospitalization):

• Antipseudomonal cephalosporin (ceftazidime or cefepime) OR acylureidopenicillin/β-lactamase inhibitor OR carbapenem (meropenem preferred, up to 6g daily in divided doses) PLUS ciprofloxacin OR macrolide plus aminoglycoside (gentamicin, tobramycin, or amikacin). 1

Multidrug-Resistant Organism Coverage

Carbapenem-Resistant Enterobacterales (CRE)

For bloodstream infections:

• Ceftazidime/avibactam 2.5g IV q8h (preferred, weak recommendation, very low evidence). 1
• Meropenem/vaborbactam 4g IV q8h or imipenem/cilastatin/relebactam 1.25g IV q6h are alternatives. 1
• Polymyxin-based combinations: Colistin 5 mg CBA/kg IV loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h PLUS tigecycline 100mg IV loading, then 50mg IV q12h OR meropenem 1g IV q8h by extended infusion. 1

Difficult-to-Treat Pseudomonas aeruginosa

• Ceftolozane/tazobactam 1.5-3g IV q8h (3g for hospital-acquired/ventilator-associated pneumonia). 1
• Ceftazidime/avibactam 2.5g IV q8h. 1
• Colistin monotherapy or combination therapy (weak recommendation, low evidence). 1

Renal Dose Adjustments

Critical adjustments for common agents:

• Meropenem: CrCl 26-50 mL/min: 1g q12h; CrCl 10-25 mL/min: 500mg q12h; CrCl <10 mL/min: 500mg q24h
• Piperacillin-tazobactam: CrCl 20-40 mL/min: 2.25g q6h; CrCl <20 mL/min: 2.25g q8h
• Vancomycin: Dose based on pharmacokinetic calculations targeting trough 15-20 mg/mL; monitor levels closely in renal impairment 2
• Linezolid: No renal adjustment required 2
• Colistin: Adjust using formula: 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h after loading dose 1

Duration of Therapy

• Typical duration: 7-10 days for most infections with adequate source control and clinical response. 1
• Extended duration (10-14 days) for hospital-acquired/ventilator-associated pneumonia, bloodstream infections, or slow clinical response. 1
• Longer courses (14-21 days) for Staphylococcus aureus bacteremia, Legionella, undrainable foci, or immunocompromised patients. 1
• Procalcitonin-guided therapy may allow shorter treatment duration in responding patients. 1

De-escalation Strategy: Mandatory Daily Reassessment

Antimicrobial regimens must be reassessed daily for potential de-escalation. 1

• Discontinue MRSA coverage if sputum or blood cultures do not grow MRSA and clinical improvement occurs. 2
• Switch to targeted MSSA therapy (oxacillin, nafcillin, or cefazolin) once MSSA is confirmed to reduce C. difficile risk and resistance. 2, 4
• Narrow to most appropriate single therapy once susceptibility profiles are known, typically within 3-5 days. 1
• Discontinue combination therapy within the first few days in response to clinical improvement or infection resolution. 1

Common Pitfalls and Caveats

• Do not delay antibiotics for diagnostic testing—blood cultures and other specimens should be obtained rapidly but never delay the one-hour administration window. 1
• Avoid sustained antimicrobial prophylaxis in severe inflammatory states of noninfectious origin (severe pancreatitis, burns). 1
• Empiric MRSA coverage in all ICU CAP patients may not improve outcomes in settings with low MRSA prevalence—review local epidemiologic data. 5
• Healthcare-associated UTI with sepsis is a high-risk scenario for inadequate empiric coverage; these patients require broader coverage than community-acquired UTI. 6
• Tigecycline monotherapy is not recommended for pneumonia; use only in combination if tigecycline MIC ≤2 mg/L. 1
• Aminoglycoside monotherapy is only appropriate for urinary tract infections, not systemic infections. 1
• Carbapenem use should be reserved for documented ESBL or CRE when possible to preserve this class, but do not withhold in critically ill patients with risk factors. 1