What is the appropriate antibiotic regimen and dosing for an ESBL‑negative (extended‑spectrum β‑lactamase‑negative) Klebsiella pneumoniae urinary tract infection, including recommendations for uncomplicated cystitis versus complicated infection or pyelonephritis and adjustments for impaired renal function?

Antibiotic Management for ESBL-Negative Klebsiella pneumoniae Urinary Tract Infection

First-Line Therapy for Uncomplicated Cystitis (ESBL-Negative)

For uncomplicated cystitis caused by ESBL-negative Klebsiella pneumoniae, prescribe nitrofurantoin 100 mg orally twice daily for 5–7 days, trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days (only if local resistance <20%), or fosfomycin 3 g as a single oral dose. 1, 2

• Nitrofurantoin achieves approximately 93% clinical cure and 88% microbiological eradication against common uropathogens including Klebsiella, with minimal resistance worldwide. 2
• Trimethoprim-sulfamethoxazole provides 93% clinical cure and 94% microbiological eradication when the organism is susceptible, but should only be used when local E. coli and Klebsiella resistance is documented <20% and the patient has not received this agent within the prior 3 months. 1, 2
• Fosfomycin 3 g single dose delivers 91% clinical cure rates with therapeutic urinary concentrations maintained for 24–48 hours, though it should be reserved for uncomplicated lower UTI only. 2, 3

Parenteral Therapy for Complicated UTI or Pyelonephritis (ESBL-Negative)

For complicated UTI or pyelonephritis requiring hospitalization, initiate ceftriaxone 1–2 g IV once daily (2 g preferred for severe infections) or cefepime 1–2 g IV every 12 hours, then transition to oral therapy once clinically stable. 1, 2, 4

• Ceftriaxone provides excellent urinary concentrations and broad-spectrum coverage against Klebsiella pneumoniae while awaiting susceptibility results, with once-daily dosing that simplifies administration. 1, 2
• Cefepime 2 g IV every 12 hours is appropriate for severe infections or when Pseudomonas coverage is needed, though the dose must be reduced to 1 g every 24 hours when creatinine clearance falls below 30 mL/min to prevent neurotoxicity. 2, 4
• Alternative parenteral options include piperacillin-tazobactam 3.375–4.5 g IV every 6 hours or aminoglycosides (gentamicin 5 mg/kg once daily, amikacin 15 mg/kg once daily) when multidrug-resistant organisms are suspected. 1, 2

Oral Step-Down Therapy for Complicated UTI

Once the patient is afebrile for ≥48 hours and hemodynamically stable, transition to oral fluoroquinolones (ciprofloxacin 500–750 mg twice daily for 7 days or levofloxacin 750 mg once daily for 5–7 days) if the isolate is susceptible and local resistance is <10%. 1, 2

• Fluoroquinolones demonstrate superior efficacy compared to oral β-lactams for complicated UTIs, achieving approximately 90% clinical and 91% microbiological cure rates. 2
• Trimethoprim-sulfamethoxazole 160/800 mg twice daily for 14 days is an alternative when the organism is susceptible and fluoroquinolones are contraindicated. 1, 2
• Oral cephalosporins (cefpodoxime 200 mg twice daily for 10 days, ceftibuten 400 mg once daily for 10 days) achieve 15–30% higher failure rates than fluoroquinolones and should be reserved for situations where preferred agents are unavailable. 1, 2

Treatment Duration

A 7-day total course is sufficient when symptoms resolve promptly, the patient remains hemodynamically stable, and afebrile status is maintained for at least 48 hours. 1, 2

• Extend therapy to 14 days for delayed clinical response, in male patients when prostatitis cannot be excluded, or when underlying urological abnormalities (obstruction, incomplete voiding, indwelling catheter) are present. 1, 2
• For uncomplicated cystitis in women, 3–5 days is adequate with first-line agents (nitrofurantoin 5 days, TMP-SMX 3 days, fosfomycin single dose). 2, 3

Renal Dose Adjustments

For patients with creatinine clearance 30–60 mL/min, reduce cefepime to 1 g IV every 24 hours; for CrCl 11–29 mL/min, reduce to 500 mg every 24 hours; for CrCl <11 mL/min, reduce to 250 mg every 24 hours. 4

• Nitrofurantoin should be avoided when eGFR <30 mL/min/1.73 m² because urinary drug concentrations become insufficient for bacterial eradication. 2
• Levofloxacin dosing for CrCl 20–49 mL/min requires a 750 mg loading dose followed by 250 mg every 48 hours to prevent drug accumulation and toxicity. 2
• Trimethoprim-sulfamethoxazole for CrCl 15–30 mL/min should be reduced to one double-strength tablet (160/800 mg) once daily. 2

Critical Management Steps

Always obtain urine culture with susceptibility testing before initiating antibiotics in complicated UTIs to enable targeted therapy, given the broader microbial spectrum and higher resistance rates. 1, 2

• Replace indwelling catheters that have been in place for ≥2 weeks at the onset of catheter-associated UTI, as this hastens symptom resolution and reduces recurrence risk. 2
• Address underlying urological abnormalities (obstruction, foreign bodies, incomplete voiding, vesicoureteral reflux) through urgent source-control procedures, because antimicrobial therapy alone is insufficient without source control. 2
• Reassess patients at 72 hours if there is no clinical improvement with defervescence; extended treatment and urologic evaluation may be needed for delayed response. 2

Common Pitfalls to Avoid

Do not use aminoglycosides (gentamicin, amikacin) until creatinine clearance is calculated, as these are nephrotoxic and require precise weight-based dosing adjusted for renal function. 2

• Avoid fluoroquinolones empirically if local resistance exceeds 10% or the patient has recent fluoroquinolone exposure within the prior 3 months. 1, 2
• Do not use nitrofurantoin, fosfomycin, or pivmecillinam for complicated UTIs or when upper tract involvement is suspected, as these agents have insufficient tissue penetration. 2, 3
• Do not treat asymptomatic bacteriuria in catheterized patients, as this leads to inappropriate antimicrobial use and resistance without clinical benefit. 2
• Avoid oral β-lactam agents as step-down therapy when fluoroquinolones or trimethoprim-sulfamethoxazole are available, because oral cephalosporins are associated with 15–30% higher failure rates. 1, 2

Special Considerations for ESBL-Negative vs. ESBL-Positive

ESBL-negative Klebsiella pneumoniae retains susceptibility to third-generation cephalosporins, fluoroquinolones, and trimethoprim-sulfamethoxazole, allowing use of standard first-line agents without requiring carbapenems. 5, 6

• Carbapenems (meropenem 1 g three times daily, imipenem/cilastatin 0.5 g three times daily, ertapenem 1 g once daily) should be reserved for ESBL-producing organisms or multidrug-resistant pathogens to preserve their efficacy. 1, 2, 5
• Piperacillin-tazobactam and cefepime maintain bactericidal activity against non-ESBL Klebsiella irrespective of inoculum size, but their activity against ESBL strains is limited and inoculum-dependent. 6
• Gentamicin historically was considered the drug of choice for Klebsiella UTI, though contemporary guidelines favor broader-spectrum agents due to rising aminoglycoside resistance. 7