What is the recommended treatment for urinary tract infections (UTIs) caused by gram-negative rods?

Treatment of UTIs Caused by Gram-Negative Rods

For uncomplicated cystitis caused by gram-negative rods, nitrofurantoin 100mg twice daily for 5 days is the preferred first-line agent, followed by fosfomycin 3g single dose or TMP/SMX for 3 days if local resistance is <20%. 1

Uncomplicated Cystitis (Lower UTI)

First-Line Agents

• Nitrofurantoin: 100mg twice daily for 5 days - preferred due to minimal collateral damage and preserved susceptibility patterns 1
• Fosfomycin: 3g single oral dose - convenient single-dose regimen with activity against ESBL-producing gram-negative rods, though bacterial eradication rates are lower than other first-line agents 1
• Pivmecillinam: 400mg twice daily for 3 days - extended gram-negative spectrum with minimal resistance, though not available in North America 1

Second-Line Agents (When First-Line Unavailable or Contraindicated)

• TMP/SMX: 160/800mg twice daily for 3 days - only if local E. coli resistance is <20% and patient has not received it in the preceding 3-6 months 1
• Fluoroquinolones: Ciprofloxacin 250mg twice daily or levofloxacin 250mg once daily for 3 days - reserve due to collateral damage concerns and rising resistance 1, 2
• Oral cephalosporins: Cephalexin or cefixime - less effective than other options, use only when alternatives unavailable 1, 3

Critical Resistance Considerations

The 2024 JAMA guidelines emphasize that empirical treatment must account for local resistance patterns 1. The 2011 IDSA guidelines note that nitrofurantoin, fosfomycin, and mecillinam maintain good in vitro activity across most geographic regions despite rising resistance to other agents 1. Fluoroquinolone resistance now exceeds 10% in many regions, and TMP/SMX resistance commonly exceeds 20% 1.

Pyelonephritis (Upper UTI)

Oral Therapy for Outpatient Management

• Fluoroquinolones (if local resistance <10%):
  • Ciprofloxacin 500mg twice daily for 5-7 days 1
  • Levofloxacin 750mg once daily for 5 days 1, 2
• TMP/SMX: 160/800mg twice daily for 7 days (historical 14-day regimens no longer necessary) - only if pathogen known to be susceptible 1
• Oral β-lactams: Less effective than fluoroquinolones; if used, give initial IV dose of ceftriaxone 1g or consolidated 24-hour aminoglycoside dose, then continue oral therapy for 10-14 days 1

Parenteral Therapy for Hospitalized Patients

• Ceftriaxone: 1-2g IV daily for 7 days - recommended empiric choice due to low resistance rates 1
• Fluoroquinolones: Levofloxacin 750mg IV daily or ciprofloxacin 400mg IV every 12 hours 1, 2
• Aminoglycosides (with or without ampicillin): Gentamicin 5-7mg/kg IV daily - nephrotoxicity risk increases after 7 days 1
• Extended-spectrum cephalosporins or penicillins (with or without aminoglycoside) 1
• Carbapenems: For suspected ESBL-producing organisms or multidrug-resistant pathogens 1, 4

Duration of Therapy

The 2024 guidelines provide clear recommendations: 7 days for β-lactams and 5-7 days for fluoroquinolones 1. This represents a significant departure from historical 14-day regimens, which were based on small 1970s-1990s trials 1.

Gram-Negative Bacteremia from Urinary Source

Seven days of total antimicrobial therapy is recommended when source control has been addressed 1. Multiple RCTs demonstrate noninferiority of 7 days compared to 14 days for clinical cure, clinical failure, relapse, and all-cause mortality 1.

Special Considerations for Resistant Organisms

ESBL-Producing Enterobacteriaceae

• Uncomplicated cystitis: Nitrofurantoin, fosfomycin, or pivmecillinam remain effective oral options 1, 4
• Pyelonephritis/complicated UTI: Carbapenems (meropenem, ertapenem), ceftazidime-avibactam, or ceftolozane-tazobactam 4
• Fosfomycin has in vitro activity against ESBL-producing gram-negative rods but should NOT be used for complicated UTIs or pyelonephritis - restricted to uncomplicated cystitis only 1, 5

Carbapenem-Resistant Enterobacteriaceae (CRE)

Treatment options include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, colistin, aminoglycosides including plazomicin, cefiderocol, or combination therapy 4

Pseudomonas aeruginosa

For documented or presumptive Pseudomonas, combination therapy with an anti-pseudomonal β-lactam is recommended 2. Options include ceftazidime, cefepime, piperacillin-tazobactam, carbapenems, ceftolozane-tazobactam, or ceftazidime-avibactam 4, 6

Common Pitfalls to Avoid

• Do not use oral β-lactams as first-line for pyelonephritis - they are less effective than fluoroquinolones or TMP/SMX 1
• Do not use TMP/SMX empirically if local resistance exceeds 20% or patient received it in preceding 3-6 months - prior use is an independent risk factor for resistance 1
• Do not use fosfomycin for complicated UTIs, pyelonephritis, or infections with non-fermenting organisms - it lacks sufficient efficacy data and should be restricted to uncomplicated cystitis 1, 5
• Do not routinely use fluoroquinolones for uncomplicated cystitis - reserve for pyelonephritis or when first-line agents are contraindicated to minimize collateral damage 1
• Do not extend treatment duration beyond 7 days for pyelonephritis or bacteremia from urinary source unless specific clinical circumstances warrant it 1