If a patient's urine culture grows Proteus and is resistant to cefazolin (a first-generation cephalosporin) and cefoxitin (a second-generation cephalosporin), should they be treated with ceftriaxone (a third-generation cephalosporin)?

From the Guidelines

Treating a patient with a Proteus urinary tract infection resistant to cefazolin and cefoxitin with ceftriaxone is not recommended. This decision is based on the concept of cross-resistance among cephalosporins, as highlighted in the European Association of Urology guidelines on urological infections 1. When Proteus shows resistance to first and second-generation cephalosporins, it often indicates the presence of extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases that can also inactivate third-generation cephalosporins like ceftriaxone.

Key considerations for treatment include:

• The use of a combination of antibiotics such as amoxicillin plus an aminoglycoside or a second-generation cephalosporin plus an aminoglycoside, as recommended by the European Association of Urology guidelines 1.
• The potential use of an intravenous third-generation cephalosporin as empirical treatment for complicated UTI with systemic symptoms, but with caution due to potential resistance.
• Avoiding the use of ciprofloxacin and other fluoroquinolones for empirical treatment of complicated UTI in patients from urology departments or when patients have used fluoroquinolones in the last 6 months, as per the guidelines 1.

Alternative antibiotics such as fluoroquinolones (e.g., ciprofloxacin 500 mg twice daily for 7 days), trimethoprim-sulfamethoxazole (160/800 mg twice daily for 7-14 days), or carbapenems (e.g., ertapenem 1 g daily) should be considered based on susceptibility testing. Complete susceptibility testing should guide the final antibiotic selection, ensuring the chosen treatment will be effective against this particular resistant strain. Managing any urological abnormality and/or underlying complicating factors is also crucial, as emphasized by the guidelines 1.

From the FDA Drug Label

Ceftriaxone for Injection is indicated for the treatment of the following infections when caused by susceptible organisms: ... URINARY TRACT INFECTIONS (complicated and uncomplicated) Caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae

The patient's urine culture grows Proteus, which is listed as a susceptible organism for ceftriaxone. However, the patient's Proteus is resistant to cefazolin and cefoxitin. Resistance patterns to one cephalosporin do not necessarily predict resistance to other cephalosporins, as spectrum of activity and mechanisms of resistance can vary between different generations of cephalosporins.

• The FDA label does not provide direct information on cross-resistance between cefazolin, cefoxitin, and ceftriaxone for Proteus species.
• The label indicates that ceftriaxone is effective against Proteus mirabilis, but it does not address the specific scenario of resistance to other cephalosporins. Given the information available, it is unclear whether the patient's Proteus would be susceptible to ceftriaxone. Therefore, caution should be exercised, and susceptibility testing should be considered to guide therapy 2.

From the Research

Treatment of Urine Culture with Proteus

• The patient's urine culture grows Proteus and is resistant to cefazolin and cefoxitin, which are first- and second-generation cephalosporins, respectively.
• The question is whether the patient should be treated with ceftriaxone, a third-generation cephalosporin.

Susceptibility of Proteus to Ceftriaxone

• According to the study 3, ceftriaxone exhibits high susceptibility for uropathogens commonly implicated in cases of uncomplicated UTI, including Proteus mirabilis.
• However, the study also notes that ceftriaxone increases the risk of healthcare facility-onset Clostridioides difficile infection (HOCDI) more than any other antibiotic group.

Alternative Treatment Options

• The study 4 recommends treatment options for UTIs due to AmpC-β-lactamase-producing Enterobacteriales, including nitrofurantoin, fosfomycin, pivmecillinam, fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems.
• The study 5 suggests that cefazolin is definitively efficacious and cost-effective for adults with community-onset cefazolin-susceptible EKP bacteremia, compared to broader-spectrum antibiotics.
• The study 6 found that cefepime, imipenem, and amikacin may be used in patients with higher antimicrobial resistance.

Conclusion Regarding Ceftriaxone Treatment

• Based on the studies, it is not clear whether ceftriaxone is the best treatment option for the patient, given the resistance to cefazolin and cefoxitin.
• However, the studies suggest that ceftriaxone may be effective against Proteus mirabilis, but its use should be weighed against the risk of HOCDI.
• Alternative treatment options, such as those listed in the studies 4, 5, and 6, may be considered based on the patient's specific circumstances and local susceptibility patterns.