KEYWORDS: cefazolin; surrogate marker; cefixime; uncomplicated; urinary tract; infections

INTRODUCTION:

For uncomplicated urinary tract infections (uUTIs) caused by Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, the increasing resistance patterns observed to oral antibiotics i.e. trimethoprim-sulfamethoxazole and fluoroquinolones has prompted oral third-generation cephalosporins (3GCs), namely cefpodoxime, cefdinir and cefixime, as viable alternative treatment options.1 Thus, timely reporting of oral 3GC susceptibility may avoid usage of other broad-spectrum antibiotics or intravenous therapy. However, many oral cephalosporin agents are unavailable for testing in automated susceptibility systems, and breakpoints for some oral cephalosporins still need   to  be  elucidated.  Surrogate  testing   allows clinicians to use the preferred oral cephalosporin without requiring the clinical laboratory to perform additional susceptibility testing separately.2 

For E.coli, K. pneumoniae, and P. mirabilis isolates from uUTIs, CLSI (Clinical and Laboratory Standards Institute) recommends using cefazolin as a surrogate marker to predict susceptibility to seven oral cephalosporins, including the 3GCs cefpodoxime and cefdinir;  however, it does not provide guidance for cefixime.3 Our aim was to determine whether cefazolin’s susceptibility results can predict susceptibility to cefixime amongst urinary isolates of E. coli, K. pneumoniae, and P. mirabilis isolated from cases of uUTIs.

METHODOLOGY

Urine cultures from patients suspected of uUTIs submitted to the Bacteriology Laboratory, Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India, were collected between August 2023 and November 2023. Specifically, the isolates of E. coli, K. pneumoniae, and P. mirabilis with pure growth of ≥ 1,00,000 CFU/mL from these urine cultures were included in the study. Routine antimicrobial susceptibility testing (AST) was performed by Kirby-Bauer disc diffusion technique for discs of gentamicin (10 μg), cefixime (5 μg), cefepime (30 μg), ceftazidime (30 μg), cefuroxime (30 μg), ciprofloxacin (5 μg), trimethoprim-sulfamethoxazole (1.25/23.75 μg), fosfomycin (200 μg), nitrofurantoin (300 μg), norfloxacin (10 μg), and cefazolin (30 μg). Categorical agreement and error rates were calculated using cefazolin as the surrogate drug for cefixime. Discrepancies in categorical agreement are defined as minor errors (mE), major errors (ME), and very major errors (VME). A minor error was an intermediate test result reported as susceptible or resistant and vice-versa. Very major errors are resistant isolates reported as susceptible, and major errors are susceptible isolates reported as resistant.4

RESULTS

We included 31 E. coli, six K. pneumoniae, and two P. mirabilis urine isolates from patients aged three months to 74 years (median age = 42.5 years). Amongst 39 total isolates, 26 (66.7%) tested resistant to cefazolin. On comparing cefazolin and cefixime, it was observed that there was a categorical agreement in 36/39 isolates (92.3%) with ME seen in 3 isolates (18.8%). (Table 1)

There were no VME or mE. In all three occasions of discrepancies, the isolate was susceptible to cefixime but resistant to cefazolin. Thus, using cefazolin as a surrogate marker yielded a 100% positive predictive value of susceptibility to cefixime.

DISCUSSION

Cefazolin, a parenteral first-generation cephalosporin, has been extensively used as an alternative to penicillin for treating susceptible staphylococcal and streptococcal infections, most commonly skin soft tissue infections. In addition, cefazolin may be used to treat complicated urinary tract infections and systemic infections due to susceptible isolates of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.5

 In clinical microbiology laboratories since 2014, cefazolin found its utility as a surrogate marker when CLSI recommended its use to predict the susceptibility of seven oral antimicrobial agents in cases of uUTI caused by E. coli, K. pneumoniae, and P. mirabilis. These seven agents include cephalexin (a first-generation cephalosporin); cefaclor, cefprozil, cefuroxime axetil, loracarbef (second-generation cephalosporins); cefdinir and cefpodoxime (third generation cephalosporins).3,6 The breakpoints of cefazolin for various indications are included in Table 2.

The peak urine concentrations attained after standard dosing of the above-mentioned seven oral cephalosporins are much higher than the cefazolin susceptible breakpoint MIC, i.e., ≤16 µg /ml, therefore supporting the use of cefazolin as the surrogate marker. CLSI has pointed out that some isolates may be susceptible to the more potent oral agents (cefuroxime, cefpodoxime, and cefdinir) while testing resistant to cefazolin. Thus, if the cefazolin test result is resistant and the clinician wishes to use the three drugs mentioned above, the applicable drug should be tested individually. 3,6

CONCLUSION

The current recommendations by CLSI for cefazolin as a surrogate marker for oral third-generation cephalosporins do not comment on cefixime. This study shows promising results in arriving at cefixime susceptibility results based on cefazolin reports. Similar to the other third-generation oral cephalosporins, a susceptible cefazolin result indicates susceptibility to cefixime, but if the isolate is resistant to cefazolin, cefixime needs to be tested individually.

CONFLICT OF INTERESTS STATEMENT 

The authors declare no conflict of interest.

SOURCE OF FUNDING

None

AUTHORS’ CONTRIBUTIONS

KPA: Conceptualization; Data curation; Analysis; Writing the draft 

SM: Conceptualization; Supervision; Validation; Review and editing. 

PK: Data curation

MN: Conceptualization; Analysis; Writing the draft; Review and editing. 

BKD: Supervision; Validation

REFERENCES

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4. CLSI. Development of In Vitro Susceptibility Test Methods, Breakpoints, and Quality Control Parameters. 6th ed. Clinical and Laboratory Standards Institute; 2023.

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