Extended-spectrum β-lactamases (ESBLs) are rapidly evolving plasmid transferrable enzymes that confer unique patterns of antibiotic resistance on various bacterial species. Such organisms pose special challenges to laboratory identification, as well as antibiotic selection, administration, and follow-up. Although such infections are increasingly common in the obstetric population, issues surrounding ESBLs are not widely recognized by practicing obstetricians, and controversies exist regarding diagnosis and management. This article provides the practitioner with a summary of clinically pertinent information that will assist in the proper care of pregnant patients with ESBL infection.
Extended-spectrum β-lactamases (ESBLs) are rapidly evolving plasmid transferrable enzymes that confer unique patterns of antibiotic resistance on various bacterial species. Such organisms pose special challenges to laboratory identification, as well as antibiotic selection, administration, and follow-up. Although such infections are increasingly common in the obstetric population, issues surrounding ESBLs are not widely recognized by practicing obstetricians. Several critical issues surrounding ESBL infections in pregnancy are illustrated by the following case.
A 31-year-old multiparous woman presented at 12 weeks’ gestation with fever, nausea, and flank pain. She reported a history of a urinary tract infection prior to pregnancy that was treated with ciprofloxacin and another urinary tract infection at 10 weeks’ gestation treated with nitrofurantoin.
When she was admitted with presumed pyelonephritis, urine culture was drawn and she was started empirically on ceftriaxone, 1 g every 24 hours. Her vital signs were remarkable for maternal tachycardia to 110 bpm and a temperature of 102°F. Review of her prenatal records revealed a urine culture positive for an ESBL producing Escherichia coli with reported sensitivity to carbapenems and nitrofurantoin. She had completed therapy with nitrofurantoin, but no follow-up urine culture was noted.
On the third hospital day her urine culture results returned with >100,000 colonies, ESBL Escherichia coli with resistance to cephalosporins, ampicillin and susceptible to meropenem, ertapenem, cefoxitin, gentamicin, nitrofurantoin, and trimethoprim/sulfatazadine. Her antibiotic regimen was changed to intravenous ertapenem and a peripherally inserted central catheter line was obtained. After she was afebrile for 48 hours, she was discharged with 12 additional days of home health and ertapenem administration. A test of cure was sent prior to the peripherally inserted central catheter line being removed and produced negative results. She was given nitrofurantoin for ongoing suppressive therapy and delivered at term without complications.
Urinary tract infections are one of the most common complications in pregnancy. Pregnant women with cystitis experience increased rates of pyelonephritis and preterm labor. Gram-negative pathogens are the most common source of urinary tract infections in pregnancy, with Enterobacteriaceae , in particular Escherichia coli and Klebsiella , accounting for 90% of these infections. In recent years, the prevalence of these infections complicated by antibiotic-resistant bacteria has significantly increased. In particular, ESBL infections are a major concern, with some epidemiologic reviews illustrating a 300% increase in the urinary tract infections complicated by ESBL organisms.
An ESBL is any acquired β-lactamase that can confer resistance to the oxyiminocephalosporins (eg, cefotaxime, ceftriaxone, ceftazidime) and monobactams (eg, aztreonam), but not to the cephamycins (eg, cefoxitin and cefotetan) and carbapenems (eg, imipenem, meropenem, and ertapenem). An ESBL differs from AmpC type β-lactamases, which are other common isolates from extended-spectrum cephalosporin-resistant Gram-negative bacteria. AmpC β-lactamases hydrolyze broad and extended-spectrum cephalosporins but are not inhibited by clavulanic acid or other β-lactamase inhibitors. There are various different β-lactamase enzymes within the broader classification of ESBLs, the most common of which are the SHV, TEM, and CTX-M types.
ESBLs are primarily produced by the Enterobacteriaceae family of Gram-negative organisms, in particular K pneumoniae and Escherichia coli , but can also be produced by nonfermentative Gram-negative organisms, such as Acinetobacter baumannii and Pseudomonas aeruginosa . Laboratory reporting is problematic because ESBLs may have different degrees of activity against different cephalosporins. Thus the Centers for Disease Control and Prevention (CDC) recommends that an ESBL organism should be reported with resistance to cephalosporins, ampicillin, and susceptible to meropenem, even if in vitro testing suggests susceptibility.
Epidemiology
The true prevalence of ESBL infections is unknown. This is likely in part due to lack of recognition and reporting by laboratories. Studies indicate that due to the previously mentioned difficulties in detection of ESBL organisms, almost one fourth of all laboratories failed to detect extended-spectrum cephalosporin resistance or aztreonam resistance in ESBL or AmpC β-lactamase organisms.
Worldwide there is a large geographic difference in the distribution of ESBL infections, with rates as low as 1% reported in countries such as The Netherlands and as high as 40% in areas such as France and Italy. There are few data about geographic patterns of ESBL infections in the United States. While data from our institution indicate that 3% of Escherichia coli isolates exhibit ESBL activity, 19% of all ESBL isolates in reproductive-aged women occur during pregnancy. Thus, an understanding of clinical issues relating to ESBL organisms is of particular importance to obstetricians.
The most commonly reported risk factors for these infections include recent antibiotic exposure, contact with health care settings, intensive care unit admission, increased severity of illness, use of indwelling catheters, female gender, and presence of comorbidities such as old age or diabetes. Outbreaks have been reported in neonatal intensive care units, and thermometers, oxygen probes, liquid soap, ultrasound gel, and health care workers are documented vectors of infection. Studies have also revealed an increase in hospital stay and mortality due to delay in the appropriate antibiotic administration.
Laboratory identification
Laboratory identification of ESBL is particularly challenging. While an ESBL organism will typically display resistance to at least 1 expanded-spectrum cephalosporin or aztreonam, the in vitro minimum inhibitory concentration (MIC) may not be high enough for the strain to be called “resistant” under current interpretations of the National Committee for Clinical Laboratory Standards (NCCLS). Due to the significance of ESBL infections, the NCCLS has developed broth microdilution and disk diffusion screening tests using selected antimicrobials. K pneumoniae and Escherichia coli should be identified as ESBL infections if the test results demonstrate any of the following: presented in the Table .
| Disk diffusion | MICs |
|---|---|
| Cefpodoxime ≤22 mm | Cefpodoxime ≥2 μg/mL |
| Ceftazidime ≤22 mm | Ceftazidime ≥2 μg/mL |
| Aztreonam ≤27 mm | Aztreonam ≥2 μg/mL |
| Cefotaxime ≤27 mm | Cefotaxime ≥2 μg/mL |
| Ceftriaxone ≤25 mm | Ceftriaxone ≥2 μg/mL |
The CDC encourages the use of >1 of the 5 agents suggested above, which will improve the sensitivity of detection. Cefpodoxime and ceftazidime show the highest sensitivity for ESBL detection.
For other isolates of Enterobacteriaceae , such as Proteus mirabilis or Pseudomonas aeruginosa , the NCCLS has not determined methods for screening and confirming ESBLs. A study by Schwaber et al explored whether the current NCCLS strategy suggested for Escherichia coli and Klebsiella could be applied to the other strains, and found poor specificity.
Methods of ESBL testing include the double-disk approximation test, the 3-dimensional test, Etest (AB Biodisk, Solna, Sweden), and the Vitek test (bioMerieux Vitek, Hazelton, MO). While both the double-disk and 3-dimensional test are reliable, they are hard to perform and interpret. The e-test has 2-sided test strips with either ceftazidime and ceftazidime/clavulanic acid, or ceftazidime and ceftazidime/clavulanic acid. The company recommends using both types. These strips have a decreasing gradient of the single drug on one end, and on the other end a decreasing gradient of the single drug plus a fixed gradient of clavulanic acid. A >3 log reduction in the MIC of cefotaxime or ceftazidime in the presence of clavulanic acid is considered a positive test. The Etest has been shown to be highly sensitive and easy to perform.
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