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Treatment Options for Community-acquired UTIs Caused by Extended Spectrum β-Lactamase-producing E. coli
Abstract & Commentary
By Stefany Bowers, PharmD Candidate, Marisa Chun, PharmD Candidate, and Jessica C. Song, MA, PharmD, Stefany Bowers and Marisa Chun are PharmD Candidates at the University of the Pacific and Jessica Song is PharmD at the University of the Pacific, is Associate Editor for Infectious Disease Alert.
Stephany Bowers, Marisa Chun, and Jessica C. Song all report no financial relationships relevant to this field of study.
Extended spectrum β-lactamase (ESBL)-producing Escherichia coli has emerged as an increasingly common cause of community-acquired urinary tract infections (UTIs). These isolates are frequently resistant to many standard oral treatments such as trimethoprim-sulfamethoxazole, fluoroquinolones, penicillins, and cephalosporins.1
ESBLs can be classified further into specific types of lactamases. Some of the most common examples include CTX-M, SHV, and TEM, CTX-M ESBL-producing isolates such as E. coli, have recently become a significant concern for many institutions worldwide. Isolates producing CTX-M ESBLs have been shown to originate from the community setting and are becoming progressively more prevalent globally, as demonstrated by published reports from Europe and Asia. A recent study done at the University of Hong Kong showed that a significant proportion of women in the community had ESBL-producing E. coli, mostly due to the spread of CTX-M 14 β-lactamase. Optimizing the treatment of UTIs caused by ESBL-producing E. coli is a pressing concern, because without proper pharmacological therapy, more serious complications such as bacteremia or pyelonephritis may ensue.2,3,4
In recent years, the lack of new antibiotics has resulted in the medical community taking a closer look at older antibiotics such as fosfomycin, novel antibiotic combinations such as cefdinir + amoxicillin-clavulanate, and newer carbapenems such as ertapenem for the treatment of resistant isolates such as ESBL-producing E. coli. Various studies have indicated that the use of these medications is an effective treatment for UTIs caused by ESBL-producing E. coli. This article takes a more in-depth look at the spectrum of activity and pharmacological and pharmacokinetic properties of the previously mentioned drugs and their roles as therapeutic options for patients with community-acquired UTIs.1,3,5
Spectrum of Activity and Pharmacological & Pharmacokinteic Properties of Fosfomycin
Fosfomycin, a bactericidal phosphonic acid derivative, is a broad-spectrum antibiotic used to treat both gram-positive and gram-negative bacterial infections. Specifically, it inhibits uridine diphosphate GlcNAc enolpyruvate transferase, thereby inhibiting the first step in the synthesis of peptidoglycan. This action disrupts cell-wall synthesis of bacteria and induces cell death.2
Fosfomycin is usually given orally as a soluble salt form known as fosfomycin tromethamine and is available in the United States under the brand name of Monurol. This particular salt formulation of fosfomycin increases the bioavailability of drug in the body. It is approved as safe and effective for adult women as a 3-gram single dose administered orally. Its most common indication is for the treatment of uncomplicated UTIs caused by either E. coli or Enterococcus faecalis. In recent studies, fosfomycin has been proven to be effective against ESBL-producing E. coli.6
In a study conducted by Falagas et al, fosfomycin showed impressive antimicrobial activity against gram-positive species such as Staphylococcus epidermis, Streptococcus pneumoniae, S. aureus, and E. faecalis. The broad-spectrum activity of fosfomycin also allows it to be effective against gram-negative bacteria such as E. coli, Klebsiella pneumoniae, Enterobacter species, Serratia marcescens, Salmonella typhi, and Proteus species.2
Fosfomycin tromethamine is administered orally and is rapidly absorbed and converted to the free acid known as fosfomycin. It has a relatively long elimination half-life around 5.7 ± 2.8 hours and a low molecular weight of 138.059. These characteristics give it the ability to easily penetrate various tissues such as the bladder wall, prostate, kidneys, and seminal vesicles, and allows it to cross the placenta. While an individual is fasting, the oral bioavailability is 37%. Under fed conditions, the bioavailability of fosfomycin is reduced to 30%. After administration of a single 3-gram oral dose on an empty stomach, maximum serum concentrations are achieved within two hours. Following administration of the same dose after a high-fat meal, maximum serum concentrations are achieved within four hours. Fosfomycin does not undergo extensive metabolism and is mainly excreted through the urine and feces.2,6
Data concerning drug interactions with fosfomycin are limited. Cimetidine, which is a potent cytochrome p450 inhibitor, has no effect on fosfomycin. Metoclopramide can reduce the bioavailability of fosfomycin.2
Fosfomycin is associated with a low rate of adverse events. A majority of the adverse events are gastrointestinal (diarrhea, 9%) and dermal in nature and do not usually necessitate discontinuation of treatment. Less common adverse effects include severe nausea, neutropenia, and eosinophil count changes.2
Spectrum of Activity and Pharmacological & Pharmacokinetic Properties of Cefdinir + Amoxicillin-Clavulanate
Cefdinir is an oral extended-spectrum, semisynthetic cephalosporin. It is generally classified as a third-generation cephalosporin with activity similar to cefotaxime and cefixime. In a comparison to cefixime, cefpodoxime, cefaclor, and cephalexin in vitro, cefdinir demonstrated superior activity against oxacillin-sensitive Staphylococcus aureus and coagulase-negative staphylococci, Streptococcus pneumoniae, S. pyogenes, Escherichia coli, and Moraxella catarrhalis. Cefdinir is approved for treatment of skin infections, a variety of upper respiratory tract infections, and community-acquired pneumonia in both adult and pediatric patients. Formulations include capsules and a strawberry-flavored suspension. Uncomplicated UTIs due to non-ESBL strains treated with cefdinir resulted in a 91.3% clinical cure rate in a study conducted by Prakash et al. Furthermore, this recent study upheld previous findings that no ESBL-producing E. coli isolates showed susceptibility to cefdinir monotherapy.4,7
Following oral administration of the capsules or oral suspension, maximal plasma concentrations occur 2-4 hours post dose. The estimated bioavailability of cefdinir capsules is 21% following administration of a 300 mg dose and 16% following administration of a 600 mg dose. Estimated absolute bioavailability of cefdinir oral suspension is 25%. Cefdinir has a half-life of about 1.7 hours, is 60%-70% protein bound, and excretion occurs primarily via renal excretion. Dosage adjustments are recommended in patients with CrCL < 30 mL/min or undergoing hemodialysis.7
Clavulanic acid binds to and inhibits β-lactamases, exhibiting weak antimicrobial activity. Clavulanic acid reestablishes amoxicillin's activity against β-lactamase-producing bacteria, making the combination very effective in inhibiting ESBLs in vitro. Amoxicillin-clavulanate is commonly used to treat infections such as acute otitis media, lower respiratory tract infection, sinusitis, skin/skin-structure infections, and UTIs. Although amoxicillin-clavulanate as a monotherapy has shown activity against ESBL-producing E. coli, a high degree of resistance to both ESBL-producing and -nonproducing E. coli isolates from urine samples have been reported in some areas.4,8
Amoxicillin-clavulanate is administered orally as tablets, chewable tablets, extended-release tablets, and oral suspension. Approximately 74%-92% of a dose of amoxicillin is absorbed. Peak serum levels of both amoxicillin and clavulanic acid occur within 1-2.5 hours following an oral dose. It has a half-life of about one hour and displays 25% protein binding. Amoxicillin and its metabolites are excreted into the urine primarily via tubular secretion and glomerular filtration. Both cefdinir and amoxicillin-clavulanate achieve high concentrations in the urine.8
Evidence of Cefdinir + Amoxicillin-Clavulanate, Fosfomycin, and Amoxicillin-Clavulanate as Treatment Options for Community-acquired ESBL-producing E. coli UTI
A recent case-control study (Spain) assessed different treatment options for cystitis caused by susceptible ESBL-producing E. coli isolates. Patients (n= 37) treated with amoxicillin-clavulanate potassium (500 mg/125 mg every 8 hours, for 5-7 days) achieved cure rates of 84%. In this in vitro study, 29% of the isolates showed resistance to amoxicillin-clavulanate, and cure rates dropped below 90% in those with MICs > 8 mcg/mL. In addition, patients (n = 28) treated with fosfomycin (3 g single dose) achieved cure rates of 93%.1 The estimated costs of generic amoxicillin-clavulanate and fosfomycin are subject to change, depending on vendor sources, but approach $7.35-$10.29 (5-7 day course) and $37, respectively, in San Jose, CA.
A novel combination of antibiotics that appears to be a promising treatment for ESBL-producing E. coli UTIs was recently highlighted in an ESBL isolate susceptibility study by Prakash et al. The investigators found that the addition of a fixed concentration of amoxicillin-clavulanate to cefdinir ($9.35-$13.09/course for combination) yielded a susceptibility rate of 89.1%, based upon an MIC < 1 mcg/mL of cefdinir in the presence of the β-lactamase inhibitor combination. The authors reasoned that the clavulanate component of the amoxicillin-clavulanate served to inhibit the ESBL, resulting in effective cefdinir activity against most isolates.4 This study provides evidence that the co-administration of cefdinir with amoxicillin-clavulanate is not only theoretically promising, but may be a potential treatment for ESBL-producing E. coli UTIs due to its high activity and absence of resistance in isolate studies. However, clinical trials will need to be conducted to confirm the clinical utility of this novel antibiotic combination.
Spectrum of Activity and Pharmacological & Pharmacokinetic Properties of Ertapenem
ESBLs cleave the β-lactam ring; carbapenems resist this hydrolysis and, therefore, remain active. Three carbapenems are currently FDA approved for use in the treatment of UTIs: imipenem/cilastatin, doripenem, and ertapenem. Ertapenem, the only carbapenem that can be administered once daily, has a comparable spectrum of activity to the other carbapenems, with activity against gram-positive, gram-negative, and anaerobic organisms. However, unlike the other carbapenems, ertapenem lacks activity against Pseudomonas aeruginosa and Acinetobacter spp. Ertapenem exhibits excellent activity against Enterobacteriaceae and, therefore, represents a drug of interest in the treatment of ESBL-producing, gram-negative bacterial infections. Ertapenem is eliminated mainly in urine, where it reaches high concentrations.9,10,11
Ertapenem is administered parenterally via intravenous (IV) or intramuscular (IM) routes. Its half-life of about 4.5 hours is prolonged due to extensive protein binding (95%), allowing for once-daily dosing, while retaining a similar safety profile to other carbapenems. Patients with creatinine clearances below 30 mL/min should receive a 50% lower dose, and this agent should be avoided in patients undergoing peritoneal dialysis.11
Evidence of Ertapenem as a Treatment Option for Community-acquired ESBL-producing E. coli UTI
Numerous recent studies have been done to test the susceptibility to ertapenem of ESBL-producing Enterobacteriaceae isolated from urine samples in various health care settings. These studies invariably showed that ertapenem provides the highest level of activity against such strains in comparison to various other antibiotics tested. Ertapenem was found to be active against 100% of ESBL-producing E coli, including CTX-M, SHV, and TEM isolates.12,13 Furthermore, ESBL-producing E. coli also have shown little to no resistance to ertapenem in several urine isolates during in vitro studies thus far. This provides another desirable advantage over other antibiotic choices, as well as other carbapenems, such as imipenem, which showed a slight level of resistance to ESBL-producing isolates in a study by Taneja et al (8.2%).12,13,14
In light of its important antibiotic potency, once-daily dosing, advantageous pricing, safety profile, and lack of resistance shown in vitro, ertapenem may represent a useful therapeutic alternative for UTIs caused by ESBL-producing E coli. However, the acquisition cost of this agent (San Jose, CA) approaches $268.85-$376.39 for a five-seven day treatment course.
As community onset CTX-M ESBL-producing E. coli UTIs become more prevalent worldwide, more effective therapeutic options are needed. It is important for laboratories to test for ESBL producers from outpatient urine cultures to allow for culture-directed therapy and prevent progression to more serious infections. Several studies of ESBL isolate susceptibility show that fosfomycin, cefdinir + amoxicillin-clavulanate, and ertapenem yield high activity against most isolates. Future investigations should further explore larger patient populations to determine the utility of these treatment options.