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    Treating UTIs in the age of antibiotic resistance: Strategies for the practicing OB/GYN


    Treatment of ESBL lower UTIs

    In cases of ESBL lower UTIs, an oral antibiotic available for use in the US is fosfomycin, which is a phosphonic acid derivative. Discovered in 1969, it has been widely used in Europe and recently has been approved in the US by the FDA for treatment of uncomplicated UTIs. Fosfomycin tromethamine, marketed as Monurol, has bactericidal activity against both gram-negative and gram-positive bacteria, and acts by inhibiting bacterial cell wall synthesis by a mechanism different from beta-lactam antibiotics.10 It is administered as a single 3-g dose mixed in 30 cc of water and had effectiveness similar to a 7-day course of conventional treatment in a study of treatment of asymptomatic bacteriuria during pregnancy.11 Regimens have also included 3 g orally on Days 1, 3, and 5 in patients with symptomatic acute cystitis.12 In a 2010 review, 97% of ESBL-producing E coli and 81% of ESBL-producing K pneumoniae were susceptible to fosfomycin.13 However, a 2016 review showed that while fosfomycin has retained clinical effectiveness against ESBL-producing E coli, increasing resistance patterns are being seen, associated with increased use of fosfomycin in Europe.14

    ESBL pyelonephritis

    For women with pyelonephritis from ESBL-producing organisms, IV antibiotics with broad activity and good tissue penetration are recommended, making the carbapenem antibiotic group an ideal choice. Carbapenem antibiotics have a modified beta-lactam ring which is different from penicillins and cephalosporins, and provides significant resistance to beta-lactamase-producing microorganisms, including ESBL-producing Enterobacteriaceae.15 They have the greatest spectrum of activity within the beta-lactam class of antibiotics with broad gram-negative and gram-positive activity and are also active against N gonorrhoeae, Pseudomonas aeruginosa, gram-positive organisms including Listeria and anaerobes, including Bacteroides fragilis.16 Carbapenems, like other beta-lactam antibiotics, exhibit bactericidal activity by binding to penicillin-binding proteins in the organism’s cell wall and disrupting peptidoglycan cross-linking, weakening the cell wall and resulting in death of the organism. Carbapenems that have been used for serious UTIs in pregnancy include imipenem, ertapenem, and doripenem, and are listed as FDA Class B medications. Carbapenems are available only in IV formulations. As such, a patient may need prolonged IV access to complete an extended course of therapy.

    Imipenem was the first carbapenem antibiotic, approved in 1985. It is inactivated in the proximal renal tubule by the normal human enzyme renal dehydropeptidase I and must be combined with cilastatin, a specific inhibitor of this dehydropeptidase enzyme. Imipenem-cilastatin, marketed as Primaxin, is administered at a dose of 500 mg IV Q6h for complicated UTIs, such as pyelonephritis. Carbapenem dosing must be adjusted in patients with decreased renal function and should be used with caution in individuals with underlying central nervous system (CNS) disease, such as brain lesions or a history of seizures. CNS toxicity has included change in mental state, myoclonus, and seizures. Given its similar beta-lactam ring structure to penicillins, it, like the other beta-lactam-based antibiotics (cephalosporins, monobactams) must be used with caution in patients with a history of significant allergy to penicillin.15,16

    Ertapenem, marketed as Invanz, is approved for complicated UTIs and pelvic/intra-abdominal infections. It is active against most Enterobacteriaceae and anaerobes, but less active than the other carbapenems for P aeruginosa, Acinetobacter, and gram-positive bacteria, particularly enterococci and penicillin-resistant pneumococci.15,16 It has a long half-life, and can be administered as a single daily dose of 1 g IV/intramuscular, making it convenient for patients who require a prolonged course of therapy. Other approved indications for ertapenem include treatment of postpartum endomyometritis, septic abortion, and postsurgical infections. In pyelonephritis, it may be given parenterally for 10-14 days. Alternatively, it may be given for 3 days, then switched to oral therapy if clinical response is seen, to complete a 10- to 14-day course of therapy. Veve et al. compared patients with ESBL-producing UTIs, initially hospitalized and then discharged on either ertapenem or fosfomycin for continued outpatient therapy and found cure rates to be comparable.17

    Dorapenem, marketed as Doribax, is approved for both complicated UTIs and intra-abdominal infections. Dosing is 500 mg IV every 8 hours to complete a 10- to 14-day course of therapy. It has a spectrum of activity similar to meropenem, although it appears to have more potent in vitro activity against P aeruginosa than ertapenem or meropenem.16


    Christopher Hicks, MD
    Dr Hicks is Resident in the Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport, Connecticut.
    Zane Saul, MD
    Dr Saul is Chief, Section of Infectious Disease, Department of Internal Medicine, Bridgeport Hospital, Bridgeport, Connecticut, and ...


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