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

     

    One of the major causes of antibiotic resistance in Enterobacteriaceae has been the production of enzymes, known as beta-lactamases, capable of inactivating some members of the penicillin and cephalosporin class antibiotics, which share a similar beta-lactam chemical ring structure. Most recently within this class of antibiotics, extended-spectrum beta-lactamase (ESBL) enzymes have arisen, which have even greater activity. Besides resistance to penicillins and cephalosporins, ESBL-producing organisms commonly carry other enzymes, which gives them additional resistance to fluoroquinolones, aminoglycosides, and sulfamethoxasole-trimethoprim, and are sometimes known as multidrug-resistant organisms (MDROs).3,4 Resistance of gram-negative bacteria in both the community and hospital settings has grown substantially in recent years, with prevalence of ESBL-producing E coli increasing from 7.8% to 18.9% in the United States from 2010 to 2014.5,6 In a review of our own hospital’s 2015 antibiogram, 9% of E coli and 13% of K pneumoniae were ESBL producers (unpublished data), making infections due to resistant organisms much more frequent. Given ESBL resistance to many of our commonly used antibiotics, these infections are becoming more difficult to treat, leaving the ob/gyn with fewer effective drugs from which to choose, resulting in more drugs that are less familiar to our specialty.7 In fact, the CDC now lists antibiotic resistance of gram-negative organisms as one of its biggest threats.8

    Here we describe issues that an ob/gyn might encounter when dealing with multidrug-resistant (MDR) UTIs and reviews antibiotics that are both safe for use in pregnancy and effective against these MDROs.

    Treatment of non-ESBL UTIs

    Asymptomatic bacteriuria (ASB) was originally defined as the presence of 105 colony-forming units of the same bacteria obtained in 2 consecutive voided samples. Untreated ASB may result in pyelonephritis in up to 30% to 40% of pregnant patients and screening for ASB is performed at the first prenatal visit.1 Currently, treatment is recommended after 1 positive culture is obtained. Acute cystitis is defined as a symptomatic lower UTI in the absence of fever, back pain, or systemic symptoms. Gram negative organisms of the Enterobacteriaceae family comprise the majority of these infections.

    Typical antibiotic regimens for lower tract infections such as ASB and acute cystitis have included nitrofurantoin, oral second- and third-generation cephalosporins, (cefaclor, cefpodoxime), and trimethoprim-sulfamethoxasole. Choice of antibiotic should be based upon either local or individual susceptibility results and treatment continued for 4 to 7 days.1,2,9 Pyelonephritis presents as fever, chills, flank pain, costovertebral angle tenderness, and/or nausea in the presence of bacteriuria. Pyelonephritis in pregnancy can lead to sepsis, adult respiratory distress syndrome, shock, and maternal death. Treatment requires a longer duration of antibiotic therapy as compared to ASB or cystitis and generally the patient is treated initially with intravenous (IV) therapy followed by oral antibiotics to complete a 10- to 14-day course. Parenteral cephalosporin antibiotics such as ceftriaxone with favorable gram negative organism coverage are often administered.

    Use of beta lactam antibiotics

    Penicillin and cephalosporins are chemically derived from a beta-lactam ring structure. They work by interfering with bacterial cell wall biosynthesis by binding to the penicillin-binding proteins (PBPs) responsible for the integrity of the bacterial cell wall. A common mechanism of antibiotic resistance involves development of enzymes known as beta-lactamases, which can destroy the beta-lactam ring in penicillins and make the organisms resistant to the antibiotic. Pharmaceutical companies deal with this form of antibiotic resistance by either modifying the beta-lactam ring structure to create a new class of antibiotic—such as cephalosporins, cephamycins, monobactams, or carbapenems—or with side chains added to the beta-lactam ring (eg, extended-spectrum penicillins or advanced generation cephalosporins) to make the drug less vulnerable to the microorganism’s beta-lactamase enzymes. Alternatively, the penicillin or cephalosporin can be combined with a beta-lactamase inhibitor such as sulbactam, clavulinic acid, or tazobactam. These beta-lactamase inhibitors inactivate the microorganism’s beta-lactamase enzymes so that the antibiotic partner of the drug can still bind and inhibit the PBPs necessary for cell wall formation and integrity. Examples of these combinations are ampicillin + sulbactam, amoxicillin + clavulinic acid, piperacillin-tazobactam, and ceftolozane-tazobactam. Many different beta-lactamase enzymes have been identified and each carries specific resistance patterns, although individually they generally they do not confer complete resistance to the extended-generation cephalosporins, extended-spectrum penicillins, or beta-lactamase inhibitor combination drugs. We refer the reader to these references for more detail.3-5

    ESBL-producing organisms are resistant to beta-lactam antibiotics (penicillins, cephalosporins, monobactams), and many penicillin-beta lactamase inhibitor combinations, despite modifications made to their chemical structures. The genetic information for these enzymes is often carried on plasmids, enabling genes to be easily shared among other organisms, thus facilitating their spread. These organisms may also carry resistance factors to nitrofurantoin, aminoglycosides, fluoroquinolones, and sulfonamide-based antibiotics. These broadly active beta-lactamases are responsible for some of the current rise in antibiotic microbial resistance. Similar to the rise of community-acquired MRSA outside of the hospital setting, there has been a substantial rise in ESBL-producing E coli infections in community settings. Given their resistance to many commonly used antibiotics, these infections are becoming more difficult and challenging to treat.

    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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