Robert J Stiller, MD, Christopher Hicks, MD, and Zane Saul, MD
Dr Stiller is Chief, Section of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport, Connecticut, and Clinical Professor of Obstetrics and Gynecology, Yale University School of Medicine.
Dr Hicks is Resident in the Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport, Connecticut.
Dr Saul is Chief, Section of Infectious Disease, Department of Internal Medicine, Bridgeport Hospital, Bridgeport, Connecticut, and Clinical Instructor of Medicine, Yale University School of Medicine.
None of the authors has a conflict of interest to report in respect to the content of this article.
Ob/gyns have witnessed how development of antibiotic resistance has affected disease management in our specialty. Increased resistance of Neisseria gonorrhea (N gonorrhea) to penicillins and quinolones, emergence of methicillin-resistant staphylococcus aureus (MRSA) and resistance of Group B Streptococcus to erythromycin and clindamycin have led us to modify our antibiotic treatment regimens. Whether antibiotics are appropriately or inappropriately prescribed, they can lead to loss of effectiveness by allowing only organisms with resistance to survive and multiply in a process similar to natural selection. Alternatively, organisms can share genetic information through plasmids, which are small segments of DNA that can code for production of resistance factors.
Urinary tract infections (UTIs) complicate 3% to 10% of pregnancies and are among the most common reasons for antibiotic use in obstetrics.1 Clinically relevant disease may include lower urinary tract conditions such as asymptomatic bacteriuria and acute cystitis or upper tract urinary infections such as pyelonephritis. In pregnancy, these infections are most frequently caused by the Enterobacteriaceae group of organisms, which include the gram negative rods, Escherichia coli (E coli) (82.5%), Klebsiella pneumoniae (K pneumoniae) (7.6%), Proteus mirabilis (4.9%), and Enterobacter species (5.7%). Gram positive organisms such as Streptococcus species (21.4%), Staphylococcus species (6.5%), and Enterococcus species (5.7%) also cause infections, although frequencies of specific organisms vary among case series.2
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.
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
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
Of great concern is that antibiotic resistance to the carbapenems has also been recently reported. K pneumoniae carbapenemase (KPC) was first identified in 1996 as a beta-lactamase enzyme capable of inactivating the carbapenem class of antibiotics, along with penicillins and cephalosporins.18 Carbapenems enter gram-negative organisms through outer membrane proteins known as porins and inactivate the enzymes needed for peptidoglycan cross-linking, ultimately causing cell death. Resistance to carbapenems can also develop either by loss of these outer membrane porin channels, or by modifications of the penicillin-binding proteins, so that they do not bind with the carbapenems.18 A recent article by Khari et al highlights the challenges in treating KPC-producing K pneumoniae-associated pyelonephritis in pregnancy, which they managed with a prolonged course of an extended-infusion cefepime and oral fosfomycin.19
To meet this challenge, a new option in treatment of these MDR gram-negative infections has been the combination of a new beta-lactamase inhibitor, avibactam, combined with a third-generation cephalosporin, ceftazidime. Ceftazidime-avibactam, marketed as Avycaz, demonstrates greater resistance to beta-lactamases produced by MDR pathogens, including some KPC-producing organisms. Avibactam has greater activity than other beta-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam.20,21 Ceftazidime-avibactam is approved for complicated UTIs including pyelonephritis and is given at a dose of 2.5 g IV q 8 hrs for 7 to 14 days. Combinations of avibactam with other beta-lactam antibiotics are in development and may provide additional options in the treatment of MDRO infections. Lastly, investigators are reevaluating the use of colistin, of the polymyxin class of antibiotics, originally used in the 1950s. These antibiotics cause cell death by disrupting the gram-negative cell membrane.22 While they were discontinued due to concerns of nephrotoxicity and due to the development of safer antibiotics, this class of antibiotic is being reintroduced in cases of extensive gram-negative resistance.
An additional concern is that, as patients develop colonization with resistant organisms, this may affect commonly used treatment regimens for conditions such as intra-amniotic infection and postpartum endometritis, in which therapy is often started empirically with combined penicillin, gentamicin, and clindamycin/metronidazole in the absence of genital cultures. The need for organism identification will become more pressing as resistance to our commonly used antibiotics regimens increases, with delay in starting appropriate therapy resulting in increased morbidity.
It is likely that ob/gyns will encounter MDR pathogens previously seen only in the critical care areas that will now occur in both the inpatient and outpatient obstetrical settings. Previous exposure to antibiotics, hospitalization, and the presence of an indwelling catheter increase the risk of resistant organisms. As antibiotic resistance is becoming more widespread, awareness of antibiotic sensitivities and consultation with infectious disease specialists in cases of MDR infections will help practitioners to provide optimum care in these difficult cases. In cases of ESBL-associated UTIs, it is important to obtain a test of cure 10 to 14 days after treatment to confirm eradication of the infection. Carbapenems, fosfomycin, and newer cephalosporin/beta-lactamase inhibitors appear safe for use in pregnancy and provide activity against ESBL-producing Enterobacteriaceae that are resistant to our previously used therapies. Strategies such as good handwashing, contact precautions when dealing with patients with resistant organisms, and appropriate antibiotic stewardship (limiting the use of unnecessary antibiotics, limiting broad-spectrum antibiotics when a narrow agent is available, institutional antibiotic cycling) will help us to better deal with these infections in the future.
MDRO urinary tract infections are now being seen in the community at higher frequencies with ESBL-producing E coli increasing from 7.8% to 18.9% in the US from 2010 to 2014.
Consider antibiotic resistance for infections that do not respond to conventional therapy.
Be knowledgeable of local antibiograms when treating UTIs empirically. Obtain culture and sensitivities studies on all patients at higher risk for antibiotic resistance.
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