Robert J. Stiller, 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.

Ob/gyns have witnessed how development of antibiotic resistance has affected disease management in our specialty. Increased resistance of 

) to penicillins and quinolones, emergence of methicillin-resistant 

 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.

 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 

 group of organisms, which include the gram negative rods, 

 species (5.7%). Gram positive organisms such as 

 species (5.7%) also cause infections, although frequencies of specific organisms vary among case series.

One of the major causes of antibiotic resistance in 

 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).

 Resistance of gram-negative bacteria in both the community and hospital settings has grown substantially in recent years, with prevalence of ESBL-producing 

increasing from 7.8% to 18.9% in the United States from 2010 to 2014.

 In a review of our own hospital’s 2015 antibiogram, 9% of 

 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.

 In fact, the CDC now lists antibiotic resistance of gram-negative organisms as one of its biggest threats.

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.

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 

 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.

 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.

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.

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.

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.

 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.

 Regimens have also included 3 g orally on Days 1, 3, and 5 in patients with symptomatic acute cystitis.

 In a 2010 review, 97% of ESBL-producing 

 However, a 2016 review showed that while fosfomycin has retained clinical effectiveness against ESBL-producing 

, increasing resistance patterns are being seen, associated with increased use of fosfomycin in Europe.

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 

 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 

 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.

Ertapenem, marketed as Invanz, is approved for complicated UTIs and pelvic/intra-abdominal infections. It is active against most 

 and anaerobes, but less active than the other carbapenems for 

, and gram-positive bacteria, particularly enterococci and penicillin-resistant pneumococci.

 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.

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 

Of great concern is that antibiotic resistance to the carbapenems has also been recently reported. 

 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.

 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.

 A recent article by Khari et al highlights the challenges in treating KPC-producing 

-associated pyelonephritis in pregnancy, which they managed with a prolonged course of an extended-infusion cefepime and oral fosfomycin.

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.

 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.

 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 

 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 

 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.

None of the authors has a conflict of interest to report in respect to the content of this article.

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Articles

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.

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

Dr. Stiller is Chief, Section of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,
	Bridgeport Hospital, Yale New Haven Health System, Bridgeport, Connecticut.

Dr. Sharuk is Resident Physician, Department of Obstetrics and Gynecology,
	Bridgeport Hospital, Yale New Haven Health System, Bridgeport, Connecticut.

Dr. Laifer is Chief, Section of Obstetrics, Department of Obstetrics and Gynecology, Bridgeport Hospital,
	Yale New Haven Health System, Bridgeport, Connecticut.

		The authors have no conflicts of interest to report with respect to the content of this article.

	Obstetricians often find themselves in clinical situations in which they have to ask the question, “Is delivery indicated for the benefit of the mother and/or fetus, or can this pregnancy be safely continued?” Many clinical scenarios pose risks that can be difficult to predict, even when using our best judgment and tools. Although it is not perfect, antenatal fetal monitoring is one such tool that we use in everyday practice to assess fetal health.

 It can help us to decide to deliver a preterm fetus if compromise is suspected, or reassure us that delivery can be safely delayed.

	Amniocentesis for fetal lung maturity (FLM) assessment is another tool in our armamentarium that can help us decide which at-risk fetuses or mothers might be better delivered rather than subjected to continued expectant management. More specifically, if the risk of respiratory distress syndrome (RDS) is low (ie, FLM confirmed), delivery before fetal or maternal complications occurs becomes would be more likely. For example, risk of stillbirth and RDS is higher in patients with poorly controlled pregestational diabetes, making documentation of lung maturity an important management tool. Performing amniocentesis to assess FLM, however, has recently come under strong criticism.

	Published in 2013, American College of Obstetricians and Gynecologists (ACOG) Committee Opinion No 560, “Medically Indicated Late-Preterm and Early-Term Deliveries,” reviewed evidence about neonatal morbidities associated with the late preterm (34–36 6/7 weeks) and early-term (37–38 6/7 weeks) pregnancy.

	In addition to major neonatal morbidities (such as RDS, intraventricular hemorrhage, and necrotizing enterocolitis), minor morbidities (such as temperature instability, hyperbilirubinemia, feeding difficulties, and admission to newborn intensive care units) were also considered. The two important and useful purposes that the document served were discouraging elective delivery prior to 39 weeks because of increased neonatal morbidity in these late-preterm and early term deliveries, even when lung maturity was documented and providing guidance and recommendations as to when pregnancies might be delivered in a setting complicated by selected medical or fetal complications.

	The authors suggested that “amniocentesis for the determination of lung maturity in well dated pregnancies generally should not be used to guide the time of delivery.”

 However, we believe that the rationales cited were rather simplistic. If a patient needs to be delivered, then she should be delivered, regardless of fetal lung maturity. And if a patient doesn’t need to be delivered, then we should wait.

	The ACOG authors listed a number of maternal and fetal complications and suggested gestational age intervals for delivery. For example, in women with placenta previa, delivery between 36 0/7 weeks and 37 6/7 weeks-a 14-day window-was suggested. In women with pregestational diabetes with vascular complications and those with chronic hypertension on medication, delivery between 37 0/7 weeks and 39 6/7 weeks-a 21-day window-was recommended. For poorly controlled pregestational diabetes, it was recommended that the timing of delivery be “individualized.”

	How does an ob/gyn decide when in that wide 14- to 21-day window delivery should be performed? How do we manage patients with these conditions and offer consultation to referring doctors? Like the uncertainty of a Category II fetal heart rate monitor tracing, some conditions are not simply black or white. Of course, we can all agree that if there is clear maternal or fetal compromise, immediate delivery regardless of lung maturity is recommended. But there are various maternal and fetal complications that confer potential-but perhaps not immediate-risks to continuing the pregnancy.

	For many years evaluation of FLM helped us decide when, during a possible 2– to 3-week interval, delivery could more safely be conducted. So how did amniocentesis lose favor in these situations? There was recognition that amniocentesis might be misused in justifying an early delivery in the absence of a strong medical indication. A series of studies shows, not surprisingly, that fetuses delivered at 34–37 weeks, even in the presence of documented lung maturity, have greater neonatal morbidity than those delivered at 39 weeks.

	Those studies, however, did not address the risks to these fetuses of remaining undelivered, especially in the setting of coexisting maternal complications. Retrospectively comparing women who underwent amniocentesis at 34–36 weeks to women who were able to deliver at 39 weeks or greater was not a fair comparison. It just confirms what we already know: If the indication for delivery is purely elective and no harm will come if we wait until 39 weeks, it is, in fact, best to wait.

	Another contributing factor was discontinuation in 2012 of the Abbott TDx FLM assay, a commercial rapid FLM test. Some centers are no longer able to process amniotic fluid because thin-layer chromatography for lecithin–sphingomyelin (L/S) ratios is not readily available at all institutions.

	At Bridgeport Hospital, a community teaching hospital in Bridgeport, Connecticut, we have moved to lamellar body analysis and found it very helpful, using a value of >50,000 μL as representing lung maturity in the nondiabetic patient. We reserve L/S testing as a send-out for diabetic patients and those with borderline results. A recent meta-analysis confirms that its accuracy is similar to that of L/S ratio testing.

	Despite the recent approach that ACOG has advocated, we maintain that there may be significant clinical benefit for evaluation of FLM.

	In clinical practice, we cannot predict what will happen in a complicated pregnancy by waiting an additional 1–3 weeks. Take, for example, a woman with a previous classical cesarean delivery, in whom the potential exists for a catastrophic complication such as uterine rupture. In that case, one might not choose to delay delivery until 37 6/7 weeks, and that is acceptable under the new ACOG guidelines, especially if lung maturity is ensured. In a decision analysis study, Stotland et al used mathematic modeling and showed a trade-off of 22 cases of RDS to prevent 1 case of hypoxic ischemic encephalopathy after uterine rupture if delivery at 36 weeks was used.

	When trying to counsel a patient with several unknown risks (ie, risk to the fetus with immediate delivery, risk of possible fetal or maternal complications with delayed delivery), knowledge about lung maturity provides useful adjunctive information that is unique and relevant to the patient, and not just in the form of statistics. Our patients deserve the most accurate assessment of risks and benefits we can provide.

	Another part of the equation in deciding the value of amniocentesis involves the overall risk of RDS during the late preterm/early preterm periods. Risk of RDS does decrease with increasing gestational age. One study showed that if FLM testing indicated maturity, the risk of RDS was 3%. However, if it indicated immaturity, the risk increased to 30%, depending upon gestational age.

	Lastly, for institutions with limited nursery capabilities, the information on lung maturity, although not perfect, may help in determining whether patients might safely be delivered at their primary hospital, rather than after transfer to distant sites.

	We are not alone in these concerns. Towers et al, authors who come from four university centers, wrote a recent editorial in the American Journal of Obstetrics and Gynecology positing a similar argument about the value of amniocentesis for lung maturity determination in these at-risk patients.

	We don’t want to discount the potential risks associated with amniocentesis for FLM, which include rupture of membranes, initiation of labor, and infection. It is important to note that the greatest risk has been associated with diagnostic (genetic) amniocentesis in the second trimester, when risk of labor or rupture could result in loss of the pregnancy.

	In a recent study on amniocentesis risks in the third trimester, the procedure was not associated with a statistically increased risk of urgent delivery or perinatal death.

 Nevertheless, amniocentesis for FLM should be considered only when it is technically feasible and safe, based on ultrasound evaluation of the position of the fetus, location of the placenta, and amniotic fluid volume.

	The Executive Summary Guidelines from the NICHD workshop “Timing of Indicated Late Preterm and Early Term Births” state “it is critical that the totality of the clinical picture be taken into account when deciding the optimal timing of delivery.”

	We strongly believe that knowledge of FLM through amniocentesis, albeit not perfect, nor a guarantee that an infant will not suffer any neonatal morbidity, will help us to better plan deliveries of women with complicated pregnancies and who carry risk, should the pregnancy continue. 

	1. American College of Obstetricians and Gynecologists. Antepartum fetal surveillance. ACOG Practice Bulletin no. 145. July 2014.

	2. American College of Obstetricians and Gynecologists. ACOG Committee Opinion no. 560. Medically Indicated late-preterm and early-term deliveries. 

	3. Bates E, Rouse DJ , Mann ML, Chapman V, Carlo WA, Tita ATN. Neonatal outcomes after demonstrated fetal lung maturity before 39 weeks of gestation. 

	4. Kamath BD, Marcotte MP, DeFranco EA. Neonatal morbidity after documented fetal lung maturity in late preterm and early term infants. 

	5. Besnard AE, Wirjosoekarto SA, Broeze KA, Opmeer BC, Mol BW. Lecithin/sphingomyelin ratio and lamellar body count for fetal lung maturity: a meta-analysis. 

	6. Stotland N, Lipshitz L, Caughey A. Delivery strategies for women with a previous classical cesarean delivery: a decision analysis. 

	7. Neerhof MG. Haney EI, Silver RK, Ashwood ER, Lee I-S, Piazze JJ. Lamellar body counts compared with traditional phospholipid analysis as an assay for evaluating fetal lung maturity. 

	8. Towers CV, Freeman RK, Nageotte MP, Garite TJ, Lewis DF, Quilligan EJ et al. The case for amniocentesis for fetal lung maturity in late-preterm and early-term gestations. 

	9. Hodor JG, Poggi SH, Spong CY, et al. Risk of third-trimester amniocentesis: a case-control study. 

	10. Spong CY, Mercer BM, D’Alton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. 

Knowledge of fetal lung maturity provides useful adjunctive information that is unique and relevant to a patient.

Robert J. Stiller, MD

Articles

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

Clinician to Clinician: Reaffirming the role of lung maturity testing in the at-risk pregnancy