“Triple Therapy” Facing Triple Threat

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For decades, peripartum infections have traditionally been treated with ampicillin and gentamicin, plus potentially clindamycin. Yet recent events have sparked a reevaluation of this empiric antimicrobial regimen for such infections: worsening anaerobic organism resistance to clindamycin, an intravenous clindamycin shortage in the US in summer 2023, and recent Clinical and Laboratory Standards Institute changes to the susceptibility breakpoints for aminoglycosides for gram-negative bacteria (eg, Enterobacterales).

Additionally, from an infectious diseases perspective, we tend to think of peripartum infections arising from genitourinary flora. Complicating treatment choices, there are different considerations from an obstetrics/gynecology or neonatology perspective—such as “baby in” or “baby out:—which are very important to review as new regimens move forward. In a 2012 survey of US obstetricians involved in chorioamnionitis care, 212 respondents indicated the use of more than 25 antimicrobial regimens and a wide range of durations, indicating significant clinical variation.¹ Given the rising maternal mortality rate in the US and the knowledge that 14.3% of maternal deaths are a result of infection or sepsis, there is a call to action to optimize management of peripartum infections.²

Intraamniotic infections (IAI) are polymicrobial infections of the amniotic fluid, placenta, fetus, fetal membranes, or decidua with significant implications for both maternal and fetal health if not recognized and treated urgently with intrapartum antibiotics and delivery of the fetus. Chorioamnionitis is one type of IAI that is associated with a 2- to 3.5-fold increased odds of neonatal adverse outcomes depending on gestational age, as well as higher odds of adverse maternal outcomes, including 2.3 higher odds of requiring cesarean delivery.^3-6 Ascension of microorganisms from the vagina into the previously sterile amniotic sac is the primary mechanism of infection, though hematogenous dissemination (Listeria) or introduction after a procedure (eg, amniocentesis, chorionic villus sampling) is also possible.^4,6 A second type of IAI, postpartum endometritis, has a similar microbiology as chorioamnionitis but develops after delivery of the fetus; it represents an infection of the upper genital tract and peritoneal/retroperitoneal space, most often seen after cesarean delivery.^7,8 Additional IAI (eg, septic abortion, pelvic septic thrombophlebitis) could be diagnosed depending on anatomic involvement.

When managing IAI, it is important to rapidly identify pregnant women with infection and initiate antimicrobials. However, there are significant, varied reasons that pregnant women may have a noninfectious fever. There is something unique about the laboring experience that drives fever, and that mechanism is yet to be understood.⁹ Drug exposure (including prostaglandins used to induce labor) and epidural anesthesia are known to cause noninfectious fever in 15% to 25% of pregnant patients; epidural anesthesia may mask other signs of infection (fundal tenderness) or induce other signs of infection (maternal or fetal tachycardia).^9,10 The clinical diagnosis of a peripartum infection such as chorioamnionitis includes presence of fever plus additional clinical factors such as uterine tenderness, purulent amniotic fluid, and other vital sign abnormalities. But there is no gold standard diagnostic test that gives results in a timely fashion (ie, cultures) to say whether a person is infected.⁴ The clinical diagnosis of IAI is clearly critical for both mother and fetus in light of the very serious complications that can occur if antibiotics are not rapidly initiated, but this creates significant clinical variability in identifying infectious versus noninfectious fever because of clinical concern of the serious issues if IAI is missed.

Once IAI is suspected or confirmed, clinicians should consider the likely causative pathogen(s) of infection. There are organisms that should always be considered in IAI, considering the well-noted polymicrobial nature when cultures are obtained. Of high concern is group B streptococci (GBS) due to high colonization rates (10%-30%) at baseline, and the concern that approximately 50% of women who are colonized will transmit the organism to their newborn through vertical transmission during labor or after the rupture of membranes.¹¹ In 2014, the Cochrane Review noted the most commonly isolated organisms in these polymicrobial infections were Mycoplasma hominis, Ureaplasma urealyticum, Chlamydia trachomatis, Neisseria gonorrhea, Trichomonas vaginalis, Bacteroides spp, Gardnerella vaginalis, Escherichia coli, anaerobic streptococcus and GBS.^12,13 Notably, many of these studies referenced in the Cochrane Review use microbiologic data from the 1970s and 1980s, some of which were taken from samples such as placental tissue cultures, amniotic fluid cultures, or vaginal cultures. Many of the peripartum infection Cochrane reviews noted a lack of data upon which to make recommendations; this is a common theme when evaluating peripartum infection data, partially related to ethical concerns about designing trials inclusive of pregnant women. Also worth noting are clinical chorioamnionitis and a slightly different entity of histologic chorioamnionitis, as well as subclinical chorioamnionitis and noninfectious inflammation—so sometimes the data may not correlate with the clinical scenario that the bedside clinician is evaluating.

Furthermore, cultures do not always correlate with the microorganisms identified in the amniotic fluid by RNA gene sequencing, which greatly resemble vaginal flora; it is generally proposed that a dysbiosis occurring, particularly around Lactobacillus, may be generating the predisposition to IAI.⁶This vaginal flora includes organisms not traditionally covered with a “triple therapy” regimen, but the use of triple therapy and its variants still generates a clinical cure. Note that genital mycoplasmas such as Ureaplasma spp and Mycoplasma hominis are found in the lower genital tract of most women. They are noted to provoke robust inflammatory reactions affecting the maternal and fetal compartments, and they are identified in patients with and without signs of clinical IAI.¹⁰ In endometritis and postpartum fevers, results of multiple studies have shown cases involving Gardnerella, Ureaplasma, or Chlamydia trachomatis; however, clinical therapy directed at these organisms was not required for clinical cure.¹⁴ Virulence factors in the genital mycoplasmas may explain their invasive potential, though not their pathogenesis—other organisms such as streptococci have higher pathogenicity.⁶ In an endometritis cohort with Enterococcus spp, a lack of enterococcal coverage did not impact treatment failure rates.¹⁵

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The American College of Obstetricians and Gynecologists (ACOG) set guidelines for management and published the Intrapartum Management of Intraamniotic Infection committee opinion paper in 2017, which was reaffirmed in 2022.⁴ There are concerns regarding the quality of data on which these recommendations were based, such as the inclusion of antimicrobials that are no longer available or that represent outdated regimens (eg, penicillin monotherapy), and the inclusion of small studies with low numbers of patients enrolled.

Given this is often a clinical diagnosis and that cultures, if even obtained, typically don’t result for a few days, antimicrobial selection for a given patient case is generally empiric. There are multiple studies evaluating different regimens. In 1983, Blanco et al wrote that “the newer cephalosporins are also effective as single-agent therapy,” in reference to using ceftazidime compared with clindamycin and tobramycin in an endometritis cohort, which also had a 9% bacteremia rate. There was no difference in cure rate, side effects, or length of stay.¹⁵ In septic abortion, the combination of ampicillin, gentamicin, and metronidazole was considered universally efficient over the multitude of other regimens utilized clinically. However, Fouks et al noted that piperacillin/tazobactam monotherapy covered 93.3% of all isolates.¹⁶ Logically, broad-spectrum coverage will be successful, but with the urgent public health threat of antimicrobial resistance, narrow-spectrum antimicrobials are preferred whenever possible. The pregnant women population is traditionally considered healthy and without significant antimicrobial resistance, but there are increasing reports of resistance in geographic areas with high gram-negative resistance rates.¹⁷ Regardless of antimicrobial choice, one of the remarkable things about these infections is that a short duration of antibiotics is almost universally agreed upon in the literature.

Enterococcus spp and Ureaplasma spp can be missed in cephalosporin-based regimens, and Ureaplasma spp need the specific addition of azithromycin.⁷ None of the ampicillin, gentamicin, and clindamycin combinations cover genital mycoplasmas. However, this regimen has a greater than 95% success rate in treating maternal infections as well as reducing neonatal sepsis; therefore it is unclear if specific genital mycoplasma coverage is needed.¹⁰ Another analysis noted that when comparing regimens with Bacteroides fragilis activity and those without, there was still an 80% success rate, “raising questions about the type of woman in which a broad-spectrum regimen is necessary.”¹⁸

When confronted with risks such as the emergence of antimicrobial resistance (primarily in Enterobacterales or Bacteroides), changing antimicrobial susceptibility breakpoints (eg, aminoglycosides), and adverse drug events, it is reasonable to consider alternative, modern antimicrobial regimens.⁷ Although ampicillin and gentamicin are primary regimens in IAI, when penicillin allergy regimens plus the potential needs for GBS prophylaxis or surgical site infection prophylaxis in cesarean deliveries are included, there are at least 19 different ACOG-endorsed regimens.^4,11 Cefoxitin was shown to be effective in a real-world cohort study and is endorsed as an “alternative” regimen by ACOG­—one that dodges the clindamycin shortage and gentamicin susceptibility breakpoint changes.¹⁹ Although the additional alternative regimens may be too narrow (ampicillin/sulbactam) or too broad (ertapenem), depending on the microorganisms that are predominant in the local community, there are other Goldilocks-esque regimens that could replace ampicillin/gentamicin plus clindamycin, such as cefoxitin, cefotetan, or piperacillin/tazobactam.

References

1.Greenberg MB, Anderson BL, Schulkin J, Norton ME, Aziz N. A First Look at ChorioamnionitisManagement Practice Variation among US Obstetricians. Infect Dis Obstet Gynecol. 2012;2012:628362. doi:10.1155/2012/628362

2. Pregnancy Mortality Surveillance System | Maternal and Infant Health | CDC. Published March 31, 2023. Accessed April 10, 2024. https://www.cdc.gov/reproductivehealth/maternal-mortality/pregnancy-mortality-surveillance-system.htm

3.Venkatesh K, Glover A, Vladutiu C, Stamilio DM. Association of chorioamnionitis and its duration with adverse maternal outcomes by mode of delivery: a cohort study. BJOG Int J Obstet Gynaecol. 2019;126(6):719-726. doi:10.1111/1471-0528.15565

4.Intrapartum Management of Intraamniotic Infection. Accessed October 10, 2022. https://www.acog.org/en/clinical/clinical-guidance/committee-opinion/articles/2017/08/intrapartum-management-of-intraamniotic-infection

5.Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A randomized trial of intrapartum versus immediate postpartum treatment of women with intra-amniotic infection. Obstet Gynecol. 1988;72(6):823-828. doi:10.1097/00006250-198812000-00001

6. Romero R, Gomez-Lopez N, Winters AD, et al. Evidence that intra-amniotic infections are often the result of an ascending invasion – a molecular microbiological study. J Perinat Med. 2019;47(9):915-931. doi:10.1515/jpm-2019-0297

7. Pek Z, Heil E, Wilson E. Getting With the Times: A Review of Peripartum Infections and Proposed Modernized Treatment Regimens. Open Forum Infect Dis. 2022;9(9):ofac460. doi:10.1093/ofid/ofac460

8.Duff WP. Gabbe’s Obstetrics: Normal and Problem Pregnancies. 58 - Maternal and Perinatal Infection in Pregnancy: Bacterial. 8th ed. Elsevier, Inc; 2021.

9.Goetz l L. Maternal fever in labor: etiologies, consequences, and clinical management. Am J Obstet Gynecol. 2023;228(5):S1274-S1282. doi:10.1016/j.ajog.2022.11.002

10.Tita ATN, Andrews WW. Diagnosis and Management of Clinical Chorioamnionitis. Clin Perinatol. 2010;37(2):339-354. doi:10.1016/j.clp.2010.02.003

11.Prevention of Group B Streptococcal Early-Onset Disease in Newborns. Accessed June 22, 2023. https://www.acog.org/en/clinical/clinical-guidance/committee-opinion/articles/2020/02/prevention-of-group-b-streptococcal-early-onset-disease-in-newborns

12.Chapman E, Reveiz L, Illanes E, Cosp XB. Antibiotic regimens for management of intra‐amniotic infection. Cochrane Database Syst Rev. 2014;(12). doi:10.1002/14651858.CD010976.pub2

13.Czikk MJ, McCarthy FP, Murphy KE. Chorioamnionitis: from pathogenesis to treatment. Clin Microbiol Infect. 2011;17(9):1304-1311. doi:10.1111/j.1469-0691.2011.03574.x

14.Watts DH, Eschenbach DA, Kenny GE. Early Postpartum Endometritis: The Role of Bacteria, Genital Mycoplasmas, and Chlamydia trachomatis. Obstet Gynecol. 1989;73(1):52. Accessed June 15, 2023. https://journals.lww.com/greenjournal/abstract/1989/01000/early_postpartum_endometritis__the_role_of.13.aspx

15.Blanco JD, Gibbs RS, Duff P, Castaneda YS, St Clair PJ. Randomized comparison of ceftazidime versus clindamycin-tobramycin in the treatment of obstetrical and gynecological infections. Antimicrob Agents Chemother. 1983;24(4):500-504. doi:10.1128/aac.24.4.500

16.Fouks Y, Samueloff O, Levin I, Many A, Amit S, Cohen A. Assessing the effectiveness of empiric antimicrobial regimens in cases of septic/infected abortions. Am J Emerg Med. 2020;38(6):1123-1128. doi:10.1016/j.ajem.2019.158389

17.Salmanov AG, Vitiuk AD, Zhelezov D, et al. Prevalence of postpartum endometritis and antimicrobial resistance of responsible pathogens in ukraine: results a multicenter study (2015-2017). Wiadomosci Lek Wars Pol 1960. 2020;73(6):1177-1183.

18.Mackeen AD, Packard RE, Ota E, Speer L. Antibiotic regimens for postpartum endometritis. Cochrane Database Syst Rev. 2015;(2). doi:10.1002/14651858.CD001067.pub3

19. Bailey P, Schacht L, Pazienza G, et al. Cefoxitin for Intra-amniotic Infections and Endometritis: A Retrospective Comparison to Traditional Antimicrobial Therapy Regimens Within a Healthcare System. Clin Infect Dis. Published online January 31, 2024:ciae042. doi:10.1093/cid/ciae042