Oral and intramuscular treatment options for early postpartum endometritis in low-resource settings: a systematic review.

Review

Oral and Intramuscular Treatment Options for Early Postpartum Endometritis in Low-Resource Settings A Systematic Review Dana Meaney-Delman, MD, MPH, Linda A. Bartlett, and Denise J. Jamieson, MD, MPH

MD,

OBJECTIVE: To suggest options for oral and intramuscular antibiotic treatment of early postpartum endometritis in low-resource community settings where intravenous antibiotics are unavailable.

analysis of pathogens from intrauterine postpartum endometritis samples. Based on these results, and with consideration of existing recommendations for antibiotic use during breastfeeding, we suggest oral and intramuscular antimicrobial options for the treatment of early postpartum endometritis after vaginal delivery in lowresource settings.

DATA SOURCES: Studies were identified through MEDLINE from inception through December 2014. Search terms included [(“anti-bacterial agents [MeSH]” or “anti-infective agents [MeSH]”) and (“endometritis [MeSH]” or “puerperal infection [MeSH]”)]. A second search using the terms [(“endometritis or endomyometritis or puerperal infection) and (“antibiotics or antimicrobials or anti-bacterial agents or anti-infective agents)”] was also used. Additionally, all references from selected articles were reviewed, a hand-search of a subject matter expert library was conducted, and a search of ClinicalTrials.gov was performed. METHODS OF STUDY SELECTION: We conducted a systematic review of the literature in two phases. Phase I provides a summary of clinical cure data from prospective studies of oral and intramuscular antimicrobial regimens as well as summarizes evidence from trials of intravenous antimicrobials. Phase II is a quantitative

Michael G. Gravett,

MD,

TABULATION, INTEGRATION, AND RESULTS: Reports involving oral or intramuscular antimicrobial treatment of postpartum endometritis are rare and of generally poor quality. Antimicrobial trials of postpartum endometritis treatment and intrauterine microbiology studies suggest five antimicrobial regimens may be effective: oral clindamycin plus intramuscular gentamicin, oral amoxicillin–clavulanate, intramuscular cefotetan, intramuscular meropenem or imipenem–cilastatin, and oral amoxicillin in combination with oral metronidazole. CONCLUSION: This review provides suggestions for oral, intramuscular, and combined antimicrobial regimens that may warrant additional study. Experimental trials should consider clinical effectiveness, safety and side effects profiles, and feasibility of community-based treatment. (Obstet Gynecol 2015;125:789–800)

From the National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; Johns Hopkins School of Public Health, Baltimore, Maryland; and the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), An Initiative of Seattle Children’s, Seattle, Washington. The authors thank Michael Monsour for his statistical contributions. Corresponding author: Dana Meaney-Delman, MD, MPH, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop C12, Atlanta, GA 30345; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15

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DOI: 10.1097/AOG.0000000000000732

P

uerperal sepsis is a frequent cause of maternal morbidity and mortality in resource-limited countries, where it has been reported as the third leading cause of maternal death.1 Among the infections that cause sepsis in the postpartum period, the most common is postpartum endometritis (sometimes referred to as endomyometritis or endomyoparametritis), a polymicrobial ascending infection of the uterine cavity that manifests as fever, pelvic pain, and malodorous vaginal discharge.2 Postpartum endometritis is estimated to occur after 1–5% of vaginal births with infection rates 5-fold

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

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to 20-fold higher among women with cesarean deliveries.3,4 The incidence is higher in resource-constrained settings where home birth is common and hygienic conditions are often lacking.2,5–9 Untreated, postpartum endometritis case fatality rates have been estimated to be 17%, but with early recognition and appropriate antibiotics coupled with community-based interventions, the rate can be reduced to 2%.10 In resource-constrained settings, women often lack access11 to broad-spectrum intravenous antibiotics, the standard of care for treatment for postpartum endometritis.12,13 Early recognition of postpartum endometritis, combined with oral or combined oral and intramuscular antibiotic regimens, can expand access to care for these women and improve morbidity and mortality.12 Regimens that can be selfadministered or provided by skilled birth attendants or community health workers are particularly attractive.14 A systematic evidence review was performed to inform oral, intramuscular, and combined oral and intramuscular antibiotic regimens for consideration in the treatment of early postpartum endometritis in low-resource community settings where women lack access to intravenous antibiotics.

SOURCES We conducted a multistage systematic review in accordance with Meta-analysis Of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.15 The review was conducted in two phases (I, II): a clinical effectiveness phase and a pathogens phase. These phases were predetermined through the use of an analytic framework (Fig. 1). We searched MEDLINE from inception to December 2014 to identify all publications in the medical literature addressing the systematic review questions. Searches were developed in consultation with a Centers for Disease Control and Prevention expert librarian. The phase I PubMed search, from inception through December 2014, was formatted as: “[(anti-bacterial agents [MeSH] or anti-infective Population at risk: Postpartum women in low-resource settings

Clinical diagnosis of postpartum endometritis

agents [Mesh]) and (endometritis [MeSH] or puerperal infection [MeSH])]” and limited to articles published in English only. A second PubMed search, “[(endometritis or endomyometritis or puerperal infection) and (antibiotics or antimicrobials or antibacterial agents or anti-infective agents)],” was conducted to capture articles not yet indexed by medical subject heading from January 2011 to December 2014. Additionally, we examined the bibliographies of all selected articles to identify additional references. Lastly, a hand-search of subject matter expert endnote library (M.G.G.), selected article references, and ClinicalTrials.gov was completed. The same search strategy was utilized for phase II; however, an additional PubMed search with the following terms: [(“organisms or bacteria or pathogens”) and (“postpartum [MeSH]”) and (“endometritis or endomyometritis”)] was also conducted.

STUDY SELECTION The initial research question in phase I was: “Among postpartum women with a clinical diagnosis of postpartum endometritis, which oral, intramuscular, or combined oral and intramuscular antibiotic regimen(s) have demonstrated clinical cure proportions of 85% or greater?” The threshold of 85% clinical cure was chosen based on an acceptance rate of 15% treatment failure rate, a failure rate that is similar to that of the standard combined intravenous antibiotic treatment regimens used to treat postpartum endometritis.12 An initial scoping search of PubMed demonstrated limited evidence on oral and intramuscular treatment. Because the goal was to explore possible regimens for further study in experimental trials, the authors expanded the analytic framework to include an assessment of the clinical cure with intravenous antibiotic regimens, which can inform the choice of antibiotic classes for oral and intramuscular regimens. The same 85% clinical cure threshold was chosen and the secondary research question for phase I was “Among postpartum women with a clinical diagnosis of postpartum

Uterine pathogens

Antibiotic treatment

Outcome: Clinical cure

Phase II Research question 2 Phase I Research question 1

Fig. 1. Analytic framework for the treatment of early postpartum endometritis: a systematic review to inform oral and intramuscular antibiotic choices in low-resource settings. Meaney-Delman. Postpartum Endometritis. Obstet Gynecol 2015.

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Postpartum Endometritis



endometritis, which intravenous antibiotic regimen(s) have clinical cure proportions of 85% or greater?” For inclusion in phase I, studies must report the number of women treated and clinically cured with antibiotics after a clinical diagnosis of postpartum endometritis. The diagnosis of postpartum endometritis could follow vaginal or cesarean delivery. The number of women treated and clinically cured was abstracted from each study, tabulated, and aggregated for each antibiotic regimen. (Table 1) Selected studies were quality-rated according to the methodology outlined by the American College of Obstetricians and Gynecologists (Box 1). Phase II examined studies reporting intrauterine organisms associated with postpartum endometritis and was guided by the following question: “Among postpartum women diagnosed clinically with postpartum endometritis, which pathogens have been identified and with what frequency have they been reported in the literature?” Given the inherent polymicrobial nature of the normal vagina and cervix, studies reporting organisms identified by vaginal or endocervical culture were excluded. For inclusion in phase II, articles must contain peer-reviewed primary data related to the number and type of pathogens identified by pretreatment endometrial culture among patients with a clinical diagnosis of postpartum endometritis. Data abstracted included the number of patients cultured and the number of isolates by genus and species. A rank order was generated by calculating the ratio of the number of total isolates compared with the number of total patients cultured (in all studies) and multiplied by the number of studies that identified that pathogen (Tables 2 and 3). By calculating the rank order of organisms in this manner, the relative frequency of isolate reporting was determined across the body of literature. For both phase I and phase II reviews, randomized controlled trials, prospective cohort studies, and observational and descriptive studies from all countries were included; retrospective studies, case reports, and non-English articles were excluded. Unpublished reports, abstracts, duplicate reports, policy guidelines, and review articles were excluded; however, these select articles were used to identify additional sources of primary data. The corresponding author (D.M.-D.) performed the literature searches, screened all titles and abstracts, conducted full-text reviews, and abstracted data from each study. A second reviewer (D.J.J.) reviewed abstracted data and full-text articles chosen for inclusion. Complete concordance of data abstraction was achieved between reviewers. Experts

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in obstetrics, microbiology, infectious diseases, international women’s health, and public health reviewed the manuscript and cited references to ensure accuracy and completeness.

RESULTS In phase I, 449 articles were identified, of which 66 met the inclusion criteria. We identified 15 articles16–30 reporting 16 antibiotic regimens that included oral or intramuscular routes of administration (Table 1). Oral antibiotics are easier to administer. Data are available on five single-agent oral antibiotic regimens: amoxicillin plus clavulanate, erythromycin, metronidazole, fosfomycin, and tinadazole.17,19,22,26,30 Among the single oral agents, only amoxicillin–clavulanate demonstrated a greater than 85% clinical efficacy rate; 100% (95% confidence interval [CI] 90–100) clinical cure was achieved in 36 patients treated.17 The same study evaluated combined oral ampicillin and metronidazole, and clinical cure was achieved in 36 of 37 patients (97%; 95% CI 86–100).17 A small study (n524) involving treatment with oral clindamycin and intravenous gentamicin achieved an 88% (95% CI 69–96),29 although the contribution of oral clindamycin to achieve a clinical cure is unknown with this regimen. Data on the use of oral antibiotics to treat postpartum endometritis are very limited, sample sizes are small, and the majority of the studies are of low quality. Five studies include treatment with single-agent intramuscular antibiotics. Two small studies reported high clinical efficacy rate: aztreonam (100%; 95% CI 81–100; n516)20 and imipenem (91%; 95% CI 73–98; n523).25 Two small studies report clinical cures with fosfomycin treatment orally and intramuscularly (80%; 95% CI 38–96; n55)19 and intramuscularly only (84%; 95% CI 67–93; n531).28 Single-agent gentamicin treatment also demonstrated low clinical cure rates (63%; 95% CI 31–86; n58).20 An additional six studies reported clinical cure with intramuscular antibiotics as part of combined antibiotic regimens: 1) intravenous clindamycin plus intramuscular gentamicin (100%; 95% CI 94–100; n554)27; 2) intravenous cefazolin plus intramuscular gentamicin (84%; 95% CI 72–92; n551)27; 3) intravenous penicillin plus intramuscular kanamycin (78%; 95% CI 71–84; n5168)18,23; 4) intravenous clindamycin plus intramuscular kanamycin (75%; 95% CI 41–93; n58)23; and 5) intravenous penicillin plus intramuscular tobramycin (62%; 95% CI 48–75; n545).31 Among these, the regimen demonstrating the highest clinical cure was intravenous clindamycin plus intramuscular gentamicin, although cefazolin plus intramuscular

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Table 1. Postpartum Endometritis Clinical Cure Rates With Various Antibiotic Regimens No. Treated/ % No. Cured Cured

Antibiotic Single agent oral or IM antibiotic regimens Amoxicillin–clavulanate (oral) Fosfomycin (oral or IM) Metronidazole (oral) Erythromycin (oral) Tinidazole (oral) Single-agent IM antibiotic regimens Aztreonam (IV or IM) Imipenem (IM) Fosfomycin (IM) Gentamicin (IV or IM) Combination oral and IM antibiotic regimens Clindamycin (IV) +gentamicin (IM) Ampicillin (oral) +metronidazole (oral) Clindamycin (oral) +gentamicin (IV) Cefazolin (IV) +gentamicin (IM) Penicillin (IV) +kanamycin (IM) Clindamycin (IV) +kanamycin (IM) Penicillin (IV) +tobramycin (IM) Single-agent (IV) antibiotic regimens Amoxicillin–clavulanate Chloramphenicol Ertapenem Imipenem–cilastatin Cefotaxime Clindamycin Ticarcillin Cefotetan Piperacillin–tazobactam Ceftazidime Ampicillin+sulbactam Piperacillin Meropenem Mezlocillin Ticarcillin–clavulanate Moxalactam Cefamandole Cefmetazole Ampicillin Ciprofloxacin Cefoxitin Ceftizoxime

95% CI

36/36

100

90–100

4/5 20/25 10/13 10/17

80 80 77 59

38–96 61–91 50–92 36–78

16/16 21/23 26/31 5/8

100 91 84 63

81–100 73–98 67–93 31–86

78/78

100

94–100

36/37

97

86–100

21/24

88

69–96

43/51

84

72–92

131/168

78

71–84

6/8

75

41–93

28/45

62

48–75

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Antibiotic Combination IV antibiotic regimens Penicillin+gentamicin +clindamycin Clindamycin +gentamicin (daily) Metronidazole +tobramycin Trospectinomycin +aztreonam Clindamycin +tobramycin Ampicillin +metronidazole +aminogylcoside Metronidazole +gentamicin Clindamycin +aztreonam Ampicillin+gentamicin +clindamycin Clindamycin +gentamicin Clindamycin (daily) +gentamicin (daily) Penicillin+tetracycline Penicillin+gentamicin

No. Treated/ % No. Cured Cured

95% CI

2/2

100

34–100

90/94

96

90–98

16/17

94

73–99

198/212

93

89–96

141/152

93

88–96

11/12

92

65–99

32/35

91

78–97

272/299

91

87–94

38/42

90

78–96

1,194/1,397

85

84–87

45/55

82

70–90

43/61 81/126

70 64

58–80 56–72

CI, confidence interval; IM, intramuscular; IV, intravenous.

14/14 17/18 111/120 27/29 273/296 82/90 20/22 228/253 104/115 30/34 328/378 61/71 127/147 155/181 135/159 184/221 76/92 206/252 106/130 80/102 397/514 86/111

100 94 93 93 92 91 91 90 90 88 87 86 86 86 85 83 83 82 82 78 77 77

78–100 74–99 86–96 78–98 89–95 83–95 72–97 86–93 84–95 73–95 83–90 76–92 80–91 80–90 79–90 78–88 74–89 77–86 74–87 70–85 73–81 69–84

(continued )

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Table 1. Postpartum Endometritis Clinical Cure Rates With Various Antibiotic Regimens (continued )


gentamicin did cure 43 of 51 patients.27 Overall, limited data exist with regard to the use of intramuscular antibiotics for the treatment of postpartum endometritis, and the data are of low quality. In the majority of the studies available for review, intramuscular antibiotics are a component of a combined antibiotic regimen. Because the evidence for oral and intramuscular antibiotic treatment was limited, evidence from intravenous antibiotic regimens was also examined. The evidence was more robust, both in the number of studies and in the study quality. However, sample sizes tended to be small and most studies were not powered to detect statistically significance. Nevertheless, many intravenous regimens demonstrated high numbers of patients clinically cured (Table 1). When data from all studies were aggregated, multiple single-agent antibiotics reached the 85% clinical cure threshold: amoxicillin–clauvulanate,17 ampicillin– sulbactam,17,32–37 aztreonam,20 cefotaxime,38–40 32,41–45 46 cefotetan, ceftazidime, chloramphenicol,47 36,47 48 clindamycin, ertapenem, imipenem–cilastatin,49 50 meropenem, mezlocillin,51–53 piperacillin,54,55



Box 1. Evidence and Recommendation Grading System Studies were reviewed and evaluated for quality according to the method outlined by the American College of Obstetricians and Gynecologists: I—Evidence obtained from at least one properly designed randomized controlled trial II-1—Evidence obtained from well-designed controlled trials without randomization* II-2—Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group II-3—Evidence obtained from multiple time series with or without the intervention (Dramatic results in uncontrolled experiments also could be regarded as this type of evidence.) III—Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees Based on the highest level of evidence found in the data, recommendations are provided and graded according to the following categories: Level A—Recommendations are based on good and consistent scientific evidence; Level B—Recommendations are based on limited or in consistent scientific evidence; or Level C—Recommendations are based primarily on consensus and expert opinion. *Or randomized controlled trials with major design flaws. Modified from Management of late-term and postterm pregnancies. Practice Bulletin No. 146. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;124:390–6.

piperacillin–tazobactam,48 ticarcillin,47 and ticarcillin– clavulanate.16,56–58 Among the combined antibiotic regimens that achieved high rates of cure,46,59 eight contained an aminoglycoside—either gentamicin or tobramycin—as part of the regimen46,59 and five of these included clindamycin.46,59 In phase II, 530 articles were reviewed, of which 38 provided genus or speciated information related to organisms identified by endometrial culture at the time of diagnosis (before antibiotic treatment). We identified 38 studies17,18,21,22,25,29,30,33,34,36,37,40,42,44,46,48,49,51,55,57–73 that reported pathogens from endometrial samples of patients with a clinical diagnosis of postpartum endometritis. We then generated a list of the most common 20 genus and family (Table 2). The most common genus was bacteroides; Gram-positive and Gramnegative organisms were present in women with postpartum endometritis in both aerobic and anaerobic

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forms. The top 10 bacteria by genus represent 84% of all the isolates identified. Given that antimicrobial susceptibility may vary within a genus, we also evaluated the most common intrauterine organisms by species (Table 3). Overall, 54 speciated organisms were reported within the studies included in our search. Escherichia coli was the single most commonly identified bacteria. Similar to the genus list, the speciated list indicates that Grampositive and Gram-negative organisms are present in both aerobic and anaerobic forms within the top 20 speciated organisms.

DISCUSSION Based on the available data compiled in this review, we identified five possible oral, intramuscular, or combined antibiotic regimens for the treatment of postpartum endometritis in low-resource setting where intravenous antibiotics are unavailable, and we would recommend that these be considered for further study. Although our review includes data that encompass the treatment of postpartum endometritis after both vaginal delivery and cesarean delivery, we would recommend that these regimens be studied initially as treatment of mild, early cases of postpartum endometritis after vaginal delivery only and that those treated in this manner should be closely monitored. On completion of this review, we generated a list of antibiotics for possible further study based on clinical cure and antimicrobial spectrum. Then, for each antibiotic proposed as part of an oral or intramuscular regimen, we assessed current recommendations for compatibility with breastfeeding. LactMed,74 a database maintained by the National Library of Medicine, and the 2001 recommendations of the American Academy of Pediatrics were consulted.75 Ultimately, if the proposed antibiotics were among those recommended by LactMed and the American Academy of Pediatrics, we included these antibiotics in the final suggested list (Table 4). The specific rationale for the choice of proposed regimens is provided subsequently. In regimen 1, using clindamycin and gentamicin, alone or in combination, was reported in 37 studies, encompassing all routes of administration. A total of 1,420 patients were treated with intravenous clindamycin and gentamicin with an overall 87% response rate; these data include many high-quality studies. In addition, clinical cure has been demonstrated when clindamycin was combined with a different aminoglycoside, tobramycin. Limited data of clindamycin and gentamicin with oral and intramuscular administration routes

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Table 2. Intrauterine Pathogens Associated With Postpartum Endometritis Most Common Pathogens by Genus and Family Rank* Order

Genus

Family

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Bacteroides Staphylococcus Streptococcus Escherichia Enterococcus Peptostreptococcus Ureaplasma Peptococcus Lactobacillus Mycoplasma Gardnerella Corynebacterium Enterobacter Proteus Clostridia Klebsiella Haemophilus Neisseria Candida

20

Pseudomonas

Bacteroidaceae Staphylococcaceae Streptococcaceae Enterobacteriaceae Enterococcaceae Peptococcaceae Mycoplasmataceae Peptococcaceae Lactobacillaceae Mycoplasmataceae Bifidobacteriaceae Corynebacteriaceae Enterobacteriaceae Enterobacteriaceae Clostridiaceae Enterobacteriaceae Pasteurellaceae Neisseriaceae Saccharomycetaceae or Moniliaceae Pseudomonadaceae

No. of Isolates

No. of Patients Cultured

No. of Articles

Gram Stain

Aerobe† or Anaerobe

1,227 760 1,342 622 586 435 378 266 361 288 310 182 182 141 156 113 37 40 18

3,269 3,415 7,217 3,570 2,454 2,367 939 1,404 1,779 931 2,112 1,609 2,963 2,437 1,805 2,090 419 893 413

31 30 32 31 25 22 9 19 16 9 17 13 25 24 16 18 5 9 6

Negative Positive Positive Negative Positive Positive Other Positive Positive Other Variable Positive Positive Negative Positive Negative Negative Negative Other

Anaerobe Aerobe Aerobe Aerobe Aerobe Anaerobe Other Anaerobe Anaerobe Other Anaerobe Anaerobe Aerobe Aerobe Anaerobe Aerobe Aerobe Aerobe Other

27

1,436

12

Negative

Aerobe

* Rank order determined by calculating (number of total isolates/number of total patients)3(number of studies). † Classification based on Murray PR, Witebsky FG. The clinician and the microbiology laboratory. In: Mandell, Douglas, Dolan, editors. Mandell, Douglas and Bennett’s Principles and Practices of Infectious Diseases. Philadelphia (PA): Churchill Livingstone Elsevier; 2010. p. 248.

demonstrate high rates of clinical cure. Data indicate that intramuscular gentamicin achieves similar serum concentrations to intravenous gentamicin,76,77 and therapeutic serum concentrations can be achieved with oral clindamycin, provided the appropriate dose is used. Overall, clinical efficacy and pharmacokinetic data support the study of oral clindamycin and intramuscular gentamicin in combination for the treatment of postpartum endometritis. In terms of antimicrobial coverage, the combined regimen of clindamycin and gentamicin provides coverage for Gram-negative and Gram-positive organisms, including both anaerobes and anaerobes. E coli and Bacteroides, Staphylococcus, Streptococcus, Peptostreptococcus, Peptococcus, and Lactobacillus infections are susceptible to this antibiotic regimen. Enterococcus species may not be universally susceptible to these antimicrobials78; however, as a polymicrobial infection, the eradication of the majority of organisms may shift the balance enough that the immune system can eradicate the infection.64,79 Close monitoring is warranted with all oral or intramuscular antibiotic treatment and for women treated with this regimen, one should consider adding oral amoxicillin or amoxicillin–clavulanate if marked

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clinical improvement is not seen and intravenous antibiotics remain unavailable.80 Of note, genital mycoplasmas have been identified in endometrial cultures of patients with postpartum endometritis30,36,55,81; however, their pathogenicity is questionable. Combination antibiotic regimens that are do not include mycoplasma coverage eradicate the infection, suggesting these organisms are unlikely to play a major role in the infection.2,82 In regimen 2, limited data suggest oral amoxicillin– clavulanate may be effective for treatment of postpartum endometritis. In addition, seven studies of a similar antibiotic (ampicillin–sulbactam) administered intravenously show high clinical efficacy rates83; amoxicillin– clavulanate and ampicillin–sulbactam have similar antimicrobial spectrums. Both provide antimicrobial coverage of E coli and Bacteroides, Staphylococcus, Streptococcus, Peptostreptococcus, Peptococcus, Lactobacillus, and Enterococcus infections.84 Combined with the broad antimicrobial spectrum, the oral route of administration makes this an attractive choice for treatment of postpartum endometritis, particularly because there are multiple dosing forms available that achieve adequate serum levels. Of note, an alternate antibiotic regimen would need to be available for penicillin-allergic



Table 3. Intrauterine Pathogens in Postpartum Endometritis by Species Most Common Pathogens by Species Rank Order* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Speciated Pathogen Escherichia coli Enterococcus Bacteroides bivius Staphylococcus epidermis Ureaplasma Peptostreptococcus NOS Lactobacillus Staphylococcus aureus Bacteroides NOS Mycoplasma Streptococcus agalactiae (Group B) Gardnerella Peptococcus NOS Streptococcus NOS Fusobacterium Sreptococcus faecalis Bacteroides fragilis Corynebacterium Bacteroides melaninogenticus Proteus mirabilis Clostridia NOS Peptostreptococcus asaccharolyticus b-hemolytic streptococcus NOS Streptococcus viridans Enterobacter NOS Klebsiella NOS Klebsiella pneumonia Peptostreptococcus magnus Chlamydia trachomatis Peptostreptococcus anaerobius Enterobacter cloacae Veillonella Neisseria gonorrhea Prevotella Proteus NOS Eubacterium Bacillus Bacteroides oralis Candida Clostridia perfringes Streptococcus pyogenes (Group A) Enterobacter aerogenes Staphylococcus NOS Citrobacter Porphyromnas Pseudomonas aeruginosa Morganella morgagni Pseudomonas NOS

No. of Isolates


No. of Articles

Gram Stain†

Aerobe or Anaerobe†

622 586 532 799 378 380 361 368 338 288 305

3,570 2,454 2,358 2,451 939 2,180 1,779 2,588 2,394 931 3,026

31 25 20 20 9 20 16 22 21 9 25

Negative Positive Negative Positive — Positive Positive Positive Negative — Positive

Aerobe Aerobe Anaerobe Aerobe — Anaerobe Anaerobe Aerobe Anaerobe — Aerobe

310 180 324 250 291 216 182 124

2,112 1,109 2,875 2,866 1,160 2,686 1,609 1,520

17 14 20 24 8 23 13 16

Variable Positive Positive Positive Positive Negative Positive Negative

Anaerobe Anaerobe Aerobe Anaerobe Aerobe Anaerobe Aerobe Anaerobe

107 136 66

1,872 1,376 568

19 11 9

Negative Positive Positive

Aerobe Anaerobe Anaerobe

319

2,436

7

Positive

Aerobe

72 117 52 61 20 46 41

732 1,865 437 1,653 127 591 648

9 14 4 14 3 6 7

Positive Negative Negative Negative Positive — Positive

Aerobe Aerobe Aerobe Aerobe Anaerobe — Anaerobe

45 36 39 104 34 32 31 17 18 20 19

1,027 620 770 335 565 535 558 322 413 429 465

10 7 8 1 5 5 5 5 6 5 5

Negative Negative — Negative Negative Negative Positive Negative — Positive Positive

Aerobe Aerobe — Anaerobe Aerobe Aerobe Aerobe Anaerobe — Anaerobe Aerobe

23 35 17 49 10 12 17

867 892 1,000 355 452 539 984

7 4 10 1 6 5 6

Negative Positive Negative Negative Negative Negative Negative

Aerobe Aerobe Aerobe Anaerobe Aerobe Aerobe Aerobe (continued )

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Table 3. Intrauterine Pathogens in Postpartum Endometritis by Species (continued ) Most Common Pathogens by Species Rank Order* 49 50 51 52 53 54

Speciated Pathogen

No. of Isolates


No. of Articles

Gram Stain†

Aerobe or Anaerobe†

7 18 7 6 1 1

141 1,125 233 239 123 335

2 6 3 2 1 1

Positive Positive Positive Positive — Positive

Anaerobe Aerobe Anaerobe Aerobe — Aerobe

Peptostretococcus prevotti Acinetobacter Peptostretococcus micros Proprionibacterium Neisseria NOS Listeria monocytogenes

NOS, NOS. * Rank order determined by calculating: (no. of total isolates/no. of total patients)3(no. of studies). † Classification based on Murray PR, Witebsky FG. The clinician and the microbiology laboratory. In: Mandell, Douglas, Dolan, editors. Mandell, Douglas and Bennett’s Principles and Practices of Infectious Diseases. Philadelphia (PA): Churchill Livingstone Elsevier; 2010. p. 248.

patients, which is estimated to affect 5–10% of the population.85,86 In regimen 3, although no studies of intramuscular use of single-agent cefotetan were identified, four studies demonstrate clinical efficacy for the treatment

of postpartum endometritis with intravenous cefotetan with a combined 89% efficacy.32,41,42,45 Additionally, data from the use of three other cephalosporins, cefotaxime, ceftazidime, and cefmetazole demonstrate high efficacy rates.39,40,46,61 Among these cephalosporins,

Table 4. Recommended Antibiotic Regimens for Postpartum Endometritis Strength of Regimen Recommendation 1

B

Antibiotic(s) Clindamycin plus Gentamicin

Administration Route

Dose

Frequency

Oral

600 mg

Every 6 h

IM

4.5 g

Oral

875 mg

2

B

Amoxicillin– clavulanic acid

3

B

Cefotetan

IM

2g

4

B

Meropenem or imipenem– cilastatin

IM

500 mg

5

B

Amoxicillin plus Metronidazole

Oral

500 mg

Oral

500 mg

LactMed*

May disrupt infant gastrointestinal flora Every 24 h May disrupt infant gastrointestinal flora; poorly excreted in breast milk Every 12 h Acceptable to use; restlessness, diarrhea, and rash occur occasionally Every 8 h May disrupt infant gastrointestinal flora; acceptable to use Every 8 h May disrupt infant gastrointestinal flora; acceptable to use Every 8 h May disrupt infant gastrointestinal flora; acceptable to use Every 8 h Candida infection and diarrhea reported

AAP† Compatible

Compatible

Compatible

Compatible

AAP, American Academy of Pediatrics; IM, intramuscular. * http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT. † American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.

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cefotetan is the only one available for twice-daily intramuscular dosing; the others require more frequent dosing. The spectrum of activity for cefotetan includes Gram-negative, Gram-positives, aerobes, and anaerobes, common pathogens associated with postpartum endometritis. Although this agent shows promise for further study, availability in some resource-constrained areas may be an issue and this may not be an option for penicillin-allergic patients. In regimen 4, a single-agent carbapenem, administered intramuscularly such as meropenem or imipenem– cilastatin is likely to be effective for the treatment of postpartum endometritis. Five studies of various carbapenems, including imipenem–cilastatin,25,49,87 meropenem,50 and ertapenem,48 administered intramuscularly or intravenously, demonstrate high clinical efficacy rates. Although the data are limited, intramuscular imipenem–cilastatin was efficacious in one small study25 and in two additional studies intravenously.49,87 However, meropenem may be a better option because the side effect profile for imipenem–cilastatin includes seizures and neurotoxicity, which are less frequently observed with meropenem.88,89 Meropenem administered intravenously was efficacious in one study; however, thrice-daily dosing may limit the feasibility using these antimicrobials to treat postpartum endometritis in the community. In regimen 5, we identified one small study involving ampicillin and metronidazole–combination oral therapy, which achieved a 98% cure rate, and the spectrum of activity for amoxicillin is identical to ampicillin. These drugs are considered interchangeable for treatment, but amoxicillin is more widely available. However, given that resistance to ampicillin among Gram-negative anaerobic organisms has been demonstrated and is believed to be imparted by b-lactamases,84 the addition of a b-lactamase inhibitor (such as clavulanate) should be considered. This regimen is not appropriate for patients with known penicillin allergies. Metronidazole is well absorbed orally and has excellent anaerobic coverage, providing complementary coverage to amoxicillin or amoxicillin–clavulanate. Antibiotic regimens that would be expected to be effective but that are not available for intramuscular or oral administration include piperacillin, piperacillin– tazobactam, ticarcillin, ticarcillin–clavulanate acid, ceftazidime, and cefmetazole. In addition, there may be other oral regimens (eg, cephalosporins, quinolones, trimethoprim–sulfamethoxazole) that have not yet been well studied. Other authors have recommended specific antibiotics for the treatment of postpartum endometritis. Our first-line recommendation, oral clindamycin

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plus intramuscular gentamicin, is consistent with recommendations of the Cochrane Collaboration.12 However, our recommendation includes oral and intramuscular administration routes. The World Health Organization issued recommendations in their Integrated Management of Pregnancy and Childbirth statement published in 2007.13 They recommend a combination of ampicillin intravenously in conjunction with gentamicin and metronidazole intravenously. However, if the infection is not severe, metronidazole can be given orally and oral amoxicillin can be given as an alternative to ampicillin. These recommendations are consistent with our second-line recommended antibiotic regimen. Our systematic review has several strengths. We created an analytic framework to synthesize available evidence that could inform antibiotic choices for study in resource-limited settings. It provides a multifaceted and comprehensive synthesis of the evidence. Unlike many prior studies, our analysis of intrauterine pathogens is restricted to those obtained by endometrial culture, which limits contamination by vaginal and endocervical flora. Our review has several limitations. Our searches were restricted to articles in English and most studies were not conducted in resource-limited settings. Although microbiologic flora may differ in women in low-resource settings, recent evidence suggests that the flora are similar with the exception of higher rates of sexually transmitted infections.90 The safety of antibiotic use, although not a defined outcome for this review, is a very important consideration, particularly because antibiotics can disrupt the gastrointestinal flora of breastfed infants. However, we did consider this as a factor for antibiotic choices and reviewed summaries from the trusted resources—LactMed and the American Association of Pediatrics.74 The availability and cost of antibiotic for the proposed regimens were not systematically evaluated to determine proposed regimens; we expect this will be locationspecific. Lastly, we acknowledge that antibiotic resistance may also vary regionally, a factor that should be evaluated and monitored to inform appropriate antibiotic choices. Postpartum endometritis is a serious and lifethreatening disease in resource-limited countries and claims the lives of many women as a result of lack of access to adequate care. Community preventive strategies are needed, but for women who ultimately develop the infection, access to appropriate antibiotics is critical. Women without access to intravenous antibiotics are at risk of death and require early recognition and treatment. Options for alternative

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treatment regimens, based in the community setting, should be explored to determine whether an alternative approach to antibiotic administration can reduce morbidity and mortality from postpartum endometritis globally. This review provides the foundation and basis for reasonable antibiotic choices for further study. Future studies and empiric evidence are needed to better understand safety, clinical effectiveness, availability, cost, and antibiotic tolerance and adherence. REFERENCES 1. AbouZahr C, Royston E. Maternal mortality: a global factbook. Geneva (Switzerland): World Health Organisation; 1991.

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clavulanate for treatment of postpartum endometritis.

Antibiotic regimens for postpartum endometritis.

Screening for Postpartum Depression in Well-Baby Care Settings: A Systematic Review.

Postpartum gentamicin dosing and endometritis.

Oral antihypertensive therapy for severe hypertension in pregnancy and postpartum: a systematic review.

Tooth wear: a systematic review of treatment options.

Abdominoplasty-related nerve injuries: systematic review and treatment options.

A systematic review of patient acceptance of screening for oral cancer outside of dental care settings.

Treatment options for advanced keratoconus: A review.

Patient satisfaction with E-Oral Health care in rural and remote settings: a systematic review protocol.

Treatment Interventions for Early Childhood Obesity: A Systematic Review.

Complementary and Alternative Medicine Treatment Options for Otitis Media: A Systematic Review.

Early oral feeding after total laryngectomy: A systematic review.

Susceptibility of female pelvic pathogens to oral antibiotic agents in patients who develop postpartum endometritis.

Therapeutic options for chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review.

Interpersonal psychotherapy for postpartum depression: a systematic review.

Polyphenols as novel treatment options for dermatological diseases: A systematic review of clinical trials.

Depression drug treatment outcomes in pregnancy and the postpartum period: a systematic review and meta-analysis.

Current and Future Treatment Options for Narcolepsy: A Review.

Treatment Options for Pediatric Patent Ductus Arteriosus: Systematic Review and Meta-analysis.

Endometrial echotexture variables in postpartum cows with subclinical endometritis.

Systematic review of evidence for different treatment settings in anorexia nervosa.

Lymphatic filariasis and onchocerciasis prevention, treatment, and control costs across diverse settings: a systematic review.

Antidepressants during pregnancy and postpartum hemorrhage: a systematic review.