European Journal of Obstetrics & Gynecology and Reproductive Biology, 36 (1990) 69-14 Elsevier 69 EUROBS 00947 Suspected postpartum endometritis: a controlled clinical trial of single-agent antibiotic therapy with Amox-CA (Augmentin”) vs. ampicillin-metronidazole + aminoglycoside HervC Fernandez ‘, Chantal Claquin 2, Michtile Guibert 3 and Emile Papiernik 4 ’ Department of Gynaecoiogv and Obstetrics, Hal A. Beclere, Clamart, ’ Department of Anesthesia, C.H. U. Kremlin Bicetre, ’ Department of Bacteriology, Hal A. Beclere, Clamart and 4 INSERM. Unit 187, Hal A. Beclere, Clamart, France Accepted for publication 29 September 1989 Summary Endometritis is the commonest postpartum complication and is one of the leading causes of maternal morbidity, if not mortality. The object of the present clinical trial was to assess the efficiency of single-agent therapy with Amox-CA (Augmentir?) (formulation which includes a /3-lactamase inhibitor), against stan- dard treatment which necessarily combines two or three antibiotics depending on the clinical severity of the case. 101 patients were evaluated in this comparative prospective randomized study. The mild forms were defined by a temperature between 37.9 and 38.4”C and the severe forms by a temperature of more than 38.5 o C (which alone required treatment with three antibiotics). The time until the return of apyrexia and the clinical cure rate, as well as duration of treatment, were identical in both groups. Tolerance was good: no side effect requiring discontinua- tion of treatment occurred. In the population value, the use of a single-agent therapy with amoxycillin/ clavulanic acid is not significantly different from a double or triple-agent regimen, and the convenience is increase. Postpartum endometritis; Antibiotic treatment; Single agent therapy; /3-Lactamase inhibitor Correspondence: Hervk Femandez, Department of Gynaecology and Obstetrics, 157, rue de la Porte de Trivaux, 92141 Clamart, France.. 0028-2243/90/$03.50 0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
Transcript
European Journal of Obstetrics & Gynecology and Reproductive Biology, 36 (1990) 69-14
Elsevier
69
EUROBS 00947
Suspected postpartum endometritis: a controlled clinical trial of single-agent antibiotic therapy
with Amox-CA (Augmentin”) vs. ampicillin-metronidazole + aminoglycoside
’ Department of Gynaecoiogv and Obstetrics, Hal A. Beclere, Clamart, ’ Department of Anesthesia, C.H. U.
Kremlin Bicetre, ’ Department of Bacteriology, Hal A. Beclere, Clamart and 4 INSERM. Unit 187, Hal A.
Beclere, Clamart, France
Accepted for publication 29 September 1989
Summary
Endometritis is the commonest postpartum complication and is one of the leading causes of maternal morbidity, if not mortality. The object of the present clinical trial was to assess the efficiency of single-agent therapy with Amox-CA (Augmentir?) (formulation which includes a /3-lactamase inhibitor), against stan- dard treatment which necessarily combines two or three antibiotics depending on the clinical severity of the case. 101 patients were evaluated in this comparative prospective randomized study. The mild forms were defined by a temperature between 37.9 and 38.4”C and the severe forms by a temperature of more than 38.5 o C (which alone required treatment with three antibiotics). The time until the return of apyrexia and the clinical cure rate, as well as duration of treatment, were identical in both groups. Tolerance was good: no side effect requiring discontinua- tion of treatment occurred.
In the population value, the use of a single-agent therapy with amoxycillin/ clavulanic acid is not significantly different from a double or triple-agent regimen, and the convenience is increase.
Postpartum endometritis; Antibiotic treatment; Single agent therapy; /3-Lactamase inhibitor
Correspondence: Hervk Femandez, Department of Gynaecology and Obstetrics, 157, rue de la Porte de
Postpartum endometritis is still a common and severe complication: 1 to 7% of women develop such an infection [1,2] which is leading cause of maternal morbidity or mortality in developing countries. Its incidence varies depending on the type of delivery, It ranges from 5 to 85% [3] following a Cesarean section, and is less than 5% following vaginal delivery [4-61. It tends to be higher if the mother is young and from a low socio-economic group, and if labor was prolonged and a Cesarean performed after the membranes ruptured [3-61. In the absence of any prospective study in a cohort having delivered at least once, the possible role of postpartum endometritis in the pathogenesis of secondary infertility is unknown. Endometritis is usually treated by broad-spectrum combination antibiotic therapy intended to cover the polymicrobial aerobic and flora usually present in the lower genital tract [3-71. The study concerned 101 patients. It was designed as a prospective randomized study. The object was to compare a single-agent antibiotic therapy with a standard combination antibiotic therapy [3] for efficiency. Single-agent antibiotic therapy was a formulation of Amoxicillin with a /3-lactamase inhibitor, clavulanic acid, in a single product (AugmentinR). Its spectrum of activity extends from gram positive to gram negative germs, aerobic and anaerobic germs and includes bacteroides [8-lo].
Materials and methods
The trial was conducted between March 1985 and March 1986 at the Antoine Be&re Hospital in Clamart. Patients with fever in the first 24 hours without any other obvious diagnosis (particularly urinary tract infections) were suspected of endometritis and were candidates for the study. 101 patients were included without statistical determination of minimal number of patients necessary for the study. The diagnosis of endometritis was established on a temperature of more than 37.8” C, checked once every 2 hours, with pelvic tenderness and/or malodorous lochia. Benign forms were defined by a temperature between 37.9 and 38.4 o C, and severe forms by a temperature of more than 38.5OC and/or associated with bacteremia and chills.
The exclusion criteria included a history of allergy to penicillins or cepha- losporins, exposure to prophylactic antibiotic therapy and antibiotic therapy in- stituted during the perpartum period, severe renal disease, valvular heart disease requiring prophylaxis against bacterial endocarditis, and allopurinol treatment. Before treatment, vaginal, endocervical, urine and blood samples for culture were collected, and laboratory examinations were performed which included a blood count, liver function tests, serum electrolytes with serum creatinine and determina- tion of C-reactive protein (CRP). A germ was considered to be responsible for the endometritis on the results of a direct examination which yielded a germ count of the predominant species and a polymorphonuclear cell count, compared with culture results. The characteristics of the patients, age, type of delivery (cesarean section or vaginally), were noted. The antibiotic therapy was chosen after inclusion in the trial, and the patients were randomly assigned to treatment using a random-
71
numbers table. The assessment criteria were the clinical course and clinical toler- ance.
In mild forms, treatment was administered orally either as 500 mg every 8 hours or as a combination treatment with ampicillin (500 mg) and metronidazole (500 mg) every 8 hours for 8 days. In severe forms, patients were started on parenteral treatment: either AugmentinR, 1.2 g in slow intravenous injections every 8 hours, or ampicillin, 2 g intravenously in combination with metronidazole, 500 mg i.v. infusion every 8 hours and an aminoglycoside, 1.5 mg/kg intramuscularly every 12 hours. When the patients were afebrile and clinically well, an oral antibiotic therapy similar to the regimen given in the mild forms was instituted. The total duration of the treatment was 8 days.
In ten cases an associated diagnosis of urinary tract infection as the cause of post-partum fever, when the initial signs of urinary infection were not obvious, were included in the trial, because we tested the efficiency of the therapy within a group clinically suspect of endometritis.
Therapeutic efficiency was evaluated up to the time of apyrexia and up to the time that the clinical signs of endometritis had disappeared. These two parameters defined the cure of the endometritis.
Statistical analysis was performed using the Chi-squared test, the Chi-squared Yates test, and Student’s test. The 95% confidence intervals (CI) for the difference between the two groups is defined for each parameter.
Results
Postpartum fever was observed in 101 of the 2600 deliveries performed during the 13 months of the trial, i.e., in 3.9% of the deliveries. Clinical diagnoses of fever comprised 101 cases of endometritis and 10 with urinary tract infections. The two diagnoses can be present simultaneously. Two patients, one in either group, present- ing an infection involving Staphylococcus uureus resistant to the antibiotic therapy, were excluded.
Therapeutic efficiency was compared in 99 patients, 50 in the Augmentin group and 49 in the combined-antibiotics therapy group. There was no statistical dif- ference between the two treatment groups, with respect to age, type of delivery, and initial severity of the clinical state (Table I). In particular the difference between the
TABLE I
Profile of the patient population
n Age Cesarean Vaginal Severe Mild Endo- Endom.
section delivery form form met&is and/or
urinary
infection
Augmentin 50 28.2k4.4 19 31 14 36 50 0
Combined antibiotics 49 29 f4.1 18 31 12 37 39 10
72
TABLE II
Germs recovered
Germs Augmentin Antibiotic combination
P-Hemolytic Streptococcus Escherichia coli Anaerobes on presence of
two groups with regard to urinary tract infections is not statistically significant. The incidence of endometritis was 11% after Cesarean section (37 out of 338) and 2.7% (62 out of 2262) after vaginal delivery. The bacteriological diagnosis was established in 40 out of 99 cases (40%) with 17 cases in the Augmentin group and 23 cases in the combined-antibiotics therapy group. The germs recovered are indicated in Table II. P-Hemolytic Streptococcus, Bacteroides fragilis and Escherichia Cob were most common, with no significant predominance in one group.
The time until the patient became afebrile was the same in both groups: 3.5 & 2.5 days in the Augmentin group and 2.7 f 2.0 days in the combined-antibiotics therapy group (Fig. 1). The difference was not significant. The confidence interval was from
Time
Fig. 1. Change in temperature. Solid bar, Augmentin; hatched bar, combination.
73
- 5.6 to 7.2 days. The time until the clinical signs of endometritis disappeared was slightly longer in the Augmentin group (p < 0.05) i.e., 2.3 & 1.5 days against 1.7 f 1.1 days. The confidence interval was from - 3.1 to 4.3 days. If urinary tract infections were excluded from the combined-antibiotics therapy group, the time until the clinical signs of endometritis disappeared was the same in both groups, i.e., 2-3 * 1.5 days against 2.1 -t 1.3 days with CI from -3.75 to 4.15. The duration of the treatment was similar in both groups. Clinical recovery was immediate in 100% of the Augmentin group, and only one failure was noted in the ‘three-agent combination therapy’ group in relation to the resistance to antibiotics. Two patients, one in either group, developed urticaria on days 6 and 7, respectively. Neither treatment was discontinued.
Discussion
The prevalence of post-partum endometritis is in fact difficult to determine with any accuracy. In all the trials, only signs of endometritis which developed in hospital are taken into account in formulating the diagnosis. Consequently, post- partum infections occurring after discharge are overlooked. To prevent overlooking an initially minor fever which may worsen secondarily, our policy was to treat all patients who became febrile within the first 24 hours.
According to Filker [ll], 6.5% of patients develop postpartum fever within the first 24 hours, and 3% require antibiotic therapy. If the temperature is more than 38.4”C, nearly 100% of the patients require antibiotic therapy. However, the medium-term outcome in untreated women is not indicated. According to Baskett [12], endometritis should always be suspected in the presence of fever of unknown origin. In any case, it is common to treat endometritis on the basis of its clinical signs alone, without identifying the causal germ. In our series, the infection was not labelled in two out of three cases. Augmentin is a new broad-spectrum antibiotic [lo] which can be used for the treatment of post-partum endometritis in which anaerobic germs, gram positive cocci and enterobacteria are implicated [3-71.
The clinical results of this study have shown, in the number of patients that were studied, that there was no statistical difference between single-agent antibiotic therapy and combined-antibiotics therapy in post-partum fever with the clinical diagnosis of endometritis. The difference between the two groups as regards urinary tract infections is merely due to chance. Nevertheless, this distribution did not change the results but for the time it took for the clinical signs to disappear. However, if urinary tract infections were excluded, the difference between the two groups disappeared. These results, therefore, suggested that the two treatments were equally efficient or that the two treatments were inefficient. However, this last hypothesis was improbable because the morbidity among untreated women amounted to 40% [12] compared with less than 5% among the treated women in the two antibiotic groups. Nevertheless, it was impossible to confirm that the two treatments were equivalent because the number of subjects in the trial is statistically insufficiency. Therefore, to determine a difference of 5% between the two treat- ments, with a risk (Y (= 0.05) and 1-p (= 0.90), the population should include 686 patients in a unilateral test. Consequently our result show a trend. In theory, the use
74
of a single product has the advantage of decreasing the risk of allergy or toxic reaction, even so it was equal in the two groups and kept nursing care to a minimum. The gastro-intestinal and hepatic tolerance was similar to that observed in combined-antibiotics treatment. The bacteriological efficiency of amoxicillin plus a /I-lactamase inhibitor is identical to that of a combined-antibiotics therapy aimed at a comparable flora. An increasing number of amoxycillin clavulanate-resistant Escherichia Coli strains have appeared [13-151. However, we have not found this resistance in postpartum endometritis. The total cost of antibiotic therapy with the amoxycillin/clavulanate combination appears lower in severe forms, with a con- sumption of 24 g of AugrnentirP versus 48 g of amoxycillin with 12 g of metronida- zole and 24 mg per kilo of aminoglucoside. In contrast, in mild forms, the combined-antibiotics therapy costs less than single-agent therapy.
Conclusion
This study suggests that single-agent therapy versus combined-antibiotics therapy does not seem to be significantly different in the treatment of post-partum febrile morbidity.
References
1
2
8
9
10
11
12
13
14
15
Gibbs RS, Weinstein AL. Puerperal infection in the antibiotic era. Am J Obst Gynecol
1976;124:769-778. Sweet RL, Ledger WJ. Puerperal infectious morbidity. A two-year review. Am J Obst Gynecol
1973;117:1093-1101.
Duff P. Pathophysiology and management of post-Cesarean endomyometritis. Obstet Gynecol
1986;67:269-276.
Humphrey MD. Postpartum infection: a survey. Med J Aust 1972;2:657-666.
Ott WJ. Primary Cesarean section; factors related to postpartum infection. Obstet Gynecol
