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ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1382-1387

Comparing the efficacy of cefixime versus amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria in pregnant women


Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission29-Sep-2018
Date of Decision18-Oct-2018
Date of Acceptance30-Oct-2018
Date of Web Publication31-Dec-2019

Correspondence Address:
Mahmoud A M Nafie
Shebin El-Kom, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_304_18

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  Abstract 

Objective
To evaluate efficacy of cefixime and amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria (ASB) in pregnant women.
Background
ASB can cause progressive and severe infections and endanger maternal as well as fetal health. Bacteriuria is usually associated with low birth weight, high blood pressure during pregnancy, maternal anemia, and fetal death.
Patients and methods
A prospective randomized study was conducted on 100 pregnant women having ASB in the first and early second trimester attending the pregnancy follow-up clinic in Galaa Teaching Hospital. Detailed history, laboratory investigations, obstetric, and ultrasound follow-up study were done.
Results
Maternal age (year) of patients ranged from 20 to 35 years, with a mean of 26.06 ± 4.91 years. The presence of pus and serial assessments of fetal growth were significant differences among the studied patients. Overall, 25% of patients had Intrauterine growth retardation (IUGR), 13% had premature rupture of membranes, and 13% had preterm labor. Adverse effects of drug such as presence of Gastrointestinal (GIT) upset, diarrhea, and vaginal candida infection were significantly increased in group 1 (18, 22, and 22%, respectively) than group 2 (4, 6, and 6%, respectively).
Conclusion
The use of amoxicillin/clavulanate is significantly more often accompanied by the development of adverse reactions compared with cefixime. Amoxicillin/clavulanate shows higher incidence of GIT manifestation, diarrhea, and vaginal candida infection. So, further larger studies could provide cost-benefit data necessary to inform a national screening program.

Keywords: amoxicillin, asymptomatic bacteriuria, cefixime, pregnant women, treatment


How to cite this article:
Soliman EE, Emara MA, Shahin AE, Nafie MA. Comparing the efficacy of cefixime versus amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria in pregnant women. Menoufia Med J 2019;32:1382-7

How to cite this URL:
Soliman EE, Emara MA, Shahin AE, Nafie MA. Comparing the efficacy of cefixime versus amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria in pregnant women. Menoufia Med J [serial online] 2019 [cited 2020 Apr 4];32:1382-7. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1382/274257




  Introduction Top


Urinary tract infections (UTIs) are common in pregnant women. By convention, UTI is defined either as a lower tract (acute cystitis) or upper tract (acute pyelonephritis) infection. Asymptomatic bacteriuria (ASB) or asymptomatic urinary infection is isolation of a specified quantitative count of bacteria in an appropriately collected urine specimen obtained from a person without symptoms or signs referable to urinary infection [1]. ASB occurs in 2–7% of pregnant women. It typically occurs during early pregnancy, with only approximately a quarter of cases identified in the second and third trimesters. Factors that have been associated with a higher risk of bacteriuria include a history of prior UTI, pre-existing diabetes mellitus, increased parity, and low socioeconomic status. Without treatment as many as 30–40% of pregnant women with ASB will develop a symptomatic UTI, including pyelonephritis. This risk is reduced by 70–80% if bacteriuria is eradicated [2].

Acute cystitis occurs in ~1–2% of pregnant women, and the estimated incidence of acute pyelonephritis during pregnancy is 0.5–2%. Most cases of pyelonephritis occur during the second and third trimesters. Many studies have described a relationship between maternal UTI, particularly ASB, and adverse pregnancy outcomes. Untreated bacteriuria has been associated with an increased risk of preterm birth, low birth weight, and perinatal mortality [1]. ASB is treated with an antibiotic tailored to the susceptibility pattern of the isolated organism, which is generally available at the time of diagnosis. The choice of antimicrobial agent should also consider safety during pregnancy (including the particular stage of pregnancy [3].

The optimal duration of antibiotics for ASB is uncertain. Short courses of antibiotics are preferred to minimize the antimicrobial exposure to the fetus. Short-course antibiotic therapy is usually effective in eradicating ASB of pregnancy, although single-dose regimens may not be as effective as slightly longer regimens. The use of amoxicillin/clavulanate is significantly more often accompanied by the development of adverse reactions compared with cefixime [4]. The aim of this study was to evaluate the efficacy of cefixime and amoxicillin/clavulanate in the treatment of ASB in pregnant women.


  Patients and Methods Top


A prospective randomized study was conducted on 100 pregnant women having ASB in the first and early second trimesters attending the pregnancy follow-up clinic in Galaa Teaching Hospital.

Ethical consideration

All participants were volunteers. All of them signed a written informed consent and were explained the aim of the study before the study initiation. Approval was obtained from Ethical Committee in Faculty of Medicine, Menoufia University.

Sample size

The sample size was calculated using computer sample block randomization type. Samples were obtained during routine investigations. Overall, 5 ml of blood sample was collected, where 2 ml was put in an EDTA-containing tube and tested for complete blood count (CBC) using an automated CBC analyzer (Sysmex KX-21N, Sysmex Corporation, Sawgrass Drive, Bellport, NY 11713 USA) and the remaining 3 ml of blood was collected in a plain tube and left to coagulate and then centrifuged.

Method of randomization

A total of 100 patients were randomized into two groups using a block of six randomization method, which was produced by a computer-generated random number list. This process was prepared by a statistician. The randomization list will be concealed and accessed by sequentially numbered, opaque, sealed envelopes, immediately before intervention. According to the randomization plan, a plan of interventions was sealed in closed envelops and numbered. By two independent doctors other than the investigator, packing, sealing, and numbering were all performed.

Patients included in the study were randomly divided into two groups as follows:

  • Group 1 included 50 pregnant women with ASB who received amoxicillin/clavulanate 625 mg three times per day for 7 days
  • Group 2 included 50 pregnant women with ASB who received cefixime 400 mg once per day for 7 days.


Inclusion criteria

Women who gave consent to participate in the study, women who were certain of their last menstrual period, and women who not have any medical conditions were included.

Exclusion criteria

Symptoms suggestive of infections in the urinary tract (dysuria, frequency, and urgency), history of antibiotic therapy in previous 2 weeks, history of fever, pregnancy-induced hypertension, pregnancy with diabetes mellitus, and known congenital anomalies of the urinary tract were the exclusion criteria.

All pregnant women who fulfilled the eligibility criteria were subjected to the following:

  • History taking: baseline obstetric demographic data including maternal age, gravidity, parity, period of gestation, history with an emphasis on previous UTIs, previous antibiotic intake, previous pre-natal check-up, and a history of diabetes or preeclampsia
  • General examination: to exclude any medical disease with special attention to blood pressure, pulse, temperature, and pressure.


Laboratory investigations

Blood samples

From each participant, 5 ml of blood sample was collected, of which 2 ml was used for CBC and 3 ml was collected in a plain tube, left to coagulate and then centrifuged. The serum was kept in an Eppendorf tube at 0°C for further tests. Blood glucose levels were measured.

Urine samples

The supernatant of the centrifuged urine was tested using Combi Screen 10 urinalysis strips Gima S.p.A., Via Marconi, 1 20060 Gessate (MI), Metropolitan city- Italy, with the existence of nitrite and leucocyte esterase in the urine being suggestive of infection [5]. ASB is traditionally diagnosed at 105 cfu/ml in two consecutive clean-catch urine specimens.

Both groups were followed monthly till labor through monthly urine analysis, monthly ultrasound to assess the fetal growth, and neonatal assessment after delivery to detect prematurity, distress, and low birth weight.

Detect antibiotic resistance

Antibiotic resistance was measured through bacterial growth in the presence of the antibiotic being tested. These conventional methods take typically 24 h to obtain results. Antibiotic-resistant does not mean the body is becoming resistant to the antibiotics designed to kill them.

Statistical analysis

Results were analyzed and tabulated using Microsoft Excel version 7 (Microsoft Corporation, New York, New York, USA) and SPSS, version 22. (SPSS Inc., Chicago, Illinois, USA). Two types of statistics were done: descriptive, for example, percentage, mean, and SD, and analytical, which includes χ2, Fischer exact test, and 95% confidence intervals (CIs). A value of P less than 0.05 was indicated as statistically significant.


  Results Top


Maternal age (year) of the studied patients ranged from 20 to 35 years, with mean of 25.04 ± 4.15 and 25.08 ± 5.41 years in groups 1 and 2, respectively, and parity ranged from 0 to 5, with mean of 2.16 ± 1.39 and 1.76 ± 1.47 in groups 1 and 2, respectively. Gravidity ranged from 1 to 6 with mean 3.18 ± 1.33 and 3.04 ± 1.45 in groups 1 and 2, respectively. Gestational age ranged from 6 to 18 weeks, with mean 11.64 ± 3.05 and 11.68 ± 3.26 weeks in groups 1 and 2, respectively. BMI ranged from 20.8 to 67.7 kg/m 2, with mean of 33.42 ± 5.98 and 32.26 ± 5.77 kg/m 2 in groups 1 and 2, respectively [Table 1].
Table 1: Comparison between the studied groups regarding demographics and anthropometrics data

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There were insignificant differences between both groups (P > 0.05) regarding the clinical examination. Moreover, there were insignificant differences between both groups regarding laboratory examination, except for RBC count, which was significantly higher among group 2 than group 1 [Table 2].
Table 2: Comparison between the studied groups regarding clinical examination and laboratory investigations

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Furthermore, there were no significant differences (P > 0.05) between the studied groups regarding sex of the neonate, recurrence in serial urine analysis, and resistance after antibiotic treatment and serial fetal assessments. On the contrary, there was a significant difference between serial urine analysis among the two studied groups. However, a significant difference was observed regarding serial assessments of fetal growth in group 2 only [Table 3].
Table 3: Comparison between the studied groups regarding fetal sex, serial urine analysis, resistance after antibiotic treatment, and assessment of fetal growth

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Moreover, there were no statistically significant differences (P > 0.05) between the studied groups regarding the complications such as premature rupture of membranes and preterm labor (P = 0.020 for both). On the contrary, a significant difference was recorded among the studied groups regarding adverse effects of drug, such as presence of GIT upset (P = 0.02), diarrhea (P = 0.02), and vaginal candida infection (P = 0.01). These adverse effects of drug were significantly increased in group 1 (18, 22, and 22%, respectively) than group 2 (4, 6, and 6%, respectively) [Table 4].
Table 4: Comparison between the studied groups regarding complications among both groups

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  Discussion Top


ASB is a presence of a significant quantity of bacteria in a properly collected urine specimen from a person without symptoms or signs of UTI. This is owing to urinary stasis due to progesterone effect in pregnancy in addition to different morphological and physiological changes occurring during pregnancy [5]. Antibiotics are effective against ASB during pregnancy and lower the incidence of pyelonephritis as well as prematurity and dysmaturity. Several antibiotic choices are available for treatment of ASB. Penicillins and cephalosporins are safe for use in pregnancy, but high rates of resistance to ampicillin by  Escherichia More Details coli have been reported [6]. Amoxicillin–clavulanic acid is the first choice drug for the treatment of cystitis during pregnancy. In a meta-analysis, Smaill and Vazquez [2] reported that many authors found that antibiotic treatment was effective in reducing the incidence of pyelonephritis in women with ASB. This prospective randomized study was conducted on 100 pregnant women having ASB in the first and early second trimester attending the pregnancy follow-up clinic in Galaa Teaching Hospital. The study aimed to evaluate efficacy of cefixime and amoxicillin/clavulanate in the treatment of ASB in pregnant women.

In our results, most of cases had secondary school education (62%). Similar to our results, Izuchukwu et al. [7] found that most of the participants had secondary level of education. The highest prevalence was found in women with secondary level of education, whereas the lowest prevalence was found in women with university education. This may be owing to the fact that most of the participants had secondary level of education.

In our results, most of cases had middle social level (58%). Similar to our results, Izuchukwu et al. [7] found that most affected in their study were of the middle socioeconomic class, and the least prevalence was in the high socioeconomic class. In contrast to our results, Abdel-Aziz et al. [8] found no statistically significant association between socioeconomic class and ASB (P > 0.05).

Results of our study show that 25% of neonates had IUGR, 13% had premature rupture of membranes, and 13% had preterm labor. Similar to our results, Sheiner et al. [9] found an association between ASB and low birth weight and preterm birth [odds ratio (OR)=1.9; 95% CI: 1.7–2.0]. Moreover, Meis et al. [10] found that there was a significant association between bacteriuria and preterm births (OR = 2.03; 95% CI: 1.5–2.8) but not for spontaneous preterm births (OR = 1.07; 95% CI: 0.78–1.46). In contrast to our results, Lavanya and Jogalokshmi [11] found that incidence of low-birth-weight babies (50%) and prematurity (75%) was higher in untreated ASB patients.

In our study, patients were divided into two groups, randomly: group 1 included 50 pregnant women with ASB who received amoxicillin/clavulanate 625 mg three times per day for 7 days and group 2 included 50 pregnant women with ASB who received cefixime 400 mg once per day for 7 days. Our results show insignificant difference between both groups regarding serial urine analysis on second and third follow-up. On the contrary, there was a significant difference of serial urine analysis among each of groups 1 and 2. Similar to our results, Rafal'skiĭ et al. [4] found that there is insignificant difference between patients treated with cefixime and amoxicillin/clavulanate for 7 days, where they found that at visit 2, eradication in group 1 and group 2 was 94.8% (55/58) and 98.2% (53/54), respectively (P = 0.35) and at visit 3 was 92.7% (51/55) and 92.5% (49/53), respectively (P = 0.96). Our results show insignificant difference between both groups regarding resistance after antibiotic treatment. The study carried out by Cai et al. [12] found that at the end of the follow-up period, the proportion of patients reported resistant to amoxicillin/clavulanic acid were significantly higher than other antibiotics (P = 0.03). Dull et al. [13] showed that the risk of symptomatic UTI was slightly higher in patients with AB than in non-bacteriuric controls, but the treatment of the asymptomatic colonization did not reduce the risk of subsequent symptomatic infection. They also stated that the use of antibiotics in such cases only increases the risk of progressively resistant infections with no clinical benefit. Sire et al. [14] concluded in their study that evolution of antimicrobial resistance is needed to suggest appropriate empirical treatment of UTI in developing countries, and they found that UTI resistance to amoxicillin–clavulanic acid was 67.5%.

Our results show significant differences between both groups regarding the presence of GIT upset, diarrhea, and vaginal candida infection, being more frequent among group 1 (amoxicillin/clavulanate group). Similar to our results, Rafal'skiĭ et al. [4] found that the rates of adverse events (AE) were 1.7% (one woman has diarrhea) and 13% (five women have nausea and two diarrhea) in groups 1 and 2, respectively (P = 0.02). They concluded that treatment with amoxicillin/clavulanate significantly developed more adverse events (mainly gastrointestinal) than cefixime therapy. These results disagree with the results obtained by Cai et al. [12] who found that none of the patients reported any adverse effects during antimicrobial therapy. During pregnancy, alterations in hormone levels result in changes in pH values in the lower genital tract which aids the growth of anaerobic bacteria and other pathogenic microorganisms within the vagina. Genital tract infection is a well-established risk factor for Premature rupture of membrane (PROM), and pregnant women with genital tract infections have been reported to have a significantly increased risk of UTI [15]. Taken together, these findings indicate that UTIs may be a consequence of genital tract infections, and this may explain our finding of an association between pyuria and PPROM [16].


  Conclusion Top


The use of amoxicillin/clavulanate is significantly more often accompanied by the development of adverse reactions compared with cefixime. Amoxicillin/clavulanate shows higher incidence of GIT manifestation, diarrhea, and vaginal candida infection. So, further larger studies could provide cost-benefit data necessary to inform a national screening program.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kazemier BM, Koningstein FN, Schneeberger C, Ott A, Bossuyt PM, de Miranda E, et al. Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomised controlled trial. Lancet Infect Dis 2015; 15:1324–1333.  Back to cited text no. 1
    
2.
Smaill FM, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev 2015; 8:CD000490.  Back to cited text no. 2
    
3.
Keating GM. Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria. Drugs 2013; 73:1951–1966.  Back to cited text no. 3
    
4.
Rafal'skiĭ VV, Dovgan' EV, Kozyrev V, Gustovarova TA, Khlybova SV, Novoselova AV, et al. The efficacy and safety of cefixime and amoxicillin/clavulanate in the treatment of asymptomatic bacteriuria in pregnant women): a randomized, prospective, multicenter study. Uroloqiia 2013; 24:26–28.  Back to cited text no. 4
    
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Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E. The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int 2010; 107:361–367.  Back to cited text no. 5
    
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Olson RP, Harrell LJ, Kaye KS. Antibiotic resistance in urinary isolates of Escherichia coli from college women with urinary tract infections. Antimicrob Agents Chemother 2009; 53:1285–1286.  Back to cited text no. 6
    
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Izuchukwu KE, Oranu EO, Bassey G, Orazulike NC. Maternofetal outcome of asymptomatic bacteriuria among pregnant women in a Nigerian Teaching Hospital. Pan Afr Med J 2017; 27:69–73.  Back to cited text no. 7
    
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Abdel-Aziz EM, Barnett-Vanes A, Dabour MF, Cheng F. Prevalence of undiagnosed asymptomatic bacteriuria and associated risk factors during pregnancy: a cross-sectional study at two tertiary centers in Cairo, Egypt. BMJ Open 2017; 7:e013198.  Back to cited text no. 8
    
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Sheiner E, Mazor-Drey E, Levy A. Asymptomatic bacteriuria during pregnancy. J Matern Fetal Neonatal Med 2009; 22:423–427.  Back to cited text no. 9
    
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Meis PJ, Michielutte R, Peters TJ, Wells HB, Sands RE, Coles EC, et al. Factors associated with preterm birth in Cardiff, Wales. II. Indicated and spontaneous preterm birth. Am J Obstet Gynecol 1995; 173:597–602.  Back to cited text no. 10
    
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Lavanya SV, Jogalakshmi D. Asymptomatic bacteriuria in antenatal women. Indian J Med Microbiol 2002; 20:105–106.  Back to cited text no. 11
    
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Cai T, Nesi G, Mazzoli S, Meacci F, Lanzafame P, Caciagli P, et al. Asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant strains in women with urinary tract infections. Clin Infect Dis 2015; 61:1655–1661.  Back to cited text no. 12
    
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Dull RB, Friedman SK, Risoldi ZM, Rice EC, Starlin RC, Destache CJ. Antimicrobial treatment of asymptomatic bacteriuria in noncatheterized adults: a systematic review. Pharmacotherapy 2014; 34:941–960.  Back to cited text no. 13
    
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Sire JM, Nabeth P, Perrier-Gros-Claude JD. Antimicrobial resistance in outpatient Escherichia coli urinary isolates in Dakar, Senegal. J Infect Dev Ctries 2017; 1:263–268.  Back to cited text no. 14
    
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Omoregie R, Eghafona NO. Urinary tract infection among asymptomatic HIV patients in Benin City, Nigeria. Br J Biomed Sci 2009; 66:190–193.  Back to cited text no. 15
    
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Hillebrand L, Harmanli OH, Whiteman V, Khandelwal M. Urinary tract infections in pregnant women with bacterial vaginosis. Am J Obstet Gynecol 2002; 186:916–917.  Back to cited text no. 16
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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