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The Prevalence and Antimicrobial Resistance of Haemophilus Infuenzae in Prepubertal Girls with Vulvovaginitis

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The Prevalence and Antimicrobial Resistance of Haemophilus Infuenzae in Prepubertal Girls with Vulvovaginitis The prevalence and antimicrobial resistance of Haemophilus inuenzae in prepubertal girls with vulvovaginitis Mingming Zhou The Children's Hospital, Zhejiang University School of Medicine Liying Sun The Children's Hospital, Zhejiang University School of Medicine Xuejun Chen ( [email protected] ) Chao Fang The Children's Hospital, Zhejiang University School of Medicine Jianping Li The Children's Hospital, Zhejiang University School of Medicine Chunzhen Hua The Children's Hospital, Zhejiang University School of Medicne Research article Keywords: Haemophilus inuenzae, Vulvovaginitis, Prepubertal, Antimicrobial resistance, Vulval Posted Date: July 16th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-41705/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/16 Abstract Background: To determine the prevalence of Haemophilus inuenzae vulvovaginitis in prepubertal girls and the antimicrobial resistance of H.inuenzae strains isolated from vulval specimens. Methods: Isolates of H.inuenzae from vulval swabs of prepubertal girls with vulvovaginitis received at The Children's Hospital, Zhejiang University School of Medicine during 2016-2019 were studied. Vulval specimens were inoculated on Haemophilus selective chocolate agar. Antimicrobial susceptibility tests were performed using the disk diffusion method. A cenase disk was used to detect β-lactamase. Results: A total of 4142 vulval specimens were received during the 4 years, 649 isolates of H. inuenzae were isolated from 642 girls aged 6 months to 13 years, with a median of 5y. There were peaks of isolates from April to July seen in the vulval isolates. In total, the ampicillin resistance rate was 39.1% (250/640); 33.2% strains (211/636) were for β-lactamase-positive isolates, 6.6% strains (42/635) were β- lactamase-negative and ampicillin-resistant (BLNAR) isolates. The resistance rates of H. inuenzae isolates to amoxycillin-clavulanic acid, ampicillin-sulbactam, cefuroxime, ceftriaxone, cefotaxime, meropenem, levooxacin, sulfamethoxazole-trimethoprim, azithromycin, and chloramphenicol were 26.4%, 21.8%, 24.8%, 1.7%, 1.0%, 0.2%, 0%, 47.7%, 10.2%, and 1.1%, respectively. MDR was present in 41 (6.4%) of the 642 H. inuenzae isolates, with the most prevalent MDR phenotype of ampicillin- sulfamethoxazole-trimethoprim-azithromycin resistance. Conclusions: H. inuenzae is a common cause of vulvovaginitis in prepubertal girls. Laboratories should ensure that they include media appropriate for the isolation of H. inuenzae. It’s worth noting of ampicillin resistance of H. inuenzae in clinical management. Background Vulvovaginitis is a common problem in prepubertal girls, which is most commonly attributed to poor hygiene or nonspecic irritants, but can occur as a part of bacterial infection[1]. Several studies have reported that Streptococcus pyogenes and Haemophilus inuenzae (H. inuenzae) are the most common bacterial causes of juvenile vulvovaginitis[1–4]. The association between H.inuenzae and prepubertal vulvovaginitis was rst highlighted by MacFarlane in 1987[5]. But Cox RA’s study in 1997 showed that H. inuenzaewas an underrated cause of vulvovaginitis in young girls[4]. However, until now, few studies have comprehensively explored the prevalence of H. inuenzae vulvovaginitis in prepubertal girls. Furthermore, published studies that included a large sample size are also scarce. Therefore, we described a four-year study, undertaken in the laboratory of a tertiary university hospital, to determine the prevalence of H. inuenzae vulvovaginitis in prepubertal girls and the antimicrobial resistance of H.inuenzae strains isolated from vulval specimens. Methods Page 2/16 Strain Collection and Identication This was a retrospective analysis of data from prepubertal girls who presented to the outpatient clinic of pediatric and adolescent gynecology at The Children’s Hospital, Zhejiang University School of Medicine between January 2016 and December 2019. Two vulval swabs were taken from each girl, one for microscopic examination and the other for cultivation. The nding of a large number of polymorphonuclear leukocytes on Gram-stained smears indicated the presence of inammatory reaction. The specimens were inoculated directly onto Columbia blood agar, Chocolate agar (Haemophilus and Gonorrhoeae selective chocolate agar), and Sabouraud’s agar plates in air or 5% CO2, as appropriate, at 35 °C for 24–48 h. Suspected pathogens on Haemophilus selective chocolate agar were identied by standard methods using Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS, Bruker). β -Lactamase Detection and Antimicrobial Susceptibility Test The antimicrobial susceptibility test by disk diffusion was performed and interpreted according to the Clinical Laboratory Standards Institute (CLSI) guidelines M100-S29with antibiotics ampicillin (10 µg), amoxycillin-clavulanic acid (20 µg/10 µg), ampicillin-sulbactam (10 µg/10 µg), cefuroxime (30 µg), ceftriaxone (30 µg), cefotaxime (30 µg), meropenem (10 µg), levooxacin (5 µg), sulfamethoxazole- trimethoprim (1.25/23.75 µg), azithromycin (15 µg), and chloramphenicol (30 µg) (Oxoid, UK). β- lactamase was measured using the cenase disc method (BioMérieux, France). H. inuenzae strain ATCC49247 was used for quality control throughout the test. Multi-Drug Resistance (MDR) was dened as resistant to three or more than three different types of antibiotics. Statistical Analysis Antibiotic resistant rates were analyzed with WHONET 5.6. Comparisons of antibiotic resistant rate between groups were performed with the X2 test. Age data, which were non-normally distributed, were described as medians (IQR). P values < 0.05 were considered statistically signicant. Results Sources of Isolates From January 2016 to December 2019 a total of 4142vulval swabs from children were received, increasing from 803 in 2016 to 1488 in 2019. In total, 649 swabs (15.7%) from 642 patients yielded H. inuenzae. Table 1 shows the yearly totals with an increase in numbers received but a decrease in proportion of positives for H. inuenzae. The monthly totals for positive isolates of H. inuenzae show some peaks and troughs throughout the year (Fig. 1). The numbers of isolates per month ranged from 2 in October 2017 to a maximum of 27 in July 2019. There were peaks of isolates from April to July seen in the vulval isolates. The age range of children carrying the H. inuenzae isolates was from 0.5y to 13y but 477 (75%) were between the ages of 3 and 7 years, with a median of 5y (IQR: 3)(Fig. 2). Page 3/16 Table 1 Yearly distribution of H. inuenzae strains isolated from vulval specimens, 2016–2019 Year Total received H. inuenzae positives N % 2016 803 149 18.6 2017 931 144 15.5 2018 920 155 16.8 2019 1488 194 13.0 Total 4142 642 15.5 β -Lactamase Detection and Antimicrobial Susceptibility Test In total, the ampicillin resistance rate was 39.1% (250/640); 33.2% strains (211/636) were for β- lactamase-positive isolates, 6.6% strains (42/635) were β-lactamase-negative and ampicillin-resistant (BLNAR) isolates. The resistance rates of the H. inuenzae isolates toamoxycillin-clavulanic acid, ampicillin-sulbactam, cefuroxime, ceftriaxone, cefotaxime, meropenem, levooxacin, sulfamethoxazole- trimethoprim, azithromycin, and chloramphenicol were 26.4%, 21.8%, 24.8%, 1.7%, 1.0%, 0.2%, 0%, 47.7%, 10.2%, and 1.1%, respectively (Table 2). In different years, the resistance rates of H. inuenzae strains to cefuroxime and azithromycin had a signicantly statistical difference (P < 0.05; Table 3). β-lactamase- positive H. inuenzae strains had signicantly higher resistance rates to ampicillin, amoxycillin-clavulanic acid, cefuroxime, sulfamethoxazole-trimethoprim, azithromycin, and chloramphenicol than β-lactamase- negative strains did (P < 0.01; Table 4). BLNAR H. inuenzae strains were all resistant to amoxycillin- clavulanic acid, ampicillin-sulbactam and cefuroxime while all susceptible to levooxacin, azithromycin and chloramphenicol (Table 5). Page 4/16 Table 2 Antibiotic resistances of H. inuenzae strains isolated from vulval specimens, 2016–2019 Antibiotic N %R %I %S β-lactamase 636 33.2 66.8 Ampicillin 640 39.1 6.6 54.4 Amoxycillin-clavulanic acid 349 26.4 0 73.6 Ampicillin-sulbactam 641 21.8 0 78.2 Cefuroxime 640 24.8 2.5 72.7 Ceftriaxone 350 1.7 0 98.3 Cefotaxime 288 1 0 99 Meropenem 632 0.2 0 99.8 Levooxacin 640 0 0 100 Sulfamethoxazole-trimethoprim 641 47.7 1.4 50.9 Azithromycin 469 10.2 0 89.8 Chloramphenicol 641 1.1 0 98.9 Note: S, susceptible; I, intermediate; R, resistant; * rate ofnon-susceptible. Page 5/16 Table 3 Antibiotic resistances of H. inuenzae strains isolated from vulval specimens in different years Antibiotic 2016 2017 2018 2019 N %R N %R N %R N %R β-lactamase 148 31.8 142 26.8 156 35.9 192 37 Ampicillin 148 33.1 145 37.2 155 41.9 194 42.8 Amoxycillin-clavulanic acid / / / / 154 23.4 194 28.9 Ampicillin-sulbactam 149 16.1 145 26.9 155 21.3 194 22.7 Cefuroxime# 149 17.4 145 26.2 154 23.4 194 30.4 Ceftriaxone / / / / 155 1.3 194 2.1 Cefotaxime 146 1.4 143 0.7 / / / / Meropenem 148 0 137 0.7 155 0 194 0 Levooxacin 148 0 145 0 155 0 194 0 Sulfamethoxazole-trimethoprim 149 49 145 45.5 155 47.7 194 48.5 Azithromycin# / / / / 155 7.1 191 14.7 Chloramphenicol 149 1.3 145 1.4 155 0 194 1.5 Note: R, resistant; * rate of non-susceptible. Page 6/16 Table 4 Comparison of antibiotic resistance between β-lactamase-positive and β-lactamase-negative H. inuenzae strains isolated from vulval specimens, 2016–2019 Antibiotic β-lactamase (+) β-lactamase (-) N %R %I %S N %R %I %S Ampicillin1 211 98.6 0.5 0.9 424 9.9 9.4 80.7 Amoxycillin-clavulanic acid1 126 38.9 0 61.1 222 18.9 0 81.1 Ampicillin-sulbactam2 212 26.9 0 73.1 424 19.6 0 80.4 Cefuroxime1 212 33 6.6 60.4 423 21 0.5 78.5 Ceftriaxone 127 3.1* 0 96.9 222 0.9* 0 99.1 Cefotaxime 83 1.2* 0 98.8 201 1* 0 99 Meropenem 210 0 0 100 417 0.2* 0 99.8 Levooxacin 211 0 0 100 424 0 0 100 Sulfamethoxazole-trimethoprim1 212 59.4 0.5 40.1 424 42 1.9 56.1 Azithromycin1 161 28* 0 72 307 1* 0 99 Chloramphenicol1 212 3.3 0 96.7 424 0 0 100 Note: S, susceptible; I, intermediate; R, resistant; * rate ofnon-susceptible; 1P<0.01; 2P<0.05.
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