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Multi-drug resistant Salmonella enterica serovar Typhi isolates with reduced susceptibility to ciprofloxacin in Kenya

Multi-drug resistant Salmonella enterica serovar Typhi isolates with reduced susceptibility to... Background: Typhoid fever remains a public health concern in developing countries especially among the poor who live in informal settlements devoid of proper sanitation and clean water supply. In addition antimicrobial resistance poses a major challenge in management of the disease. This study assessed the antimicrobial susceptibility patterns of Salmonella enterica serotype Typhi (S. Typhi) isolated from typhoid fever cases (2004–2007). Methods: A cross sectional study was conducted on 144 archived S. Typhi isolates (2004–2007) tested against 11 antimicrobial agents by quality controlled disk diffusion technique. Isolates resistant to ampicillin, chloramphenicol, and cotrimoxazole were considered Multidrug resistant (MDR). Thirty MDR isolates were selected randomly and further tested using minimum inhibitory concentration (MIC) E-test. Results: Sixteen percent (23/144) of the isolates were susceptible to all the antibiotics tested while 68% were resistant to three or more of the 11 antibiotics tested. The isolates showed a high susceptibility to ceftriaxone (94%) and gentamicin (97%). A high percentage of resistance was observed for the conventional first-line antibiotics; ampicillin (72%), chloramphenicol (72%), and cotrimoxazole (70%). Sixty-nine percent of the isolates (100/144) showed reduced susceptibility to ciprofloxacin. All the 30 (100%) isolates selected for MIC test were susceptible to amoxicillin-clavulanic acid. All except one of the 30 isolates were susceptible to ceftriaxone while majority 21 (70%) recorded an intermediate susceptibility to ciprofloxacin with MIC of 0.12–0.5 μg/mL. Conclusion: A large proportion of S. Typhi isolates were MDR and also showed reduced susceptibility to ciprofloxacin. Fluoroquinolone resistance is emerging and this may pose a challenge in treatment of typhoid in future. There is need for routine surveillance to monitor this phenotype in clinical settings. Keywords: Multi drug resistance in Kenya, Salmonella enterica serotype Typhi, Ciprofloxacin Introduction countries like Egypt report low incidence rate (13/ Typhoid fever posses a public health threat, recording 100,000–59/100,000 persons annually) [4–6]while others high morbidity and mortality rates mainly in developing like Kenya have reported high adjusted incidence rate of countries [1, 2]. Current published data on typhoid fever up to 247 cases per 100,000 persons in an informal settle- shows an annual global estimate of 20·6 million cases ment [7]. These figures may, however, be overestimated and 223 000 deaths. In sub-Saharan Africa, the incidence based on the controlled risk factors. The ongoing of typhoid fever is greater than 100 per 100,000 persons ‘Typhoid Fever Surveillance in Africa’ study may probably per year resulting in 33, 490 deaths accounting for 26% of give the accurate estimate [8]. global typhoid deaths in Africa [3]. Incidence may vary The high incidence rates of typhoid fever have been from one country to another due to dynamics in risk exacerbated by the emergence of S. Typhi strains resist- factor exposure levels attributed to the disease; some ant to antibiotics recommended for treatment. Centers for Disease Control and Prevention (CDC) ranks anti- biotic resistant S. Typhi as a serious threat that requires * Correspondence: winny@uonbi.ac.ke frequent monitoring and prevention to reduce the spread Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mutai et al. BMC Microbiology (2018) 18:187 Page 2 of 5 of the resistant strains [9]. In the past, first line antibiotics guidelines [14]. Escherichia coli ATCC 25922 was used for the treatment of typhoid included chloramphenicol, as the control strain. ampicillin, and trimethoprim-sulphamethoxazole. However, Multidrug resistant (MDR) S. Typhi, defined as strains re- Case definition sistant to these first-line antibiotics emerged in the MDR strains were defined as isolates resistant to late 1980s [10, 11]. This resulted in the use of fluoro- ampicillin, chloramphenicol, and cotrimoxazole. quinolones and third generation cephalosporins as al- ternatives for treatment of MDR S. Typhi cases. Determination of minimum inhibitory concentrations Increased use of fluoroquinolones such as ciprofloxa- Thirty S. Typhi isolates that were resistant to ciprofloxacin, cin for treatment has resulted in the emergence of ceftriaxone, cefotaxime, amoxicillin-clavulanic acid, nali- strains resistant or with reduced susceptibility to this dixic acid and chloramphenicol by disc diffusion technique particular antibiotic [12]. Other than the use of these were randomly selected from the 98 MDR isolates for MIC antibiotics in the treatment of human cases, there have determination. The MICs of the antibiotics were deter- been many reports on the use of antibiotics in treatment mined by E-test guided by the manufacturer’s instructions of animal disease and as growth promoters in food derived (AB Biodisk, Solna, Sweden). The cutoff MIC provided by from animals which similarly contribute to the occurrence CLSI guidelines were used to interpret the results. Escheri- and spread of antibiotic resistant bacteria [13]. chia coli ATCC 25922 was used to control for growth of Based on the current revised Clinical and Laboratory test strains and potency of the E-test strips [14]. Standards Institute (CLSI) guidelines it is important to have a clear picture of the situation regarding resistance, especially to ciprofloxacin. This study aimed at deter- Data analysis mining the antimicrobial susceptibility patterns of ar- Data generated from this study was entered on MS excel chived isolates of S. Typhi isolated from blood samples. and analyzed using SPSS version 22. The zone of inhibition by disc diffusion was measured in millimeters and interpreted as susceptible, intermediate or resistant Material and methods based on the CLSI standards. The MIC results of E-test Study design were also categorized as susceptible, intermediate or This was a cross sectional study where 144 S. Typhi resistant. Frequency of multidrug resistance isolates was archived isolates collected between 2004 and 2007 were categorized by year of isolation and phenotypes. analysed. Results Bacterial isolation Antibiotic susceptibility profile The isolates were obtained from blood samples of patients A total of 144 archived and confirmed S. Typhi presenting with typhoid fever at Aga Khan University isolates were analysed, 115 were obtained from Aga Hospital, Nairobi (AKUH) and Kenyatta National Hospital Khan University Hospital and 29 from Kenyatta (KNH), both located in Nairobi, Kenya. The archived National Hospital. Twenty three isolates were fully isolates were randomly selected and subcultured on susceptible to all the antibiotics tested. Most of the MacConkey agar to check for purity. Confirmed S.Typhi isolates tested recorded a high susceptibility to ceftri- isolates were stored at − 70 °C on freezing media until axone (94%), gentamicin (97%), cefotaxime (83%) and analyzed. The study was approved by KEMRI Scientific amoxicillin-clavulanic acid (81%). A high resistant rate Steering Committee (SSC No. 1320). was observed among the first-line antibiotics, ampicillin (72%), chloramphenicol (72%) and cotrimoxazole (70%). Antibiotic susceptibility testing Sixty-nine percent of the isolates showed an intermediate Discrete S. Typhi isolates were tested for susceptibility susceptibility to ciprofloxacin while 6% were fully resist- to various antimicrobials agents by quality controlled ant. Antibiotic susceptibility test for the 144 isolates is disk diffusion technique based on the CLSI guidelines summarized in Table 1. [14]. The antibiotics (Oxoid Ltd., Basingstoke, United Kingdom) screened included; ampicillin (10 μg), amoxicillin-clavulanic acid (30 μg), cefuroxime (30 μg), Multi- drug resistant S. Typhi ceftriaxone (30 μg), cefotaxime (30 μg) ciprofloxacin Ninety eight (68%) of the isolates were MDR. The (5 μg), nalidixic acid (10 μg), tetracycline (30 μg), chlor- highest MDR phenotype observed were those resistant amphenicol (30 μg), cotrimoxazole (25 μg) and gentami- to four drugs (98.6%). The frequency of MDR isolates cin (10 μg). The results were interpreted as sensitive, seemed to be reducing from 2004 to 2007 and this was intermediate or resistant in accordance with CLSI reflected in both hospitals as shown in Table 2. Mutai et al. BMC Microbiology (2018) 18:187 Page 3 of 5 Table 1 Antibiotic susceptibility patterns among the 144 Table 3 Minimum inhibitory concentrations to antimicrobials S. Typhi isolates Antibiotic Susceptible Intermediate Resistant (%) (%) (%) Drug Susceptible Intermediate Resistant Cefotaxime 23 (77) 2 (6) 5 (17) Number (%) Number (%) Number (%) Chloramphenicol 16 (53) – 14 (47) Amoxycillin-clavulanic acid 117 (81) 8 (6) 19 (13) Ciprofloxacin 5 (17) 21 (70) 4 (13) Ampicillin 34 (24) 6 (4) 104 (72) Ceftriaxone 29 (97) 1 (3) 0 (0) Cefotaxine 120 (83) 16 (11) 8 (6) Nalidixic acid 24 (80) – 6 (20) Ceftriaxone 136 (94) 3 (2) 5 (4) Amoxycillin-clavulanic acid 30 (100) 0 (0) 0 (0) Chloramphenicol 39 (27) 1 (1) 104 (72) Cefuroxime 98 (68) 38 (27) 8 (6) Discussion Ciprofloxacin 35 (24) 100 (69) 9 (6) Following the analysis of the trends in susceptibility Gentamicin 140 (97) 0 (0) 4 (3) pattern of S. Typhi, the results from this study showed Nalidixic acid 102 (71) 32 (22) 10 (7) that only a small percentage (16%) of the isolates were Tetracycline 37 (26) 2 (1) 105 (73) susceptible to all the eleven drugs tested while 96% were Cotrimoxazole 41 (29) 2 (1) 101 (70) resistant to one or more of the eleven antibiotics tested. Over the years prevalence of MDR S. Typhi has been on Minimum inhibitory concentration the increase in Kenya since it was first reported in All the 30 (100%) isolates selected for MIC test were 1997–1999 where then the prevalence of MDR pheno- susceptible to amoxycillin-clavulanic acid. About 97% type was estimated at 50 to 65% [15]. The prevalence were susceptible to ceftriaxone. Five isolates were resistant has since then been on the increase based on the previ- to cefotaxime (17%) and fourteen (47%) were resistant to ous studies that have been conducted. In 2001–2002 a chloramphenicol. Of the nine isolates that were resistant prevalence of 70 to 78% of MDR S. Typhi was reported to ciprofloxacin by disc diffusion only four exhibited [16] and in 2010 Mengo and colleagues recorded a complete resistance to ciprofloxacin (13%) with a MIC prevalence of 70% [17]. These figures are consistent with ≥1 μg/mL. The majority (70%) of the isolates tested what was reported in this study where 68% of the recorded intermediate susceptibility with MIC of 0.12– isolates were MDR (Table 2). This is however in contrast 0.5 μg/mL. In addition from the 10 isolates resistant to to a study from a tertiary Care Hospital in Coastal nalidixic acid by disc diffusion, resistance was observed in Karnataka, India, that reported an MDR proportion of six isolates (MIC ≥32 μg/mL) while 24 of the isolates 1.94% of S. Typhi isolates from blood samples [18] while tested were fully susceptible (MIC < 16 μg/mL) (Table 3). other studies in Nepal have recorded no MDR strains [19]. Over the counter prescription, self-medication and unrestricted use of these drugs may have driven the Table 2 Distribution of MDR S. Typhi consistent increase in the prevalence of MDR strains Parameter Aga-Khan University Kenyatta National Total no. of [20]. The use of antibiotics such as tetracyclines, sulfon- Hospital N = 115 (%) Hospital N = 29 (%) MDR isolates amides and trimethroprime, nitrofurans, aminoglyco- No. of MDR 75 (65%) 23 (79%) 98 (68%) sides, β-lactams, and quinolones by farmers as growth S. Typhi promoters for livestock production could also be predis- Year of isolation posing individuals to resistant pathogens [13, 20]. 2004 (n = 59) 31 (53%) 17 (29%) 48 (81%) In our study a high proportion of the isolates were 2005 (n = 47) 25 (53%) 4 (9%) 29 (62%) resistant to the conventional first line antibiotics (ampicillin (72%) cotrimoxazole (70%) and chloram- 2006 (n = 37) 19 (51%) 2 (5%) 21 (56%) phenicol (72%). Previously, Mengo et al. also recorded 2007 (n = 1) 0 (0%) 0 (0%) 0 (0%) high resistance to ampicillin (75%) cotrimoxazole No. of resistant antibiotics (73%) and chloramphenicol (74%) in Kenya [17]. 3(n = 8) 3 (37.5%) 0 (0%) 3 (37.5%) Contrary to the current research on antibiogram of S. 4(n = 69) 58 (84%) 10 (14.5%) 68 (98.6%) Typhi, the bacterium is showing full sensitivity to 5(n = 22) 10 (45.5%) 10 (45.5%) 20 (91%) these antibiotics since they had not been used for a long time to treatment typhoid fever [21]. A study in 6(n = 4) 3 (75%) 1 (25%) 4 (100%) Nepal reported an increased susceptibility rate of 7(n = 2) 0 (0%) 1 (50%) 1 (50%) chloramphenicol, co-trimoxazole, and ampicillin as 9(n = 1) 1 (100%) 0 (0%) 1 (100%) 98.8, 98.8, and 97.6% respectively [22]. These rates 11 (n = 1) 0 (0%) 1 (100%) 1 (100%) are quite high and show promising reemergence of Mutai et al. BMC Microbiology (2018) 18:187 Page 4 of 5 strains susceptible to these drugs that can then be lately shown increased susceptibility. In addition, there is reconsidered for the treatment of typhoid fever. an emergence of strains resistant and with intermediate Ciprofloxacin has been used as an alternative anti- susceptibility to ciprofloxacin. Therefore the use of cip- biotic in the treatment of MDR cases. However, with the rofloxacin for treatment of typhoid fever needs routine currently reviewed breakpoints of ciprofloxacin by CLSI, surveillance to prevent further spread of these strains. there has been a rather increase of isolates resistant or Abbreviations recording reduced sensitivity to this antibiotic. In this AKUH: Aga Khan University Hospital; ATCC: American type culture collection; study, MIC results of ciprofloxacin showed that 13% of CDC: Centre for disease control and prevention; CLSI: Clinical and laboratory standards institute; ESBL: Extended-spectrum β-lactamase resistance; the isolates were resistant. Reduced susceptibility to cip- KEMRI: Kenya medical research institute; KNH: Kenyatta National Hospital; rofloxacin, poses a serious threat to the treatment failure MDR: Multidrug resistant; MDRST: Multidrug resistant S.Typhi; MIC: Minimum of typhoid fever, especially in developing countries. inhibitory concentrations; NTPFS: National Typhoid and Paratyphoid Fever Surveillance System; WHO: World Health Organization Similar findings have been reported in other African countries. In Malawi 100% of all the isolates tested were Acknowledgements MDR and 10% were resistant to nalidixic acid. In the We would like to express our special gratitude to the entire Centre for Microbiology Research (CMR) laboratory staff at KEMRI for their technical Democratic Republic of Congo 30% were MDR of which support. We would also like to thank Dr. John Kiiru for assisting with the 15% showed nalidixic acid resistance and decreased sus- laboratory analysis of the samples and Dr. David Mutonga for data analysis. ceptibility to ciprofloxacin [23, 24]. Based on a National The director of CMR, Dr. Samuel Kariuki for laboratory support and for providing isolates to use in this study. Typhoid and Paratyphoid Fever Surveillance System (NTPFS) in the US among travelers 69% showed re- Funding duced susceptibility to nalidixic acid of which 99% of No funding was received. these were either resistant to ciprofloxacin or showed re- Availability of data and materials duced susceptibility [25]. One study in India recorded a The de-identified datasets analysed during the current study are available 98% of resistance to nalidixic acid among S. Typhi iso- from the corresponding author on reasonable request. lates from blood cultures [26] this same study reported Authors’ contributions an increase in susceptibility of the isolates to ampicillin WM, AM, PW and SK were involved in designing the study and laboratory and cotrimoxazole during the study period (2008–2013). analysis of the research. WM performed the laboratory test, analyzed the Recommendation to use fluoroquinolones for empirical data and drafted the manuscript. All authors read through and approved the manuscript. treatment in place of first line antibiotics may have con- tributed largely to the emergence of fluoroquinolones Ethics approval and consent to participate resistance. This study was approved by Kenya Medical Research Institute (KEMRI) Scientific Steering Committee and assigned SSC No. 1320. Since we used This study documented 94% of sensitivity to ceftriax- archived isolates to carry out the study we therefore did not have to seek one, this antibiotic may, therefore, be used as an alterna- consent from the participants. tive in the treatment of typhoid fever considering its low Consent for publication resistance proportions. Studies in Germany, India, and Not applicable. Nigeria [27–29] have however detected the presence of CTM-X gene group of extended-spectrum β-lactamase Competing interests The authors declare that they have no competing interests. resistance (ESBL) that confers resistance to ceftriaxone. With recent reports from different countries reporting Publisher’sNote resistance to ceftriaxone, routine screening of such iso- Springer Nature remains neutral with regard to jurisdictional claims in lates is important. published maps and institutional affiliations. Author details Limitations of the study Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya. We did not determine the MIC of all MDR isolates and School of Biological Sciences, Jomo Kenyatta University of Agriculture and the antibiotics tested and further detect the mutations Technology, Juja, Kenya. Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya. associated with ciprofloxacin and nalidixic acid resistance that confer fluoroquinolones resistance. Received: 5 December 2017 Accepted: 30 October 2018 Conclusion References Results from this study indicate that there is a significant 1. Buckle GC, Walker CLF, Black RE. Typhoid fever and paratyphoid fever: variation in resistance pattern among S. 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Multi-drug resistant Salmonella enterica serovar Typhi isolates with reduced susceptibility to ciprofloxacin in Kenya

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Life Sciences; Microbiology; Biological Microscopy; Mycology; Parasitology; Virology; Life Sciences, general
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Abstract

Background: Typhoid fever remains a public health concern in developing countries especially among the poor who live in informal settlements devoid of proper sanitation and clean water supply. In addition antimicrobial resistance poses a major challenge in management of the disease. This study assessed the antimicrobial susceptibility patterns of Salmonella enterica serotype Typhi (S. Typhi) isolated from typhoid fever cases (2004–2007). Methods: A cross sectional study was conducted on 144 archived S. Typhi isolates (2004–2007) tested against 11 antimicrobial agents by quality controlled disk diffusion technique. Isolates resistant to ampicillin, chloramphenicol, and cotrimoxazole were considered Multidrug resistant (MDR). Thirty MDR isolates were selected randomly and further tested using minimum inhibitory concentration (MIC) E-test. Results: Sixteen percent (23/144) of the isolates were susceptible to all the antibiotics tested while 68% were resistant to three or more of the 11 antibiotics tested. The isolates showed a high susceptibility to ceftriaxone (94%) and gentamicin (97%). A high percentage of resistance was observed for the conventional first-line antibiotics; ampicillin (72%), chloramphenicol (72%), and cotrimoxazole (70%). Sixty-nine percent of the isolates (100/144) showed reduced susceptibility to ciprofloxacin. All the 30 (100%) isolates selected for MIC test were susceptible to amoxicillin-clavulanic acid. All except one of the 30 isolates were susceptible to ceftriaxone while majority 21 (70%) recorded an intermediate susceptibility to ciprofloxacin with MIC of 0.12–0.5 μg/mL. Conclusion: A large proportion of S. Typhi isolates were MDR and also showed reduced susceptibility to ciprofloxacin. Fluoroquinolone resistance is emerging and this may pose a challenge in treatment of typhoid in future. There is need for routine surveillance to monitor this phenotype in clinical settings. Keywords: Multi drug resistance in Kenya, Salmonella enterica serotype Typhi, Ciprofloxacin Introduction countries like Egypt report low incidence rate (13/ Typhoid fever posses a public health threat, recording 100,000–59/100,000 persons annually) [4–6]while others high morbidity and mortality rates mainly in developing like Kenya have reported high adjusted incidence rate of countries [1, 2]. Current published data on typhoid fever up to 247 cases per 100,000 persons in an informal settle- shows an annual global estimate of 20·6 million cases ment [7]. These figures may, however, be overestimated and 223 000 deaths. In sub-Saharan Africa, the incidence based on the controlled risk factors. The ongoing of typhoid fever is greater than 100 per 100,000 persons ‘Typhoid Fever Surveillance in Africa’ study may probably per year resulting in 33, 490 deaths accounting for 26% of give the accurate estimate [8]. global typhoid deaths in Africa [3]. Incidence may vary The high incidence rates of typhoid fever have been from one country to another due to dynamics in risk exacerbated by the emergence of S. Typhi strains resist- factor exposure levels attributed to the disease; some ant to antibiotics recommended for treatment. Centers for Disease Control and Prevention (CDC) ranks anti- biotic resistant S. Typhi as a serious threat that requires * Correspondence: winny@uonbi.ac.ke frequent monitoring and prevention to reduce the spread Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mutai et al. BMC Microbiology (2018) 18:187 Page 2 of 5 of the resistant strains [9]. In the past, first line antibiotics guidelines [14]. Escherichia coli ATCC 25922 was used for the treatment of typhoid included chloramphenicol, as the control strain. ampicillin, and trimethoprim-sulphamethoxazole. However, Multidrug resistant (MDR) S. Typhi, defined as strains re- Case definition sistant to these first-line antibiotics emerged in the MDR strains were defined as isolates resistant to late 1980s [10, 11]. This resulted in the use of fluoro- ampicillin, chloramphenicol, and cotrimoxazole. quinolones and third generation cephalosporins as al- ternatives for treatment of MDR S. Typhi cases. Determination of minimum inhibitory concentrations Increased use of fluoroquinolones such as ciprofloxa- Thirty S. Typhi isolates that were resistant to ciprofloxacin, cin for treatment has resulted in the emergence of ceftriaxone, cefotaxime, amoxicillin-clavulanic acid, nali- strains resistant or with reduced susceptibility to this dixic acid and chloramphenicol by disc diffusion technique particular antibiotic [12]. Other than the use of these were randomly selected from the 98 MDR isolates for MIC antibiotics in the treatment of human cases, there have determination. The MICs of the antibiotics were deter- been many reports on the use of antibiotics in treatment mined by E-test guided by the manufacturer’s instructions of animal disease and as growth promoters in food derived (AB Biodisk, Solna, Sweden). The cutoff MIC provided by from animals which similarly contribute to the occurrence CLSI guidelines were used to interpret the results. Escheri- and spread of antibiotic resistant bacteria [13]. chia coli ATCC 25922 was used to control for growth of Based on the current revised Clinical and Laboratory test strains and potency of the E-test strips [14]. Standards Institute (CLSI) guidelines it is important to have a clear picture of the situation regarding resistance, especially to ciprofloxacin. This study aimed at deter- Data analysis mining the antimicrobial susceptibility patterns of ar- Data generated from this study was entered on MS excel chived isolates of S. Typhi isolated from blood samples. and analyzed using SPSS version 22. The zone of inhibition by disc diffusion was measured in millimeters and interpreted as susceptible, intermediate or resistant Material and methods based on the CLSI standards. The MIC results of E-test Study design were also categorized as susceptible, intermediate or This was a cross sectional study where 144 S. Typhi resistant. Frequency of multidrug resistance isolates was archived isolates collected between 2004 and 2007 were categorized by year of isolation and phenotypes. analysed. Results Bacterial isolation Antibiotic susceptibility profile The isolates were obtained from blood samples of patients A total of 144 archived and confirmed S. Typhi presenting with typhoid fever at Aga Khan University isolates were analysed, 115 were obtained from Aga Hospital, Nairobi (AKUH) and Kenyatta National Hospital Khan University Hospital and 29 from Kenyatta (KNH), both located in Nairobi, Kenya. The archived National Hospital. Twenty three isolates were fully isolates were randomly selected and subcultured on susceptible to all the antibiotics tested. Most of the MacConkey agar to check for purity. Confirmed S.Typhi isolates tested recorded a high susceptibility to ceftri- isolates were stored at − 70 °C on freezing media until axone (94%), gentamicin (97%), cefotaxime (83%) and analyzed. The study was approved by KEMRI Scientific amoxicillin-clavulanic acid (81%). A high resistant rate Steering Committee (SSC No. 1320). was observed among the first-line antibiotics, ampicillin (72%), chloramphenicol (72%) and cotrimoxazole (70%). Antibiotic susceptibility testing Sixty-nine percent of the isolates showed an intermediate Discrete S. Typhi isolates were tested for susceptibility susceptibility to ciprofloxacin while 6% were fully resist- to various antimicrobials agents by quality controlled ant. Antibiotic susceptibility test for the 144 isolates is disk diffusion technique based on the CLSI guidelines summarized in Table 1. [14]. The antibiotics (Oxoid Ltd., Basingstoke, United Kingdom) screened included; ampicillin (10 μg), amoxicillin-clavulanic acid (30 μg), cefuroxime (30 μg), Multi- drug resistant S. Typhi ceftriaxone (30 μg), cefotaxime (30 μg) ciprofloxacin Ninety eight (68%) of the isolates were MDR. The (5 μg), nalidixic acid (10 μg), tetracycline (30 μg), chlor- highest MDR phenotype observed were those resistant amphenicol (30 μg), cotrimoxazole (25 μg) and gentami- to four drugs (98.6%). The frequency of MDR isolates cin (10 μg). The results were interpreted as sensitive, seemed to be reducing from 2004 to 2007 and this was intermediate or resistant in accordance with CLSI reflected in both hospitals as shown in Table 2. Mutai et al. BMC Microbiology (2018) 18:187 Page 3 of 5 Table 1 Antibiotic susceptibility patterns among the 144 Table 3 Minimum inhibitory concentrations to antimicrobials S. Typhi isolates Antibiotic Susceptible Intermediate Resistant (%) (%) (%) Drug Susceptible Intermediate Resistant Cefotaxime 23 (77) 2 (6) 5 (17) Number (%) Number (%) Number (%) Chloramphenicol 16 (53) – 14 (47) Amoxycillin-clavulanic acid 117 (81) 8 (6) 19 (13) Ciprofloxacin 5 (17) 21 (70) 4 (13) Ampicillin 34 (24) 6 (4) 104 (72) Ceftriaxone 29 (97) 1 (3) 0 (0) Cefotaxine 120 (83) 16 (11) 8 (6) Nalidixic acid 24 (80) – 6 (20) Ceftriaxone 136 (94) 3 (2) 5 (4) Amoxycillin-clavulanic acid 30 (100) 0 (0) 0 (0) Chloramphenicol 39 (27) 1 (1) 104 (72) Cefuroxime 98 (68) 38 (27) 8 (6) Discussion Ciprofloxacin 35 (24) 100 (69) 9 (6) Following the analysis of the trends in susceptibility Gentamicin 140 (97) 0 (0) 4 (3) pattern of S. Typhi, the results from this study showed Nalidixic acid 102 (71) 32 (22) 10 (7) that only a small percentage (16%) of the isolates were Tetracycline 37 (26) 2 (1) 105 (73) susceptible to all the eleven drugs tested while 96% were Cotrimoxazole 41 (29) 2 (1) 101 (70) resistant to one or more of the eleven antibiotics tested. Over the years prevalence of MDR S. Typhi has been on Minimum inhibitory concentration the increase in Kenya since it was first reported in All the 30 (100%) isolates selected for MIC test were 1997–1999 where then the prevalence of MDR pheno- susceptible to amoxycillin-clavulanic acid. About 97% type was estimated at 50 to 65% [15]. The prevalence were susceptible to ceftriaxone. Five isolates were resistant has since then been on the increase based on the previ- to cefotaxime (17%) and fourteen (47%) were resistant to ous studies that have been conducted. In 2001–2002 a chloramphenicol. Of the nine isolates that were resistant prevalence of 70 to 78% of MDR S. Typhi was reported to ciprofloxacin by disc diffusion only four exhibited [16] and in 2010 Mengo and colleagues recorded a complete resistance to ciprofloxacin (13%) with a MIC prevalence of 70% [17]. These figures are consistent with ≥1 μg/mL. The majority (70%) of the isolates tested what was reported in this study where 68% of the recorded intermediate susceptibility with MIC of 0.12– isolates were MDR (Table 2). This is however in contrast 0.5 μg/mL. In addition from the 10 isolates resistant to to a study from a tertiary Care Hospital in Coastal nalidixic acid by disc diffusion, resistance was observed in Karnataka, India, that reported an MDR proportion of six isolates (MIC ≥32 μg/mL) while 24 of the isolates 1.94% of S. Typhi isolates from blood samples [18] while tested were fully susceptible (MIC < 16 μg/mL) (Table 3). other studies in Nepal have recorded no MDR strains [19]. Over the counter prescription, self-medication and unrestricted use of these drugs may have driven the Table 2 Distribution of MDR S. Typhi consistent increase in the prevalence of MDR strains Parameter Aga-Khan University Kenyatta National Total no. of [20]. The use of antibiotics such as tetracyclines, sulfon- Hospital N = 115 (%) Hospital N = 29 (%) MDR isolates amides and trimethroprime, nitrofurans, aminoglyco- No. of MDR 75 (65%) 23 (79%) 98 (68%) sides, β-lactams, and quinolones by farmers as growth S. Typhi promoters for livestock production could also be predis- Year of isolation posing individuals to resistant pathogens [13, 20]. 2004 (n = 59) 31 (53%) 17 (29%) 48 (81%) In our study a high proportion of the isolates were 2005 (n = 47) 25 (53%) 4 (9%) 29 (62%) resistant to the conventional first line antibiotics (ampicillin (72%) cotrimoxazole (70%) and chloram- 2006 (n = 37) 19 (51%) 2 (5%) 21 (56%) phenicol (72%). Previously, Mengo et al. also recorded 2007 (n = 1) 0 (0%) 0 (0%) 0 (0%) high resistance to ampicillin (75%) cotrimoxazole No. of resistant antibiotics (73%) and chloramphenicol (74%) in Kenya [17]. 3(n = 8) 3 (37.5%) 0 (0%) 3 (37.5%) Contrary to the current research on antibiogram of S. 4(n = 69) 58 (84%) 10 (14.5%) 68 (98.6%) Typhi, the bacterium is showing full sensitivity to 5(n = 22) 10 (45.5%) 10 (45.5%) 20 (91%) these antibiotics since they had not been used for a long time to treatment typhoid fever [21]. A study in 6(n = 4) 3 (75%) 1 (25%) 4 (100%) Nepal reported an increased susceptibility rate of 7(n = 2) 0 (0%) 1 (50%) 1 (50%) chloramphenicol, co-trimoxazole, and ampicillin as 9(n = 1) 1 (100%) 0 (0%) 1 (100%) 98.8, 98.8, and 97.6% respectively [22]. These rates 11 (n = 1) 0 (0%) 1 (100%) 1 (100%) are quite high and show promising reemergence of Mutai et al. BMC Microbiology (2018) 18:187 Page 4 of 5 strains susceptible to these drugs that can then be lately shown increased susceptibility. In addition, there is reconsidered for the treatment of typhoid fever. an emergence of strains resistant and with intermediate Ciprofloxacin has been used as an alternative anti- susceptibility to ciprofloxacin. Therefore the use of cip- biotic in the treatment of MDR cases. However, with the rofloxacin for treatment of typhoid fever needs routine currently reviewed breakpoints of ciprofloxacin by CLSI, surveillance to prevent further spread of these strains. there has been a rather increase of isolates resistant or Abbreviations recording reduced sensitivity to this antibiotic. In this AKUH: Aga Khan University Hospital; ATCC: American type culture collection; study, MIC results of ciprofloxacin showed that 13% of CDC: Centre for disease control and prevention; CLSI: Clinical and laboratory standards institute; ESBL: Extended-spectrum β-lactamase resistance; the isolates were resistant. Reduced susceptibility to cip- KEMRI: Kenya medical research institute; KNH: Kenyatta National Hospital; rofloxacin, poses a serious threat to the treatment failure MDR: Multidrug resistant; MDRST: Multidrug resistant S.Typhi; MIC: Minimum of typhoid fever, especially in developing countries. inhibitory concentrations; NTPFS: National Typhoid and Paratyphoid Fever Surveillance System; WHO: World Health Organization Similar findings have been reported in other African countries. In Malawi 100% of all the isolates tested were Acknowledgements MDR and 10% were resistant to nalidixic acid. In the We would like to express our special gratitude to the entire Centre for Microbiology Research (CMR) laboratory staff at KEMRI for their technical Democratic Republic of Congo 30% were MDR of which support. We would also like to thank Dr. John Kiiru for assisting with the 15% showed nalidixic acid resistance and decreased sus- laboratory analysis of the samples and Dr. David Mutonga for data analysis. ceptibility to ciprofloxacin [23, 24]. Based on a National The director of CMR, Dr. Samuel Kariuki for laboratory support and for providing isolates to use in this study. Typhoid and Paratyphoid Fever Surveillance System (NTPFS) in the US among travelers 69% showed re- Funding duced susceptibility to nalidixic acid of which 99% of No funding was received. these were either resistant to ciprofloxacin or showed re- Availability of data and materials duced susceptibility [25]. One study in India recorded a The de-identified datasets analysed during the current study are available 98% of resistance to nalidixic acid among S. Typhi iso- from the corresponding author on reasonable request. lates from blood cultures [26] this same study reported Authors’ contributions an increase in susceptibility of the isolates to ampicillin WM, AM, PW and SK were involved in designing the study and laboratory and cotrimoxazole during the study period (2008–2013). analysis of the research. WM performed the laboratory test, analyzed the Recommendation to use fluoroquinolones for empirical data and drafted the manuscript. All authors read through and approved the manuscript. treatment in place of first line antibiotics may have con- tributed largely to the emergence of fluoroquinolones Ethics approval and consent to participate resistance. This study was approved by Kenya Medical Research Institute (KEMRI) Scientific Steering Committee and assigned SSC No. 1320. Since we used This study documented 94% of sensitivity to ceftriax- archived isolates to carry out the study we therefore did not have to seek one, this antibiotic may, therefore, be used as an alterna- consent from the participants. tive in the treatment of typhoid fever considering its low Consent for publication resistance proportions. Studies in Germany, India, and Not applicable. Nigeria [27–29] have however detected the presence of CTM-X gene group of extended-spectrum β-lactamase Competing interests The authors declare that they have no competing interests. resistance (ESBL) that confers resistance to ceftriaxone. With recent reports from different countries reporting Publisher’sNote resistance to ceftriaxone, routine screening of such iso- Springer Nature remains neutral with regard to jurisdictional claims in lates is important. published maps and institutional affiliations. Author details Limitations of the study Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya. We did not determine the MIC of all MDR isolates and School of Biological Sciences, Jomo Kenyatta University of Agriculture and the antibiotics tested and further detect the mutations Technology, Juja, Kenya. Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya. associated with ciprofloxacin and nalidixic acid resistance that confer fluoroquinolones resistance. Received: 5 December 2017 Accepted: 30 October 2018 Conclusion References Results from this study indicate that there is a significant 1. Buckle GC, Walker CLF, Black RE. Typhoid fever and paratyphoid fever: variation in resistance pattern among S. 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