|Year : 2018 | Volume
| Issue : 1 | Page : 70-76
Changing trends of culture-positive typhoid fever and antimicrobial susceptibility in a tertiary care North Indian Hospital over the last decade
Priyanka Sharma1, Sushila Dahiya1, Neelam Manral2, Bhavana Kumari1, Sambuddha Kumar3, Sangeeta Pandey1, Seema Sood1, Bimal Kumar Das1, Arti Kapil1
1 Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India
3 Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||2-May-2018|
Dr. Arti Kapil
Department of Microbiology, All India Institute of Medical Sciences, Room No. 2061, New Delhi
Source of Support: None, Conflict of Interest: None
Purpose: The present study was undertaken to analyse the trend in prevalence of culture-positive typhoid fever during the last decade and to determine antimicrobial susceptibility profile of Salmonella Typhi and Salmonella Paratyphi A isolated from patients of enteric fever presenting to our hospital. Methods: All the culture-positive enteric fever cases during 2005–2016 presenting to our Hospital were included in the study. Antimicrobial susceptibility was done against chloramphenicol, amoxicillin, co-trimoxazole, ciprofloxacin, ofloxacin, levofloxacin, pefloxacin, ceftriaxone and azithromycin as per corresponding CLSI guidelines for each year. We also analysed the proportion of culture positivity during 1993–2016 in light of the antibiotic consumption data from published literature. Results: A total of 1066 strains-S. Typhi (772) and S. Paratyphi A (294) were isolated from the blood cultures during the study. A maximum number of cases were found in July–September. Antimicrobial susceptibility for chloramphenicol, amoxicillin and co-trimoxazole was found to be 87.9%, 75.5%, 87.3% for S. Typhi and 94.2%, 90.1% and 94.2% for S. Paratyphi A, respectively. Ciprofloxacin, ofloxacin and levofloxacin susceptibility were 71.3%, 70.8% and 70.9% for S. Typhi and 58.1%, 57.4% and 57.1% for S. Paratyphi A, respectively. Azithromycin susceptibility was 98.9% in S. Typhi. Although susceptibility to ceftriaxone and cefixime was 100% in our isolates, there is a continuous increase in ceftriaxone minimum inhibitory concentration (MIC)50and MIC90values over the time. The proportion of blood culture-positive cases during 1993–2016 ranged from a minimum of 0.0006 in 2014 to a maximum of 0.0087 in 1999. Conclusion: We found that the most common etiological agent of enteric fever is S. Typhi causing the majority of cases from July to October in our region. MIC to ceftriaxone in typhoidal salmonellae is creeping towards resistance and more data are needed to understand the azithromycin susceptibility.
Keywords: Antimicrobial resistance, enteric fever, Salmonella Paratyphi A, Salmonella Typhi, typhoid fever
|How to cite this article:|
Sharma P, Dahiya S, Manral N, Kumari B, Kumar S, Pandey S, Sood S, Das BK, Kapil A. Changing trends of culture-positive typhoid fever and antimicrobial susceptibility in a tertiary care North Indian Hospital over the last decade. Indian J Med Microbiol 2018;36:70-6
|How to cite this URL:|
Sharma P, Dahiya S, Manral N, Kumari B, Kumar S, Pandey S, Sood S, Das BK, Kapil A. Changing trends of culture-positive typhoid fever and antimicrobial susceptibility in a tertiary care North Indian Hospital over the last decade. Indian J Med Microbiol [serial online] 2018 [cited 2019 Feb 23];36:70-6. Available from: http://www.ijmm.org/text.asp?2018/36/1/70/231675
| ~ Introduction|| |
Typhoid fever remains an important public health problem in developing countries with majority of population belonging to low socioeconomic status and living under conditions of limited resources and constrained sanitation infrastructure. A recent study on longitudinal analysis of typhoid fever in Asian countries has estimated that there are 12–20 million cases and 13000–220,000 deaths each year in Asia. India has an annual incidence of 493.5/100,000 persons per years with 340.1/100,000 cases per years occurring in children of 2–5 years. In a recent systematic review, the pooled estimates of annual incidences of enteric fever in India were 377 (178–801) and 105 (74–148) cases in 100,000 person per year, respectively.
Enteric fever can lead to increase in complications and morbidity if not treated with appropriate antimicrobial agents. The effective treatment of typhoid fever is becoming increasingly difficult in India due to the emergence of ciprofloxacin resistance compounded by the fact that ceftriaxone, which is presently the drug of choice for treatment, has started to show an increasing trend of minimum inhibitory concentration (MIC) values against Salmonella enterica serovar Typhi and S. enterica serovar Paratyphi A.
In view of such a problem of emerging antimicrobial resistance, prevention of disease becomes a priority in public health. To guide public health interventions, it is important to monitor the trends of the disease, causative agents and their antimicrobial susceptibility. Some of the major issues responsible for incomplete information on the actual burden of typhoid fever in India are the uneven disease distribution of this infection in different geographical areas, occurrence of outbreaks from time to time and lack of blood culture facilities across health-care centres in India for actual estimates of disease burden.
We carried out a retrospective analysis on a collection of Salmonella Typhi and Salmonella Paratyphi A isolated from patients of enteric fever presenting to our hospital during 2005–2017 to observe the trends of culture-positive typhoid fever and antimicrobial susceptibility profiles of typhoidal salmonellae was analysed and compared with our previous report. We also analysed the positive proportion of blood culture-positive S. Typhi and S. Paratyphi A from the laboratory records during the last 24 years with effect from 1993 to 2016 and discussed it in the light of the reported antibiotic consumption data from India.
| ~ Methods|| |
All the culture-positive enteric fever cases during 2005–2016 presenting to our hospital, New Delhi, were included in the study. Ethical approval was taken from the Institutional Ethics Committee (Letter no. IESC/T-187/04.05.2012).
The clinical details and the demographic profile were recorded in the pre-defined performa. The blood culture and identification of the isolates were performed as described earlier. The demographic details and seasonality were recorded and compared over the time.
Antimicrobial susceptibility testing
Antimicrobial susceptibility testing was done by disk diffusion method using antibiotic discs for chloramphenicol (30 μg), amoxicillin (10 μg), cotrimoxazole (1.25/23.75 μg), ciprofloxacin (5 μg), cefixime (30 μg) and ceftriaxone (30 μg) (Hi-media Laboratories Ltd, Mumbai, India). The analysis of the antimicrobial susceptibility was carried out as per CLSI interpretative guidelines for the corresponding year of isolation , Susceptibility to azithromycin (15 μg) by disk diffusion and pefloxacin (5 μg) was done for isolates obtained after 2015 when the breakpoints were defined as per CLSI.
The MIC was determined for ceftriaxone, ciprofloxacin and by E-test method as per manufacturer's guidelines (Biomerieux, USA). MIC for ofloxacin and levofloxacin was determined in the strains isolated from 2013 onwards, after the recommendation of these antimicrobial agents for enteric fever in 2013. MIC for azithromycin was determined in the strains isolated after 2015 when the breakpoints were defined by CLSI. Interpretation of susceptibility was carried out as per CLSI guidelines for the corresponding years.,,,
Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 were used for the quality control of antimicrobial susceptibility testing.
Determination of blood culture-positive proportion for enteric fever
We also analysed the proportion of culture-positive enteric fever from our laboratory records during 1993–2016. The proportion of blood culture-positive samples was calculated by dividing the Salmonella positive isolates by the total number of blood samples received for culture.
The overall trend of antibiotic consumption across the years was adapted from CDDEP (The Center For Disease Dynamics, Economics and Policy) which is in public domain (https://resistancemap.cddep.org/CountryPage.php?country=India).
| ~ Results|| |
A total of 329,232 blood cultures were received during the study (January 2005–December 2016). Of these, 1066 were culture positive for typhoidal salmonellae. The male-to-female ratio for the culture-positive cases was1.56:1 (651 males and 415 females). The age-wise distribution showed that 117 (10.9%) cases occurred in <5 years age group, 644 (60.4%) cases in 5–19 years age group and 305 (28.6%) were found in >19 years of age.
The proportion of blood culture-positive enteric fever is presented in detail in [Figure 1] and [Figure 2].
|Figure 2: Seasonal variation in incidence rate of Salmonella Paratyphi A|
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Of the culture positive, 772 (72.4%) were S. Typhi and 294 (27.6%) were S. Paratyphi A.
For analysis of seasonal occurrence, a year was divided into four equal periods of 3 months each from January to December over 2005–2012. We noted that though the cases occurred in all months throughout the year, the maximum number of cases was found in July–September.
Out of the total, 772 strains of S. Typhi 679 (87.9%) were susceptible to chloramphenicol, 583 (75.5%) to amoxicillin and 674 (87.3%) were susceptible to cotrimoxazole [Table 1]. Among S. Paratyphi A, 277 (94.2%) were susceptible to chloramphenicol, 265 (90.1%) to amoxicillin and 277 (94.2%) were susceptible to cotrimoxazole out of the total 294 strains isolated during the study [Table 1].
|Table 1: Antimicrobial susceptibility to traditional first-line antibiotics in Salmonella enterica serovar Typhi and Paratyphi A isolated from blood culture samples from 2005 to 2016|
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Antimicrobial susceptibility for S. Typhi to ciprofloxacin was analysed for the isolates obtained till the year 2011 with the guidelines recommended at the time. The susceptibility was high in 2005 followed by a gradual decrease from 96.4% in 2005 to 89% in 2011. Subsequently, in 2012 the susceptibility reduced to only 4.6% with the revision of CLSI breakpoints  and then stabilised around 8%–9% in 2015–2016 [Table 2]. Out of total, 127 strains tested for ofloxacin and levofloxacin which were analysed after 2013, only 11 (8.7%) were found to be susceptible to both these antimicrobial agents. The MIC50 and MIC90 values were found to be 0.38 and 8 μg/ml for ciprofloxacin, 1 and 24 μg/ml for ofloxacin and 1.5 and 32 μg/ml for levofloxacin, respectively.
|Table 2: Antimicrobial susceptibility pattern for ciprofloxacin in Salmonella Typhi and Salmonella Paratyphi A|
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When pefloxacin was used as a surrogate following its recommendation in 2015 in S. Typhi isolated during 2015 and 2016, it also showed 8.4% susceptibility which was concordant to ciprofloxacin disc diffusion results and MIC to ciprofloxacin (in 2015–2016).
Antimicrobial susceptibility for S. Paratyphi A to ciprofloxacin was analysed for the isolates obtained till the year 2011 with the guidelines recommended at the time. The susceptibility percent varied from 87.5% to 7.6% during 2005-2011 [Table 2] but after revision of breakpoints in 2012, none of the isolates tested thereafter were found susceptible. Among the 48 strains tested for ofloxacin and levofloxacin (isolated 2013 onwards) and 29 strains tested with pefloxacin (isolated 2015 onwards), all were resistant to these antibiotics as per corresponding CLSI guidelines.
MIC50 and MIC90 values for ciprofloxacin were 1 and 12 μg/ml, for ofloxacin 2 and 32 μg/ml and for levofloxacin were 2 and 64 μg/ml, respectively.
When compared the susceptibility percentage of two serovars, it was observed that fluoroquinolone resistance is significantly high in S. Paratyphi A (P < 0.001).
Antimicrobial susceptibility to ceftriaxone and cefixime has remained 100% in our isolates; however, the MIC values showed a creeping trend towards resistance with increase in MIC50 and MIC90 values for ceftriaxone, in the last 12 years (P < 0.05), MIC50 and MIC90 values increased from 0.023 to 0.064 μg/ml and from 0.038 to 0.19 μg/ml, respectively [Figure 3]. There was no significant difference in MIC50 and MIC90 of S. Typhi and S. Paratyphi A (P > 0.05) [Figure 3].
|Figure 3: Minimum inhibitory concentration50and minimum inhibitory concentration90to ceftriaxone for Salmonella Typhi and Salmonella Paratyphi A over the last 10 years showing a creeping increase towards resistance (P < 0.5)|
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Antimicrobial susceptibility to azithromycin showed that out of a total of 95 strains of S. Typhi tested during 2015 and 2016, 94 (98.9%) were susceptible to azithromycin. MIC50 and MIC90 were 8 and 12 μg/ml.
In the absence of any CLSI breakpoints for S. Paratyphi A, it was not possible to comment on the percentage susceptible population. We found that out of total 37 strains tested for azithromycin, 24 (64.9%) strains had a MIC ≥16 μg/ml with MIC50 and MIC90 being 12 and 16 μg/ml, respectively. It was observed that the overall MIC distribution in S. Paratyphi A was higher as compared to S. Typhi.
Changing trends of culture-positive enteric fever since 1993
The year wise positive proportion of blood culture for enteric fever from 1993 to 2016 is shown in [Figure 4]. The proportion of blood culture-positive cases ranged from 0.0006 in 2014 to a maximum of 0.0087 in 1999. The temporal distribution of blood culture-positive enteric fever cases showed a nonlinear trend over the years. The positive proportion showed a rise from 1993 and peaked in 1999, then in 2001 and 2009 [Figure 4]. After 2009, there was a gradual decrease till 2014, showing a minimum positive proportion of 0.0006 only. However, from 2015 onwards, the blood culture positivity is again showing a trend towards an increase.
|Figure 4: Year-wise-positive proportion of enteric fever isolates from blood culture samples|
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| ~ Discussion|| |
Enteric fever, though a major problem in developing countries, is also a concern of global community, especially due to emergence of antimicrobial resistance in S. Typhi and S. Paratyphi A which has implications in the treatment of infections in the travellers visiting endemic areas. There is a need to monitor the burden of disease and antimicrobial resistance to guide empirical treatment choices and devise prevention strategies.
In the present study, a retrospective analysis was done for the last 12 years. We observed that the etiological agent was S. Typhi in 72% of cases. S. Paratyphi A was the second causative agent as also found in studies from other parts of India., Although the disease occurred throughout the year, there was an increase from July to September months. A similar observation was found in our earlier study reported during 1999–2005 and is in concordance with other reports from India which have related it to rainfall and water contamination. The antimicrobial susceptibility pattern for antityphoidal antibiotics over the last 12 years showed there that is a notable increase in chloramphenicol susceptible strains which has been also reported by many other studies.
During the same time, the resistance to ciprofloxacin has increased in our centre as well as other reports., CLSI revised the susceptibility breakpoints of ciprofloxacin interpretative criteria in 2012 where the MIC breakpoints were lowered from ≤1 to ≤0.06 μg/ml and zone diameter increased from ≥21 to ≥31 mm which has changed the ciprofloxacin susceptibility percentage in our strains from about 90% to 8%., Similar results are reported from other regions where the impact of revised CLSI guidelines resulted in susceptibility change from 95% to 3%. Subsequently, in 2013, ofloxacin and levofloxacin MIC breakpoint were also included in guidelines. Emergence of this decreased susceptibility to fluoroquinolones is a matter of concern in south and southeast countries of Asia. With the upcoming reports of decreased susceptibility from different regions of world, fluoroquinolones are no longer a drug of choice for enteric fever.,
Therapeutic options are now limited to injectable ceftriaxone, oral cefixime and azithromycin, so emergence of resistance to these agents would be a major concern. No isolate in our study was resistant to ceftriaxone but MIC is creeping towards resistance. In addition, there are some sporadic reports from different parts on ceftriaxone resistance in S. Typhi where CTX-M-15 and SHV-12 extended-spectrum beta-lactamases have been reported.,
Azithromycin has been used for uncomplicated cases of enteric fever since 1992 though there were no laboratory criteria for susceptibility determination. CLSI in 2015 added azithromycin MIC and disk diffusion criteria for S. Typhi and S. Paratyphi A. We tested azithromycin susceptibility in strains obtained since 2015 and found that 98.9% of S. Typhi were susceptible to azithromycin as per current CLSI guidelines. The distribution of MIC50 and MIC90 was higher in S. Paratyphi A. Some other studies have reported higher MIC distribution in S. Paratyphi A than S. Typhi., Although azithromycin susceptibility is promising in S. Typhi, 62% of strains had an MIC of 16 μg/ml, which is the breakpoint for susceptibility, and therefore, we need to be vigilant for emergence of resistance.
To understand the possible reasons of uneven disease distribution, we analysed the proportion of culture-positive enteric fever over the last two decades and compared with the antibiotic consumption data published by CDDEP and available in public domain [Figure 5].
We feel that the culture positivity might reflect the antibiotic use in the country.
In 1993, ciprofloxacin was the first-line antibiotic to treat enteric fever in our region after the emergence of multidrug-resistant Salmonella (resistant to all three first-line antibiotics, i.e., chloramphenicol, amoxicillin and co-trimoxazole) in Delhi and North India. We can see from the antibiotic use in [Figure 5]. that chloramphenicol consumption has decreased since that time.
By the year 2000, clinical failure to ciprofloxacin was reported due to the nalidixic acid resistant S. Typhi (NARST) phenotypes causing enteric fever. Since these strains were reported as ciprofloxacin susceptible by the laboratories as per the CLSI guidelines available that time, ciprofloxacin continued to be the first line of treatment. The culture-positive cases increased again during that time. When ciprofloxacin clinical failure and reports of NARST phenotypes causing enteric fever increased, cephalosporins (ceftriaxone in this case) became the choice of antibiotic to treat enteric fever.
In [Figure 5], we can see a gradual increase in the use of 3rd generation cephalosporins and declining ciprofloxacin usage during that time and the culture-positive case decreased subsequently after 2009 [Figure 4]. In absence of facilities for blood cultures available or even undertaken in most of the healthcare facilities, the empirical antibiotics used to treat all fevers in the community could be responsible for only the complicated cases presenting to the tertiary care centres. Thus, we might be identifying the cases not responding to first line. Although this is purely conjectural, we feel that the decrease in culture-positive cases may actually be driven by the empirical antibiotic choices to treat fever in the community and hospitals.
Now, the MIC to ceftriaxone is creeping towards resistance [Figure 3], and treatment with ceftriaxone has started to show poor clinical response, an increase in the proportion of culture-positive cases can be seen after 2014 [Figure 4].
| ~ Conclusion|| |
This study provides an insight about the prevalence and antimicrobial susceptibility pattern of typhoidal salmonellae over a period of 12 years (2005–2016) showing that the susceptibility trend in Salmonella can change over a short duration of time as also reported in our previous study from 1999 to 2005. The decrease in culture positive cases might suggest a decline in disease burden but may also be a reflection of the antibiotic use to empirically treat typhoid fever in the community. It is possible that the emerging antibiotic resistant strains, under the selective pressure of antibiotic use, could be the reason that only patients failing to respond to empirical treatment visit tertiary care hospitals. Therefore the culture positive cases of typhoid fever represent only a small proportion of total number of cases in a community and this can skew the antimicrobial susceptibility data towards resistance. Hence, there is a need for continuous surveillance to inform clinicians for better management of infections, availability of blood cultures in the peripheral hospitals to understand the actual burden of the disease and for government policymakers for vaccine strategies, especially in light of the increase in S. Paratyphi A prevalence. Safe supply water, personal hygiene and effective antibiotic policies can help us to control the disease and hence reduce antimicrobial resistance.
- Indian Council of Medical Research for funding the different studies during this period
- The Center for Disease Dynamics, Economics and Policy, for providing antibiotic consumption data in India.
Financial support and sponsorship
This study was financially supported by the Indian Council of Medical Research.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]