MC Vol. 19 - No.2 - 2012 ( 93 - 96 ) Talpur A. A. et al APRIL - JUNE 2012 SENSITIVITY PATTERN OF SALMONELLA TYPHI IN PATIENTS WITH TYPHOID SMALL BOWEL PERFORATIONS ALTAF AHMED TALPUR ABSTRACT NAND LAL KELLA ABDUL RASHID SURAHIO Background: Enteric fever caused by Salmonella Typhi, gram negative bacilli, is counted MUHAMMAD JAVED
as a major public health problem, especially in underdeveloped countries of tropic region. PROFESSOR AKMAL JAMAL
One of the notorious and potentially lethal complications of typhoid fever is small bowelperforation. Chloramphenicol, in 1948 converted this lethal disease to curable one. Efficacy of this drug reduced within 2 years. These strains of salmonella typhi were alsofound resistant to sulphonamide, tetracycline and streptomycin and are called as multidrug-resistant strains salmonella typhi (MDRST). Due to this resistance amoxycilin, andtrimethprim with sulphamethoxazole replaced these drugs. Emergence of MDRST led to
the use of quinolones as the first line drug. With the developing resistance to flouroquinolones,
3rd generation cephalosporins such as ceftriaxone and cefotaxime are now increasingly
being used in the treatment of typhoid fever. Materials and Methods: This prospective, descriptive study was conducted at surgical Assistant Professor,
ward- III of Liaquat university hospital, Hyderabad from Jan 2007 to Dec 2010. All
patients of either sex above the age of 02 years having high-grade fever for more than
1 week associated with features of peritonitis secondary to hollow viscus perforation
and later on confirmed through various investigations as cases of perforation of hollow
viscus due to typhoid were included in the study.
Subject’s data was collected for age, sex, mode of presentation, treatment history, &
blood culture and sensitivity pattern. Variable studied in this study were age, sex &
Sensitivity pattern of Salmonella Typhi in Typhoid small bowel perforation Antibiotics
Microbiology Technologist Raheela
assessed for sensitivity after culture of the organism were: ampicillin, amoxycilin, augmentin,
ceftriaxone, cefotaxime, ceftazidime, cefixime, cefipime, cefuroxime, chloramphenicol,
amikacin, gentamicin, Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, imipenem,
Professor and Chairman
meropenem, Piperacillin with Cefbactum and sulphonamide derivative. Results: During the study period of 4 years; a total of 41/187(21.92%) blood culture
isolates were identified for salmonella typhi. Mean age of this group of patients was
27.35 years. Amongst them 113(60.42%) were male and 74(39.57%) were female. Theantibiotics sensitivity showed that all organisms were sensitive to imipenem and meropenemwhile sensitivity of the organism to Piperacillin with Sulbactum was 97.56%. 90.24%isolates were sensitive to cefotaxime and ceftazidime while 95.12% & 92.68% to Cefipime& Ceftriaxone respectively. Sensitivity pattern of salmonella typhi to ciprofloxacin,ofloxacin, levofloxacin and moxifloxacin was 80.48%, 73.17%, 82.92% and 85.36%
respectively. 41.46% Isolates were resistant to amoxycilin; and 63.41% to Chloramphenicol. DR. ALTAF AHMED TALPUR Conclusion: This study concludes that there is an increasing resistant trend of salmonella
typhi to 2nd line drugs like ciprofloxacin, and 3rd generation cephalosporins. At the same
time there is re-emergence of chloramphenicol sensitivity. Keywords: Typhoid fever, Perforation of small bowel, Blood culture & sensitivity INTRODUCTION
Salmonella typhi are gram-negative bacilli, which are transmitted through faeco-oral
Quarterly Medical Channel www.medicalchannel.pk MC Vol. 19 - No.2 - 2012 ( 93 - 96 ) Talpur A. A. et al APRIL - JUNE 2012
route, and is responsible for typhoid fever1. One of the notorious
from these patients especially in data related to age, symptomatology
and potentially lethal complications of typhoid fever is small
especially symptoms of high grade fever with step-ladder pattern,
bowel perforation2. Enteric fever is counted as a major public
duration of symptoms of peritonitis, and duration, dose and type
health problem, especially in underdeveloped countries of tropic
of antibiotic used during this illness; and any prior investigation
region3. In one study it has been reported that highest incidence
performed to diagnose disease. Thorough examination was performed
of typhoid fever is found in South East Asia, Africa, and in Latin
with special focus on variables like fever, anemia, and abdominal
America4.In India, Nigeria and in Indonesia mortality rate due to
examination. Investigations were performed to establish diagnosis
typhoid fever is noted at 12-32% in different studies5, 6. The
and to assess general fitness. These include complete blood count,
factors responsible for increase in the incidence of typhoid fever
blood sugar, blood urea, serum electrolytes; blood culture and
in these countries is due to poor sanitary conditions, supply of
sensitivity, typhidot test, x-ray abdomen in erect position, ultrasound
contaminated water, rapid population growth, and increased
abdomen and where required ECG and chest x-ray. Preoperative
urbanization and overburden health care system1, 4.
diagnosis was made. General management of the patients was
In 1948 with the introduction of chloramphenicol this lethal
started which includes I/V fluids, I/V antibiotics like injection
disease was converted to curable disease7. Efficacy of this drug
ceftriaxone 1 gram and metronidazole 500mg(after getting blood
reduced within 2 years. However until in 1970 when resistance
samples for blood culture), nasogastric suction, measurement of
to it lead to major public health problem through out the world,
urinary volume after passing two ways foley’s catheter. Preoperative
especially in Latin America8 and in Asia9, 10.Although chloramphenicol
resuscitation performed and patient’s condition was optimized.
is still the drug of choice in many countries in the management
Patients were briefed about the diagnosis and procedure to be
of typhoid fever but is used to limited extent due to its severe
undertaken or performed. Patients were informed and permission
toxicity11. These strains of salmonella typhi were also found
was obtained. They were assured that their participation is voluntary
resistant to sulphonamide, tetracycline and streptomycin7. Due to
with no harms to them in terms of getting due treatment. They
this resistance amoxycilin, and trimethprim with sulphamethoxazole
were also given right to withdraw from study without putting any
reasons. Postoperatively same antibiotics continued until blood
It was until late 1990’s when resistance to these all-first line drugs
erupted & in one series it was found to be near 68.9% in one area
Subject’s data was collected on preformed proforma for age, sex,
of India7, 12. These strains are called as multidrug-resistant strains
mode of presentation, treatment history and blood culture &
salmonella typhi (MDRST). In Karachi typhoid fever caused by
sensitivity pattern. Variable studied in this study were age, sex,
MDRST has been isolated in 1986. However its frequency has
& Antibiotic sensitivity pattern of Salmonella Typhi in these
increased to a very large extent for the last 7 years14.
Emergence of MDRST led to the use of quinolones as the first
All the blood samples submitted for culture & sensitivity. Initial
line drug in the treatment of adult patients with typhoid fever13.
identification of salmonella typhi was made with routine culture
However sensitivity to ciprofloxacin of salmonella typhi has
technique that was later confirmed by slide agglutination method.
decreased in endemic areas of Asia, especially in Indian subcontinent
Antibiotic sensitivities were assessed by stokes or Kirby Bauer
as shown by Threlfall and Ward in their study15. In 1997 such
disc diffusion method. Antibiotics assessed for sensitivity after
strains caused typhoid fever in 8000 people and killed 150 of
culture of the organism were: ampicillin, amoxycilin, augmentin,
ceftriaxone, cefotaxime, ceftazidime, cefixime, cefipime, cefuroxime,
With the developing resistance to flouroquinolones, 3rd generation
chloramphenicol, amikacin, gentamicin, Ciprofloxacin, ofloxacin,
cephalosporins such as ceftriaxone and cefotaxime are now
levofloxacin, moxifloxacin, imipenem, meropenem, Piperacillin with
increasingly being used in the treatment of typhoid fever. In study
Sulbactum and sulphonamide derivative. Results were compiled
by Threlfall and Ward they have mentioned that all strains of
and compared to national and international literature. Data was
salmonella typhi were sensitive to these drugs15. However in
another study by Saha SK et al17 there has been reports ofsporadic resistance to these drugs as well.
Because of this increasing resistance of salmonella typhi to 2nd
During the study period of 4 years a total of 187 patients of small
line drugs and at the same time presentation of many cases of
bowel perforations, most probably due to typhoid, were admitted.
small bowel perforation secondary to typhoid fever compelled us
Blood of all these patients was sent for culture & sensitivity. Out
to conduct study to assess sensitivity pattern of this organism in
of these 41 patients (21.92%) yielded positive blood culture for
salmonella typhi. All these cultured organisms were submitted todifferent antibiotics for sensitivity. MATERIALS AND METHODS
Mean age of this group of patients was 27.35 years. Amongst
This was a prospective, descriptive study conducted at surgical
them 113(60.42%) were male and 74(39.57%) were female making
ward- III of Liaquat university hospital, Hyderabad, Pakistan
the male to female ratio of 1.52: 1.00.
from Jan 2007 to Dec 2010. All patients of either sex above the
The antibiotics sensitivity using disc diffusion method (Table.1)
age of 02 years having high-grade fever for more than 1 week
showed that all organisms were sensitive to imipenem and meropenem
associated with features of peritonitis secondary to hollow viscus
while sensitivity of the organism to Piperacillin with Sulbactum
perforation and later on confirmed through various investigations
was found in 40 (97.56%) patients. 39 (95.12%) organisms were
as cases of perforation of hollow viscus due to typhoid were
sensitive to Cefepime and 37 (90.24%) organisms to cefotaxime
included in the study. All patients below the age of 02 years and
and ceftazidime. Sensitivity of Ceftriaxone was present in 38
with non-typhoid hollow viscus perforation were excluded.
(92.68%) organisms. Cefixime and Cefuroxime showed sensitivity
These patients were admitted in ward. Detailed history was taken
in 31 (75.60%) and in 32 (78.04%) patients respectively. Quarterly Medical Channel www.medicalchannel.pk MC Vol. 19 - No.2 - 2012 ( 93 - 96 ) Talpur A. A. et al APRIL - JUNE 2012
to these 2nd line drugs18. These patients have also been found incountries like USA and UK after their visits to south east asia17,
NUMBER OF SALMONELLA TYPHI ISOLATES FOUND SENSITIVE TO ANTIBIOTICS BY DISC
The sensitivity of salmonella typhi has continuously changed. DIFFUSION METHOD (N=41)
Initially chloramphenicol was used to treat this infection. However
Antibiotics screened No & % of isolates
emergence of resistant strains to this and other first line drugs likesulphonamide derivatives, ampicillin, amoxicillin, and tetracycline
decreased their usage to treat typhoid fever. The can be depicted
from the study by Sadarsana et al at Calicut in which they havementioned that resistance of salmonella typhi to first line drugs
was < 15% in 1982 and it increased to 68.9% in 1988-89. However
recent studies have clearly mentioned the decreasing trend of
resistance of this organism to Chloramphenicol and other first linedrugs. One such study varied out by Raveendran R et al20 mentioned
27% resistance in 2003 which reduced to 14.9% in 2008.
Same trend has also been reported by Ranju C et al and Gautum
V et al in their studies. In this study 36.59% organisms wereresistant to Chloramphenicol and other first line drugs.
Since the emergence of multidrug-resistant salmonella typhi (MDRST)
in early 90’s Quinolones are the drug of choice to treat these
MDRST infections. In one study by Shaikh RB et al21 sensitivityof salmonella typhi to quinolones was reported as > 98%. Studies
by Munir T et al22 and Nadeem et al23 reported 100% sensitivity
of salmonella typhi to ciprofloxacin and ceftriaxone. In our study
sensitivity of both drugs was 80.48% and 92.68% respectively. However studies by Akhtar R et al 24 at Karachi, and Raveendran
R et al at India mentioned increasing resistance of salmonella
typhi to ciprofloxacin. In their studies they have mentioned 29/
82 organisms and 24/431 isolates were resistant to ciprofloxacinrespectively.
Due to this increasing resistance of salmonella typhi to ciprofloxacin
case of typhoid perforation has increased to the significant extent.
In their studies by Raveendran R et al, Gautum V et al, andAkhtar R et al 100% sensitivity of the organism to 3rd generationcephalosporins especially ceftriaxone has been mentioned. In study
Amongst the Quinolones, Moxifloxacin has got the highest
by Shaikh RB et al 90 –91% sensitivity of salmonella typhi to
sensitivity i-e in 35 (85.36%) patients while sensitivity pattern
ceftriaxone has been reported. Mushtaque MA in his study has
of salmonella typhi to ciprofloxacin, ofloxacin & levofloxacin was
reported 17.5% organisms resistant to Ceftriaxone.
33(80.48%), 30(73.17%) and 34(82.92%) respectively.
Sensitivity of salmonella typhi to meropenem & imipenem was
From the penicillin derivatives 17(41.46%), 7 (17.07%) and
100% while of Piperacillin with Sulbactum; it was 97.56% in this
18(43.90%) isolates were sensitive to amoxicillin, ampicillin, and
study. Study by Mushtaque MA has also reported 100% sensitivity
of organism to these antibiotics. These drugs are now considered
Among the aminoglycoside group gentamicin, and amikacin showed
safe choice in patients with typhoid bowel perforation.
positive sensitivity ratio of salmonella typhi in 27(65.85%) and32(78.04%) patients respectively. CONCLUSION
Twenty six (63.14%) & 06(14.63%) isolates were found sensitive
This study concludes that there is an increasing resistant trend of
to Chloramphenicol and sulphamethoxazole-Trimethoprim.
salmonella typhi to 2nd line drugs like ciprofloxacin, and 3rd generationcephalosporins. At the same time there is re-emergence of
chloramphenicol sensitivity. Therefore sensitivity pattern of
Salmonella typhi, the organism responsible for enteric fever is
salmonella typhi must be sought if patient is not responding to
counted as leading cause of morbidity and mortality through out
conventional antibiotics so that life- threatening complicationsassociated with typhoid fever like typhoid perforation of small
the world. It is one of the common causes of small bowel perforation
bowel may be decreased. In surgical wards patient presenting
in many developing countries especially in south East Asia. However
with typhoid perforation may be started to meropenem or imipenem
after the introduction of chloramphenicol in 1948 this lethal disease
group until sensitivity pattern is defined through blood or tissue
was counted as the completely curable disease. With the passage
of time organism got resistance to this and other first line drugslike sulphonamide derivatives, ampicillin and tetracycline. These
organisms were called as MDRST organisms. These organisms
We highly appreciate the support made by Raheela Research &
were now treated with quinolones and 3rd generation cephalosporins.
reference lab, Hyderabad and High- Q pharmaceuticals in this
There have been reports that organism is getting increasing resistance
Quarterly Medical Channel www.medicalchannel.pk MC Vol. 19 - No.2 - 2012 ( 93 - 96 ) Talpur A. A. et al APRIL - JUNE 2012 REFERENCES
sensitivity of salmonella typhi. Natl Med J India 1998; 11(6): 266-7.
Madukosiri CH, Edike T, Ghandi EO. Comparative studies of susceptibility
14. Farooqui BJ. Genetic analysis of multidrug-resistant strains of salmonella
of salmonella typhi to antibiotics and some plant extracts. Nig J of
typhi isolated in Karachi, Pakistan. Thesis. Dept of genetics/University
Biochem & Molec Biolog. 2009; 24(1): 16-21.
Neil J, Mortensen McC, Jones O. The small & large intestines. In
15. Threlfall EJ, Ward LR. Decreased susceptibility to ciprofloxacin in
Bailey & Love’s short practice of surgery by Russel RCG, Williams
salmonella enterica serotype typhi, United Kingdom. Emerg Infect Dis
Gautum V, Gupta NK, Chaudhary U, Arura DR. Sensitivity pattern of
16. Mermin JH, Villar R, Carpenter J et al. A massive epidemic of
salmonella serotypes in northern India. Braz J Infect Dis 2002; 6: 281-
multidrug-resistant typhoid fever in Tajikistan associated with consumption
of municipal water. J Infect Dis 1999; 179: 1416-22.
Nair L, Sudarsana. Changing sensitivity pattern of salmonella typhi in
17. Saha SK, Talukder SY, Islam M, Saha S. A highly ceftriaxone resistant
Calicut; Calicut Med J 2004; 2(1): e 2.
salmonella typhi in Bangladesh. Pediatr Infect Dis J 1999; 18: 387.
Edelman R, Levine MM. Summary of an international workshop on
18. Ivanoff B. Typhoid fever: global situation and WHO recommendations.
typhoid fever. Rev Infect Dis 1986; 8; 329-49.
South Asian J Trop Med Public Health 1995; 26(suppl 2): 1 –
Anderson ES, Joseph SW, Nasution Q. Febrile illness resulting in
hospital admission, A bacteriological & serological studying Jakarta,
19. Ackers ML, Puhr ND, Tauxe RV, MintzED. Labortory- based surveillance
Indonesia. Am J Trop Med Hyg 1976; 25: 116-121.
of salmonella serotype typhi infections in the United states. Antimicrobial
Mushtaque MA. What after ciprofloxacin and ceftriaxone in the treatment
resistance on the rise. JAMA 2000; 283: 2668 – 73.
of Salmonella Typhi. Pak J Med Sci 2006; 22(1): 51-54.
20. Raveendran R, Wattal C, Sharma A, Oberoi JK, Prasad KJ, Datta S.
Olark J, Galindo ES. Salmonella typhi resistant to C, A and other
High level ciprofloxacin resistance in salmonella enterica isolates from
antimicrobial agents: Strains isolated in extensive typhoid fever epidemic
blood. Indian J Med Microbiol 2008, Jan – March; 26(1): 50-3.
in Mexico. Antimicrobial agents Chemother. 1973; 4: 597-601.
21. Shaikh RB, Khemani AM, Shaikh S, Nizamani MA. Antibiotic sensitivity
Panicker CK, Vimala KN. Transferable chloramphenicol resistance in
pattern of salmonella typhi isolates in rural Sindh. Pak Armed Forces
salmonella. Nature 1972; 239: 109-110.
10. Mendel, Douglas and Bennetts. Principles & practice of Infectious
22. Munir T, Lodhi M, Butt T, Karamat KA. Incidence and Multidrug resistance
diseases, 4th Edi; Year 2005;2: 2017-2020.
in Typhoid Salmonellae in Bahawalpur area. Pak Armed Forces Med
11. Dambrot C. Women’s History. Month: Typhoid Marry. Google.http://
23. Nadeem M, Ali N, Achakzai H, Ahmed I. Profile of enteric fever in
12. Sudarsana J, Lathi N, Devi KI. Multidrug-resistant salmonella typhi in
adults at Quetta. Pak J Pathol 2002; 13(1): 12-17.
Calicut south India. IJMR [A] 95, 1992; 3: 68-70.
24. Akhtar R, Mehmood A, Hassan F. Drug sensitivity pattern of salmonella
13. Ranju C, Pais P, Ravindran GD, Singh G. Changing pattern of antibiotic
typhi. J Surg Pak sep 2006; 11(3): 97 –99. Quarterly Medical Channel www.medicalchannel.pk
Safety Data Sheet Sulfamethoxazole according to Regulation (EC) No 1907/2006 1. Identification of the substance/preparation and of the company/undertaking - pharmaceutical active substance: bacteriostatic, especially incombination with trimethoprim (e.g. BACTRIM,trimethoprim:sulfamethoxazole 1:5)F. Hoffmann-La Roche AGPostfachCH-4070 BaselSwitzerland 2. Hazards identification - Very
Hum Genet (2001) 108 : 249–254DOI 10.1007/s004390100485 Ulrike Sauermann · Peter Nürnberg · Fred B. Bercovitch · John D. Berard · Andrea Trefilov · Anja Widdig · Matt Kessler · Jörg Schmidtke · Michael Krawczak Increased reproductive success of MHC class II heterozygous males among free-ranging rhesus macaquesReceived: 27 November 2000 / Accepted: 11 January 2001 / Published online