ANTIMICROBIAL SUSCEPTIBILITY PATTERNS OF SALMONELLA SPECIES IN CONTEMPORARY MEDICAL PRACTICE: CHALLENGES AND PROSPECTS IN TREATMENT OF ENTERIC FEVERS

Treatment of enteric fever is increasingly becoming very challenging due to the increasing wave of antibiotic resistance. This study is a review of the contemporary antimicrobial susceptibility pattern of Salmonella species. The antimicrobial susceptibility pattern of Salmonella species to a wide range of antimicrobial agents was compiled for a period of 10 years (1997-2006). Data was obtained from published articles on both in vitro and in vivo susceptibility patterns of the organism to various drugs during the time interval. Data obtained were analysed using simple descriptive methods. Of the 23,504 isolates of Salmonella species reviewed, they were found to be 98% susceptible to cefepime and carbapenem, 91% to azithromycin, 82.1% to cefixime and 73% to quinolones. Also susceptibility to chloramphenicol, erythromycin, streptomycin, ampicillin, gentamicin, co-trimoxazole, augmentin and amikacin was found to be 11.9%, 10.9%, 13.0%, 16.8%, 46.3%, 38.0%, 54.3%, 6.9% and 63.0% respectively. This review has demonstrated increasing resistance of Salmonella species to antibiotics. Empirical treatment for enteric fevers should, therefore, be discouraged while quinolones, cefepime, carbapenem, azithromycin and third generation cephalosporins be given preference.


INTRODUCTION
In the 21 st century, enteric fever in the developed world is not much a disease of public health importance (Meltzer, et al., 2006;Agbakwuru, et al., 2003;and Mba, 2001).The disease however continues to occupy the central position among diseases of public health importance in parts of middle east, India and south-east Asia, parts of Latin America, the Caribbean, and sub-Saharan Africa where it is still endemic (Steinberg, et al., 2004;Nkuo-Akenji T, et al., 2001;and Fuller, et al., 2004).
One of the major challenges now in the management of typhoid fevers is the prevailing nature of the antimicrobial resistance patterns of Salmonella species (Parry, et al., 2007;Na'aya, et al., 2004;and Rathore, et al., 1996).In a study carried out in Tadjikistan (Makhnev, 2001) involving 14 antimicrobial agents representing almost all basic chemical classes against Salmonella spp., there was no absolute (100%) efficacy of the investigated agents in vivo and invitro.In Saudi Arabia (Al-Tawfig, 2007), the susceptibility pattern of Salmonella typhi/paratyhi was reported as 81.3%/56%, 89%/77%, and 89%/84% susceptible to tetracycline, ampicillin, and trimethoprim-sulfamethoxazole respectively.Also 100% susceptibility was recorded for ceftriaxone and ciprofloxacin while multidrug resistance (MDR) was detected in 20% of the 266 Salmonella spp.Studied.In another study in Vietnam (Chinh, et al., 2000), 78%(68 out of 87) MDR and 53% nalidixic acid resistance was reported among adult males in a University Teaching Hospital typhoid ward in Ho Chi Minh city.Similar but varied patterns of resistance have as well been reported in Japan (Tamura, et al., 2002), Nigeria (Akinyemi, et al., 2005), and Brazil (Alecrim, et al., 2002).
In the tropical and sub-tropical regions of the world, more often than not, physicians result to empirical treatment for suspected typhoid fevers (loosely including paratyhoid fever) (Glauser, et al., 2002;and Oboegbulam, et al., 1995).Most a times as a result of either, delays in the release of laboratory reports, or due to outright lack of appropriate diagnostic laboratory facilities (Bates, and Maitland, 2006).A proper understanding of the current antimicrobial susceptibility patterns of Salmonella spp.becomes essential.Such information would be useful to clinicians who are often confronted with the limitations of unreliable or absent microbiological results in the course of managing typhoid patients Makhnev, 2003;and Moulin, et al., 2003).This therefore informed the need for the present study.

MATERIALS AND METHODS
A systematic literature search on antimicrobial susceptibility pattern of Salmonella species was undertaken on published articles for a 10 year interval (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006).This consists of articles on both in vivo and in vitro antimicrobial susceptibility pattern of individual isolates of Salmonella typhi and Salmonella paratyphi on a wide range of antibiotics in various research centres across the globe.In vivo susceptibility reports based on the diagnosis of enteric fevers through serological methods were as well considered.The in vitro results were standardized by collating findings from studies whose methodologies were based on the diffusion and dilution methods of National Committee for Clinical Laboratory Standards (NCCLS) protocol.On the other hand the results obtained from the in vivo susceptibilities were standardized by collating data generated from monotherapies.Data obtained was analysed using simple descriptive methods.

DISCUSSION
The findings from the present study showed the average percentage of Salmonella isolates susceptible to antimicrobial agents tested ranged from 6.9% (tetracycline) to 98% (carbapenem and cefepime).There were varying degrees of susceptibility of isolates among individual drugs as well as geographical strains.
Azithromycin though found to be 97% active against Salmonella spp. in the present study, findings from Egypt (Girgis, et al., 1999) showed a 100% activity against all the strains tested including the MDR strains.In Tadjikistan (Makhnev, 2003) on the other hand, azithromycin was found to be unable to produce a 100% activity, though a susceptibility of over 90% was severally recorded; and in Dong Thap province, Vietnam (Parry, et al., 2007), all the isolates of Salmonella spp.were found to be susceptible to azithromycin.
Findings from Bangladesh (Isbandiro, et al., 1994) similarly showed a slightly higher susceptibility of 98% to azithromycin.
The quinolones had a wide but varying range of activity against the Salmonella spp.though an average susceptibility of 73% was recorded in the present study.In Switzerland (Glauser, et al., 2002), a higher figure of 84% susceptibility was recorded among patients placed on clinafloxacin monotherapy.In Lagos, Nigeria (Akinyemi, et al., 2005), a much higher susceptibility of 98% to ciprofloxacin and ofloxacin was recorded, while in Zaria, Nigeria (Ibrahim, et al., 2005) sensitivity to nalidixic acid was found to be as low as 40%.In Kuwait (Dimitrov, et al., 2007), a much higher resistance (over 50%) to nalidixic acid was recorded as well as treatment failures to ciprofloxacin monotherapy, while a resistance of over 78% by Salmonella spp. to nalidixic acid was recorded in India (Kadhiravan, et al., 2005).
Ceftriaxone and cefixime were found to have a susceptibility of 82% and 78% respectively with varying ranges along with the other cephalosporins.Susceptibility patterns of both drugs of over 95% have been recorded in some centres in both the United Kingdom (Threlfall, and Ward, 2001) and United States of America (Ackers, et al., 2000), with much lower susceptibility patterns (less than 60%) in several centres.
The percentage susceptibility of Salmonella spp. to ampicillin, tetracycline, cotrimoxazole, gentamicin, streptomycin, azithromycin and chloramphenicol was generally low (6.9% -46%).This includes the findings of Ullah, et al, in Dera Ismail Khan, Pakistan (Ullah, et al., 2005), where 50%, 71.4%, and 75% resistance was recorded by the organism against chloramphenicol, amoxycilline and cotrimoxazole respectively; the over 70% resistance recorded by similar drugs in Bangkok, Thailand (Isenberger, et al., 2002); and the report from Ho Chi Minh city, Vietnam (Smith, et al., 1994) where about 63% of the Salmonella isolates were found to be multiply resistant to chloramphenicol, ampicillin, co-trimoxazole, and tetracycline.Findings from Kolkata, India (Kundu. 2005) on the contrary showed a renewed increase in susceptibility to chloramphenicol.
Considering the life threatening complications of untreated or improperly treated typhoid fever and, the high rate of resistance recorded by majority of the drugs for its treatment.Caution should be exercised in the selection of appropriate antibiotics for proper treatment.Selection of antibiotics for treatment of enteric fever should stem from a well conducted antimicrobial susceptibility report.Susceptibility tests should be carried out on all isolates of Salmonella spp.so as to adequately guide the personnel treating the patient and avoid relapse, a common phenomenon from drug failure.
Susceptibility to carbapenem, amikacin, clavulanate potentiated amoxycillin and cefepime was in the range of 98%, 63%, 54.3% and 98% respectively.The carbapenems and the 4 th generation cephalosporins are relatively new drugs whose prescriptions has not been documented in several hospitals and clinics across the world (Chande, et al., 2002;and, Corrado, et al., 1992).and the extremely low resistance is expected.The susceptibility might be higher than this but for the interpersonal and procedural bias, which cannot be ruled out in a study of this magnitude.
The susceptibility profile of the local Salmonella isolates against the common antibiotics in use should be known by the concerned health personnel.Such data should be reviewed periodically so as to reflect the current antibiotic susceptibility pattern of the organism for quick reference.This would be very useful when patients present in very critical states leaving little or no time to wait for the susceptibility report.Such data would even be more useful in the developing world where laboratory facilities for diagnosis are either inadequate or lacking and, often times laboratory results are not available on time.Furthermore, clinical diagnosis of enteric fever should be confirmed by laboratory investigations so as to reduce over diagnosis of enteric fevers.This carries with it the attendant unnecessary and unjustifiable antibiotics consumption from empirical treatments and the subsequent development and spread of resistance.This scenario is often encountered in clinical practice especially in the developing world (Akin, et al., 2003;and Kacprzak, et al., 2002).
In conclusion, this review has found that, no single drug at present holds the absolute promise for the treatment of Salmonella infections and globally, there is a high resistance of Salmonella to majority of the drugs hitherto commonly used for its treatment.Quinolones, azithromycin, ceftriaxone, cefixime, carbapenem and cefepime are presently the drugs with the highest activity against Salmonella spp.and hence on a general note should be considered on isolation of Salmonella.Efforts should be made to establish diagnosis of typhoid beyond doubt before treatment is started as to avoid empirical prescriptions and unjustifiable antimicrobial intake.