Abstract

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The global impact of Salmonellosis is still very significant amidst the positive developments in the medical field. This review article focuses on the various manifestations or diseases in human beings due to Salmonellosis and the drugs which aid in prophylaxis and treatment of the various diseases brought about by the bacterium. The article will also touch on drug resistance issues with respect to Salmonellosis which is becoming a major global health concern.

Introduction

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Salmonellosis is a bacterial infection to the bloodstream and intestines caused by the bacterial group, Salmonella (Department of Health, New York, 2011). It is a type of zoonoses, diseases which are transmittable from animals to human beings under natural circumstances (British Association for the Advancement of Science, 1977). Salmonellosis is one of the commonest and most widely disseminated diseases transmitted via food (WHO, 2005). Salmonella results in 16 million cases of typhoid fever and 1.3 billion gastroenteritis cases annually, with over 3 million perishing from them globally (Pui et al., 2011). As such, this incurs in high economic burden and remains a grave global public health concern till today (WHO, 2005).
The outbreak of Salmonellosis is more rampant during the hot weather, especially summer, making the disease more common in tropical countries. The diagnosis of Salmonellosis is more frequent among children, the immune-compromised and geriatrics (Department of Health, New York, 2011). In Malaysia, from 1978 to 1997, a prevalence of 57% of diarrheal cases among children due to Salmonella was reported (Berger, 2010). However, this disease can infect any human being (Department of Health, New York, 2011). (See Figure 1).
Salmonella is found massively in unpasteurized milk, contaminated water, raw or undercooked eggs and meat. Infected livestock contributes to the severity of the disease just as much (Department of Health, New York, 2011). A 1977 review, Salmonella: The Food Poisoner by a Study Group of the British Association for the Advancement of Science disclosed that in 1881, a man who consumed 1.5 pounds of beef from a Salmonella enteritidis-infected cow in Germany, died 36 hours later (British Association for the Advancement of Science, 1977). The signs and symptoms in a Salmonella-infected human being usually manifest within one to three days. These include diarrhea, vomiting and abdominal cramps. Nonetheless, an infected person can harbour the bacteria for up to a few months, especially younger people and those who are administered with oral antibiotics (Department of Health, New York, 2011).
Apart from direct contact with contaminated food and water sources, typhoid and paratyphoid fever can be transmitted indirectly by travelling to high infection risk developing countries. The risk of contracting these diseases during prolonged stays in such nations can climb from 1: 30,000 in endemic regions to 1: 3,000 in high endemicity regions. Places in India bear the highest risk (Mayer et al., 2010). Hence, this allows the spread of typhoid and paratyphoid fevers to the travellers’ places of origin when they return from their trip abroad in highly-infected nations.
Salmonellosis brings about a string of diseases such as: typhoid fever, paratyphoid fever, food poisoning and gastroenteritis. In essence, Salmonella exists in various serotypes. Different serotypes result in different diseases and thus, some Salmonella serotypes are more hazardous than others, like Salmonella enterica serovar typhi, which causes the notorious typhoid fever (British Association for the Advancement of Science, 1977). On the other hand, non-typhoidal Salmonella serovars such as S. Typhimurium brings about localized gastroenteritis. However, a general consensus has been made that Salmonella comprises two species: Salmonella enterica and Salmonella bongori. In addition, the Kauffmann and White scheme classified 2,600 different serovars under the genus Salmonella (Cooke et al., 2007) as opposed to only 2501 serovars in 2004 (WHO, 2005).
While antibiotics are usually unnecessary, severe diarrheal dehydration and the spread of the infection to the intestines will result in dire consequences, including death. Less severe cases are often resolved within a week without medication (Department of Health, New York, 2011). The diseases due to Salmonellosis and the possible treatments and prophylaxis will be discussed in detail in the next section. Unfortunately, most of the antibiotics utilized to treat Salmonellosis, with time, face the issue of resistance.

Discussion

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Diseases Typhoid fever
Typhoid fever, used almost synonymously with “enteric fever”, is caused by Salmonella enterica serovar typhi. Infected individuals develop the fever after a 5 to 9-day incubation period (Raffatellu et al., 2007). Typhoid fever is more common among adults than children (Butler et al., 1999).
As mentioned earlier, typhoid fever is the most feared among all the diseases caused by the Salmonella group because S. typhi, an obligate parasite, has the capability of proliferating only in the gastrointestinal tract of human beings and not in that of animals (British Association for the Advancement of Science, 1977). This is supported by findings by Raffatellu et al. which reported that S. typhi possesses no animal reservoir and is transmissible through water and food from one human being to another (Raffatellu et al., 2007). Pui et al., 2011 also maintained that S. typhi only has human reservoir, and thus, could be easily transmitted through the consumption of mishandled food by infected individuals (Pui et al., 2011).
Pui et al., 2011 reported that the World Health Organization (WHO) estimates that 16 to 17 million typhoid cases occur annually, leading to approximately 600,000 mortality cases (Pui et al., 2011). This is parallel to the findings in a 2007 journal – “The Intestinal Phase of Salmonella Infections” which states that typhoid fever causes 16 million human cases with 600,000 deaths (Raffatellu, 2007). The statistics show that while the figures governing the number of deaths and cases do not experience any abrupt change, typhoid fever still remains a major health issue. Pui et al. further elaborates that typhoid fever is rampant in countries where food and water can be easily contaminated with sewage due to the deplorable state of the sanitary systems (Pui et al., 2011). A 1977 review by a Study Group of the British Association for the Advancement of Science reported that the endemic typhoid in Britain which occurred in the early 20th century was almost completely eradicated by systematic treatment and disposal of sewage and the introduction of chlorinated filtered water (British Association for the Advancement of Science, 1977). Thus, this supports the information in Pui et al. that prevention of contact of food and water with human waste to diminish the incidence rate of typhoid fever must be present, and this could be achieved by efficient sanitary systems (Pui et al., 2011).
Nonetheless, in the case of typhoid fever, diarrhea is an insignificant symptom unlike human gastroenteritis (Raffatellu et.al.).
The most well-known typhoid case is Typhoid Mary, spread by New-Yorker cook Mary Mallon to 22 individuals, among whom three died between 1900 and 1907. She further caused approximately 25 more cases before being isolated for life (Pui et al., 2011).
Human Gastroenteritis
Salmonella enterica serovar Typhimurium and S. Enteritidis, non-typhoidal Salmonella (NTS) serotypes, tend to cause gastroenteritis. Symptoms which include fever, nausea, vomiting and intestinal cramps usually develop 12 to 72 hours after the infection. Diarrhea is a significant symptom in gastroenteritis (Raffatellu et al., 2007). S. typhimurium most commonly infects cattle. Infected cows with diarrhea excreting S. typhimurium must be meticulously handled, and susceptible groups such as young children and geriatrics must not come in close contact with the livestock (British Association for the Advancement of Science, 1977; Department of Health, New York, 2011). The severity of S. typhimurium is supported by Ke et al. who reported that this serotype is one of the most common Salmonella serotypes which causes infectious diarrhea in the Guangdong province (Ke et al., 2009).
However, Cooke et al. reported that the data regarding non-typhoidal Salmonella infections are often hard to obtain as there is no requirement for the infected to consult with health professionals. It is estimated that for every reported case in England and Wales, there are three additional NTS cases (Cooke et al., 2007). However, in the case of uncomplicated gastroenteritis, the patient should be discouraged against taking antibiotics as they can prolong the effect of the excretion of Salmonella due the recuperation phase (British Association for the Advancement of Science, 1977)
Interestingly, a rare case of intracranial S. enteritidis abscess suffered by a 57-year-old man after glioblastoma resection is reported in an Arabian journal (Sait et al., 2011). This shows that the infection of S. enteritidis is not only confined to gastroenteritis.
Food Poisoning (Food-borne Illness)
Salmonella survives and thrives well in many types of food. Of recent, fruits and vegetables are found to be effective vehicles of Salmonellosis, in addition to eggs, livestock meat and dairy products. As such, Salmonella can enter the food chain at any stage, from food manufacturing to catering and home-prepared meals. In 2005, the greatest contributor to Salmonellosis food poisoning in Malaysia is S. typhi found in hawker food, accounting for 171 cases (Pui et al., 2011)
In minute amounts, Salmonella may not be potent enough to cause food poisoning, but when introduced into the gastrointestinal tract of susceptible individuals in large quantities, food poisoning is often inevitable (British Association for the Advancement of Science, 1977).
Paratyphoid Fever
Compared to typhoid fever, the epidemiology of paratyphoid fever is not as well-described as that of typhoid fever. Both the respective causative agents of typhoid and paratyphoid fevers, S. typhi and S. paratyphi A, have no animal reservoir (Pui et al., 2011).
It is estimated that approximately 25% of enteric fevers are due to S. paratyphi A, which is multiplying in great numbers in South Asia (Cooke et al., 2007). This is supported by a 2005 - 2008 study in a Rourkela general hospital in Orissa, India, a South Asian nation, stating that poor sanitation in slum areas and contaminated community water contributed to around-the-year Salmonellosis. A grave concern raised was the gradual increasing resistance of S. paratyphi A to various antibiotics administered (Bhattacharya et al., 2011).
However, a 2008 - 2009 research in Hongta, Yuxi City, Yunnan, China, an East Asian nation, highlighted that the Hongta District is an ideal endemic area for the transmission of S. paratyphi A, which results in paratyphoid fever A. 354 positive cases were reported in that district, with the age group (15 – 44 years) being the most susceptible (Sun et al., 2011). Another research in Yunnan, China (2011) reported that there is an area within the vicinity of Yuxi City which has an annual incidence rate of 207.45/100,000, similar to the report by Sun et al. which maintained that the annual incidence in Hongta of Paratyphoid A was 220.33/100,000 (Wang et al., 2011). Instant control measures must be implemented effectively as within the 3-year gap, the incidence rate has not dwindled much. Meteorological factors such as precipitation, temperature and humidity play a vital role in the transmission of the disease (Wang et al., 2011). Therefore, while S. paratyphi A is increasing in number in South Asia, other regions in the world must not be ruled out completely either, based on the statistics of the two researches mentioned above.
Co-infection of typhoid fever and paratyphoid fever is not likely to occur as both their transmission routes vary. Nonetheless, the disease trends of S. typhi and S. paratyphi A in developing countries are somewhat the same, and the infections caused by both serovars may be just as severe (Cooke et al., 2007).
Though not as common as diarrhea and vomiting, paratyphoid fever, along side typhoid fever, are reported also to suppress the bone marrow due to systemic infection. This condition, known as pancytopenia, is reported to have infected a four-year-old Nepali girl diagnosed with enteric fever (Pathak, et al., 2010).
Closer home, Singapore has enjoyed a conspicuous diminishment of enteric fever incidence in the last two decades compared to other developed countries, from 4.3/100,000 in 1990 to only 0.26/100,000 in 2009. This success is attributed to Singapore’s approach in planning its proactive and vigilance measures to suit the ever-changing epidemiology of enteric fevers in Singapore (Ty et al., 2010).
In essence, there is not much distinction between typhoid and paratyphoid fevers. Both share similar signs and symptoms and are synonymously known as enteric fever. The distinct difference between both fevers is: typhoid fever is caused by S. typhi, whilst paratyphoid fever is caused by S. paratyphi A.
Common Drugs for Treatment
Ciprofloxacin
Fluoroquinolones was the treatment of choice for typhoid fever effective 1990. To date, the most frequently used drugs globally to treat Salmonellosis are the fluoroquinolones. Two very distinctive examples are ciprofloxacin and ofloxacin (Cooke et al., 2007).
Ciprofloxacin is classified under the fluoroquinolone family of drugs. It targets the A subunit of the essential bacterial enzyme DNA gyrase (Hooper et al., 1987) of Salmonella. A pharmacological review from The American Academy of Family Physicians (AAFP) reported that quinolone rapidly inhibits the synthesis of DNA by promoting the separation of bacterial DNA in the DNA–enzyme complexes of DNA gyrase and Type IV DNA topoisomerase, leading to rapid bacterial death (Oliphant et al., 2002). Information from these two sources suggests that the mechanisms of drug action of ciprofloxacin and quinolones in general are similar. This explains why ciprofloxacin is categorized as a quinolone and it can be inferred that most quinolones can be used to treat Salmonellosis.
Bergan et al. hypothesized that there was homogenous distribution of ciprofloxacin systemically and thus, the high volume of distribution of the drug led to the belief that it might be twice as concentrated in the extra-vascular space (Bergan et al., 1988). This belief was confirmed two years later when studies showed that the large volume of distribution of ciprofloxacin allows the drug to penetrate into most tissues from the bloodstream. The absolute bioavailability of ciprofloxacin was reported to be approximately 70% (Vance-Bryan et al., 1990). Earlier, G. Hoffken et al. had proposed that ciprofloxacin has high volumes of distribution, which exceeds 200 L per 100 kg and effective diffusion can occur in the extra-vascular space (Hoffken et al., 1985).
Bergan et al. reported that 11.3% and 7.5% of ciprofloxacin were respectively excreted in the urine and fecal matter after an oral administration; 9.5% and 2.6% of ciprofloxacin were respectively eliminated in the urine and faeces, indicating little first-pass effect. They concluded that oral and intravenous administrations had similar metabolism both quantitatively and qualitatively (Bergan et al., 1988). On the other hand, in an earlier study by G. Hoffken et al., they discovered that the first-pass effect after oral administration was more significant. The ratio of the amount of metabolites to the total drug excreted in the urine decreased from 42.7 % after oral administration to 29.7% only after intravenous administration (Hoffken et al., 1985). The difference in results between these two studies can be associated with the health conditions of individuals studied. Thus, the only clear conclusion that can be synthesized is: Ciprofloxacin undergoes first-pass effect when administered orally. Besides, G. Hoffken et al. highlighted the presence of biologically active metabolites through bioassay testing of ciprofloxacin (Hoffken et al., 1985). This finding supports Bergan et al.’s which also stated that a biologically active metabolite, formylciprofloxacin, was detected in the urine (Bergan et al., 1988).
The renal clearance of ciprofloxacin was found to be 2.7 times higher than the creatinine clearance, implying that the drug is eliminated by glomerular filtration and tubular secretion (Bergan et al., 1988). However, in Vance-Bryan et al.’s publication, they maintained that in addition to renal clearance, ciprofloxacin is excreted via non-renal clearance routes such as via bile, metabolic degradation and transluminal secretion across the gut mucosa. Renal clearance routes only account for around 66% of the total serum clearance. The terminal disposition half-life of ciprofloxacin is between three to four hours (Vance-Bryan et al., 1990).
The data collected from all over the world via clinical trials suggest that ciprofloxacin when administered orally is relatively safe, bringing about only mild and reversible side effects. Out of 9473 courses studied, the total incidence of side effects among the patients treated with oral ciprofloxacin was only 9.3%. The incidence rate of severe reactions was only 0.6%. Side effects reported were commonly gastrointestinal reactions (Schacht et al., 1989). Nonetheless, in an older Canadian journal, it was found that while the most frequent side effects were gastrointestinal tract-related, there were incidences of adverse central nervous system effects (LeBel, 1988).
Unfortunately, as in the case of many drugs, ciprofloxacin experiences the issue of Salmonella resistance due to its extensive, specific antibacterial use. In many regions worldwide, S. typhi and S. paratyphi A infections no longer respond to fluoroquinolones, such as ciprofloxacin. Among the earlier cases of impending resistance was seen in Vietnam in 1994 when the treatment of nalidixic acid-resistant S. typhi strains proved less effective. Similar diminishment of ciprofloxacin sensitivity in treating Multidrug resistant (MDR) S. typhi was seen in a major epidemic in Tajikistan in 1997, where 60,000 people were infected after consuming contaminated water. In 2005, high levels of fluoroquinolone resistance were discerned in Karachi as far as S. typhi strains were concerned. In the United Kingdom the following year, 80% of human S. paratyphi A isolates exhibited further reduction of vulnerability to ciprofloxacin (Cooke et al., 2007).
A journal by C. Parry et al. also discussed quinolone-resistant typhoid fever in Vietnam in the 1990’s and further elaborated Cooke’s explanation of the Salmonella resistance in Vietnam. As fluoroquinolone resistance would occur, treatment may prove unaffordable for patients in endemic-stricken areas in the midst of challenging clinical evaluation for new economical typhoid treatment. For example, to effectively treat patients diagnosed with typhoid caused by quinolone-resistant Salmonella strains, a prolonged course of high-dose fluoroquinolone can fetch a cost of up to $USD 28 -42. Other examples include: azithromycin ($35- 50), oral and injectable cephalosporins ($80 – 90 and $150 – 200 respectively), as opposed to the normal treatment of nalidixic acid-sensitive typhoid which cost only $6- 10. It was discovered that these expensive treatment, however, are not very clinically effective because of higher fecal carriage rates, ultimately resulting in greater Salmonella transmission potential than the conventional quinolone-sensitive infections (Parry et al., 1998). Hence, antibiotics must not be abused and used excessively as this imprudent gesture can cause a rapid emergence of antibiotic resistance, rendering patients in high-risk impoverished nations such as India and African countries to be at a brutal disadvantage.
It was found that fluoroquinolones are not appropriate to be administered to children due to potential side effects on the cartilage as observed in young animals (Hohmann, 2001). Butler et al. also stated that fluoroquinolones are not approved to be used among children owing to their adverse effects on the growing bone (Butler et al., 1999). However, an exception is made provided that children are infected by resistant pathogens and when other antibiotics are unsuitable. Fluoroquinolones are given to children for around a week in nations where multidrug-resistant S.typhi infections are rampant (Hohmann, 2001).
Amoxicillin (AMPC)
Amoxicillin is derived from penicillin and categorized under beta-lactam antibiotics. It is degraded rapidly in an acidic environment (Aki et al., 2006). Amoxicillin is an aminopenicillin (Neu, 1979) and a relatively new semi-synthetic penicillin with a structure and activity level somewhat similar to ampicillin (Rolinson et al., 1974).
Amoxicillin is twice as effective at equivalent doses of ampicillin when administered in human beings. The concentration of blood serum amoxicillin was found to be twice that of ampicillin (Rolinson et al., 1974). This is supported by Neu’s findings which documented that amoxicillin is better absorbed in the gastrointestinal tract with blood serum levels 2 to 2.5 times higher than ampicillin (Neu, 1979). Peak blood serum concentrations are proportional to the dose of amoxicillin, with approximately 63% of it excreted in its parent form renally (Rolinson et al, 1984). Amoxicillin and clavulanic acid (Augmentin®) are well-absorbed orally and can reach peak blood serum levels in around 80 minutes, and an average half-life of around 68 minutes (Weber et al., 1984).
Food does not disturb the absorption of amoxicillin. Higher and longer-lasting levels of amoxicillin in the serum can be obtained when probenecid is administered concurrently (Rolinson et al., 1974).
Westphal et al.’s findings maintained that there exists a saturable carrier-mediated process for amoxicillin in human beings, independent of its concentration. They proposed that nifedipine, a calcium channel blocking agent, could augment the uptake of amoxicillin in the intestines via active transport because calcium channel blockade increases the absorption rate of the drug by 70% and its bioavailability by around 22% (Westphal et al., 1990).
Amoxicillin/clavulanic acid induces cholestatic hepatitis (Gresser, 2001). Nevertheless, in another study by Levine, it was found that throughout an 18-month surveillance period among children (1 month to 16 years), otitis media was the most common adverse effect of amoxicillin (856 patients out of 1009 patients). Other adverse effects include: gastrointestinal disturbances, pharyngitis, sinusitis, pneumonia, bronchitis and urinary tract infection (Levine, 1985). Yet another research revealed that the adverse effects for amoxicillin and amoxicillin/clavulanic acid are different (Salvo et al., 2007). For instance, the probability of the latter drug to cause hepatitis, Stevens-Johnson syndrome and purpura is higher than amoxicillin. It also supported the results obtained by Gresser in that amoxicillin/clavulanic acid is nine times more likely to cause hepatitis than amoxicillin alone (Gresser, 2001). Besides, the gastrointestinal, hepatic and haematological reactions are more significant for amoxicillin/clavulanic acid, whilst skin reactions are more common for amoxicillin (Salvo et al., 2007).
Amoxicillin can be used to treat typhoid fever caused by S. typhi which has become chloramphenicol-resistant. A study by Calderon reported that all typhoid patients who were administered with amoxicillin recovered fully after five days. Culture and sensitivity testing disclosed that the cultures were negative within three days and remained so after treatment (Calderon, 1974).
Co-trimoxazole (Trimethoprim-sulfamethoxazole / TMP-SMZ)
Co-trimoxazole (TMP-SMZ) is commonly administered in the treatment of non-typhoidal Salmonella infections (Hohmann, 2001).
Unfortunately, Salmonella has developed resistance against this drug (Hohmann, 2001). Chinh et al. supported this by maintaining that the emergence of multidrug-resistant (MDR) strains of Salmonella enterica serovar typhi can be observed in many countries, especially to drugs such as chloramphenicol, ampicillin and TMP-SMZ (Chinh et al., 2000). These MDR strains can be transmitted by immigrant workers in or the returning travelers to developed countries (Rowe et al., 1997).
Chloramphenicol
Chloramphenicol was the first antibiotic used for typhoid fever treatment, introduced in 1948. Then, chloramphenicol decreased the rates of typhoid death from 10% to less than 1% (Cooke et al., 2007).
Only two years later, the first chloramphenicol-resistant S. typhi was isolated in England. The drug still remained the treatment of choice as this S. typhi did not cause endemic or epidemic infections. In 1972, chloramphenicol resistance evolved into a dire clinical issue with simultaneous outbreaks in Mexico, Vietnam and India. 12 years later, chloramphenicol resistance was detected in Malaysia (Cooke et al., 2007). As such, with the global widespread of chloramphenicol-resistant strains, this first-line typhoid drug can no longer be utilized for treatment, and is replaced with the more effective ciprofloxacin (Rowe et al., 1997).
Interestingly, in India, a 1999 study of typhoid fever treatment with azithromycin and chloramphenicol in a randomized multi-centre trial concluded that the incidence of resistance was higher in chloramphenicol than the former. Besides, chloramphenicol showed 86% patient recovery and 94% Salmonella eradication, whilst azithromycin showed 88% patient recovery and 100% Salmonella eradication. Thus, this contradicts Rowe’s statement that chloramphenicol could no longer be used. Butler further reported that the higher incidence was due to frequent usage of chloramphenicol in the Indian subcontinents, as compared to azithromycin (Butler et al., 1999). It can be inferred that Salmonella strains in areas which have not been treated with a drug before can be eradicated. Nevertheless, frequent usage results in rapid resistance.
Contrary to popular belief, a 1978 study reported that the combination of a bactericidal agent and bacteriostatic agent (fosfomycin-chloramphenicol) resulted in synergism and hampered the effect of Salmonella. This led to the questioning of the antagonism concept involving bacteriostatic and bactericidal drugs (Perea et al., 1978).
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin and is used for Salmonella infections if the susceptibilities are not known (Hohmann, 2001). Chinh et al. supported Hohmann by stating that third generation cephalosporins serve as alternatives for treatment of MDR strains of S. typhi (Chinh et al., 2000).
Since fluoroquinolones are not administered in children infected with Salmonella, ceftriaxone is an alternative. Ceftriaxone is used in the treatment of typhoid fever among children and is given parenterally (Soe et al., 1987). Nevertheless, azithromycin is the more preferred drug as the frequency of relapse when azithromycin is administered is zero; relapse frequency was evident with ceftriaxone. Ceftriaxone brings about gastrointestinal disturbances but no severe side effects (Frenck et al., 2000).
Unfortunately, high-level resistance to ceftriaxone has been detected in Bangladesh among isolates of S. typhi (Chinh et al., 2000).
Azithromycin
Azithromycin is an azalide, the first broad-spectrum antibiotic group and is beneficial in the treatment of Salmonella. It possesses a nitrogen atom in the macrolide aglycone ring. This drug is rapidly transferred from the blood plasma into the tissues. Therefore, the concentration of azithromycin is higher in the tissues than in the blood plasma. The prolonged half-life of azithromycin is related to the extensive uptake of the drug and subsequent liberation of the drug from the tissues. The maintenance of a high concentration of azithromycin in the body cells and tissues allows the effective treatment of Salmonellosis. This is also attributed to the high steady state volume of distribution (31.1 L/kg.) and plasma clearance (630 mL/min) (Butler et al., 1999).
Hohmann supported the effectiveness of azithromycin by stating that it is used for treatment of both typhoidal and non-typhoidal Salmonellosis, although in a limited manner. Azithromycin has high efficacy in treating patients with multiple allergies and infections resulted by drug-resistant Salmonella strains (Hohmann, 2001). The 2000 journal by Chinh et al. reported similarly to Hohmann and documented that high intracellular concentrations of azithromycin enhances in vivo activity against S. typhi. Azithromycin displays only moderate activity in vitro. Chinh’s study also concluded that azithromycin, after being taken for approximately 5 days, could effectively treat adult uncomplicated enteric fever, MDR infections and nalidixic acid-resistant S. typhi strains (Chinh et al., 2000).
As azithromycin is not used extensively in high-risk nations like India, resistance of Salmonella towards this drug is not expected (Butler et al., 1999).
Drug resistance is an inevitable phenomenon. Salmonella, like other bacteria, can change their metabolism pathways and develop more sophisticated structures and efflux systems to render themselves less susceptible to drugs. As such, excessive use of potent drugs to treat Salmonellosis must be avoided to prevent rapid drug resistance in Salmonella strains. Besides, the search for new drugs to overcome Salmonellosis must be an on-going process. While fluoroquinolones are still the treatment of choice today, it will not be long before most Salmonella strains develop resistance to this group of drugs, like chloramphenicol.
Prevention of Salmonellosis
Quite recently, a longitudinal study in Bangalore, India, investigated the morbidity rate due to water-borne diseases and the bacteriological quality of water. It was discovered that the majority were diarrheal cases and thus, it was concluded that in developing countries, diarrheal diseases can be prevented by having sufficient safe and clean drinking water (Jadhav, 2011).
A research from the Food Science and Human Nutrition Department, University of Florida, reported that an understanding on the outbreaks and factors mediating plant produce contamination allows the development of intervention strategies to minimize the risk of such contamination by Salmonella. Therefore, Salmonellosis is not only confined to animal-based products (Fatica et al., 2011). This is supported by the findings of Romling et al. that the increase in food-borne outbreaks by Salmonella involving fruits and vegetables is due to plants being vital vectors for transmission of Salmonella between hosts (Romling et al., 2007).
Other more common methods include washing one’s hands prior to eating and cooking meat thoroughly before serving.

Conclusion

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While the advancement of medical technology proves promising, the speed at which Salmonella strains develop resistance against drugs should not be taken lightly. It is apprehensive to know that even the most effective of drugs - the fluoroquinolones, have actually become less sensitive to certain Salmonella strains in certain parts of the world to date. It will not be too long before fluoroquinolones are rendered obsolete and useless in treating Salmonellosis as Salmonella evolve and mutate into stronger strains. As such, drugs prescribed for Salmonellosis treatment and prevention should be used prudently without abuse in order to slow down the emergence of such resistance.
The continual discovery of more efficient drugs to hamper diseases caused by Salmonella strains goes hand-in-hand with the developing resistance in these strains. Thus, treatments may become more exorbitant and patients in poorer nations would not be able to afford them.
The occurrences of Salmonellosis can be prevented by good hygiene and meticulous handling of water, fruits, vegetables and meat prior to consumption. Governments in poorer nations should heed the call in improving their sanitary systems in the hope that the incidences of Salmonellosis could be plummeted. Consumers can prevent themselves from being infected with Salmonella by very simple yet crucial actions such as: washing their hands before meals and refraining from having meals at unhygienic places, especially hawker stalls.
Romling et al. documented that the biofilm formation of Salmonella strains, most notably S. enterica showed reduced vulnerability to antimicrobial agents. This biofilm can also form on plant surfaces, epithelial cells, air-liquid interface and many other surfaces. Scientists have only started studying these biofilms in recent years (Romling et al., 2007). Hopefully, future drugs which could target these biofilms instead of targeting in-built bacterial mechanisms could result in the inhibition of Salmonella.

Acknowledgements

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The authors are very grateful to the School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, for serving as the platform upon which the realization of this review is made possible.

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