|Year : 2011 | Volume
| Issue : 3 | Page : 223-229
Antimicrobial resistance in typhoidal salmonellae
BN Harish1, GA Menezes2
1 Department of Microbiology, Institute of National Importance, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry - 605 006, India
2 Department of Microbiology, Institute of National Importance, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry - 605 006;Department of Microbiology, SSR Medical College, Belle Rive, Mauritius and Sree Balaji Medical College & Hospital, Chennai, India
|Date of Submission||26-Jun-2011|
|Date of Acceptance||27-Jun-2011|
|Date of Web Publication||17-Aug-2011|
B N Harish
Department of Microbiology, Institute of National Importance, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry - 605 006
Source of Support: None, Conflict of Interest: None
Infections with Salmonella are an important public health problem worldwide. On a global scale, it has been appraised that Salmonella is responsible for an estimated 3 billion human infections each year. The World Health Organization (WHO) has estimated that annually typhoid fever accounts for 21.7 million illnesses (217,000 deaths) and paratyphoid fever accounts for 5.4 million of these cases. Infants, children, and adolescents in south-central and South-eastern Asia experience the greatest burden of illness. In cases of enteric fever, including infections with S. Typhi and S. Paratyphi A and B, it is often necessary to commence treatment before the results of laboratory sensitivity tests are available. Hence, it is important to be aware of options and possible problems before beginning treatment. Ciprofloxacin has become the first-line drug of choice since the widespread emergence and spread of strains resistant to chloramphenicol, ampicillin, and trimethoprim. There is increase in the occurrence of strains resistant to ciprofloxacin. Reports of typhoidal salmonellae with increasing minimum inhibitory concentration (MIC) and resistance to newer quinolones raise the fear of potential treatment failures and necessitate the need for new, alternative antimicrobials. Extended-spectrum cephalosporins and azithromycin are the options available for the treatment of enteric fever. The emergence of broad spectrum β-lactamases in typhoidal salmonellae constitutes a new challenge. Already there are rare reports of azithromycin resistance in typhoidal salmonellae leading to treatment failure. This review is based on published research from our centre and literature from elsewhere in the world. This brief review tries to summarize the history and recent trends in antimicrobial resistance in typhoidal salmonellae.
Keywords: β-lactamases, cephalosporins, fluoroquinolone, quinolone-resistance determining region, typhoidal salmonellae
|How to cite this article:|
Harish B N, Menezes G A. Antimicrobial resistance in typhoidal salmonellae. Indian J Med Microbiol 2011;29:223-9
| ~ Introduction|| |
Salmonella More Details are one of the most common causes of food-borne illness in humans. There are many types of Salmonella, but they can be divided into two broad categories: Those that cause typhoid and those that do not. The typhoidal Salmonella, such as S. Typhi and S. Paratyphi, only colonize humans and are usually acquired by the consumption of food or water contaminated with human faecal material. Enteric fever is most commonly caused by S. enterica subsp. enterica serovars Typhi (S. Typhi) and Paratyphi A. S. Typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos.
Salmonella diarrhoea is generally self-limiting, and antimicrobials are usually not required for treatment. They are critical, however, to the successful outcome of invasive infections and enteric fever. Further, if not treated properly, enteric fever carries a mortality rate of 30%, whilst appropriate antimicrobial treatment reduces the mortality rate to as low as 0.5%.  In this respect, in cases of enteric fever, it is often necessary to commence treatment before the results of laboratory sensitivity testing become available. Resistance to the older antimicrobials, chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole (co-trimoxazole), termed as multidrug resistance has been present for many years. Hence, the fluoroquinolone (FQ), ciprofloxacin has become the first-line drug for treatment, especially since the global emergence of S. Typhi isolates that are multidrug resistant (MDR).  Treatment failures have been defined in strains displaying decreased ciprofloxacin susceptibility (DCS) [ciprofloxacin minimum inhibitory concentration (MIC) of 0.125-1.0 μg/ml].  Nalidixic acid resistance has been a reliable indicator of such isolates, which has become common in many areas. However, switch to ciprofloxacin has led to a subsequent increase in the occurrence of typhoidal salmonellae resistant to this antimicrobial agent.  This review re-emphasizes the past and current problems encountered in the treatment of enteric fever.
Encounter with multidrug resistance
Ampicillin and trimethoprim/sulphamethoxazole were used as alternative antibiotics, to be used when chloramphenicol was contraindicated, as in the event of hematological complications, or if the organism was resistant to it. Ampicillin and amoxicillin have been the treatment of choice in pregnancy and neonates.  Since the emergence of plasmid-mediated chloramphenicol resistance in the typhoid bacillus in the early 1970s, the effectiveness of chloramphenicol as a first-line drug has been increasingly challenged by outbreaks caused by strains with resistance to this antimicrobial in countries as far apart as Mexico and India. In the succeeding five years, outbreaks occurred in Vietnam, Indonesia, Korea, Chile and Bangladesh.  A feature common to all these chloramphenicol-resistant strains from such outbreaks was that although the strains belonged to different Vi PTs, resistance to chloramphenicol - often in combination with resistance to streptomycin, sulfonamides, and tetracyclines (R-type CSSuT) - was encoded by a plasmid of the H1 incompatibility group (now termed as HI1). 
Resistance to all first line antimicrobials- ampicillin, trimethoprim-sulfamethoxazole and chloramphenicol- is defined as multidrug resistance (MDR).  Chloramphenicol acetyl transferase inactivates the drug by adding two acetyl groups to it.  A second mechanism of resistance to chloramphenicol is based on the loss of an OMP.  Ampicillin resistance is mediated by the production of β-lactamases (usually TEM-1, and therefore inhibited by clavulanic acid). Trimethoprim-sulfamethoxazole resistance is mediated by alteration in the enzyme targets dihydrofolate reductase and dihydropteroate synthase respectively. 
The indian scenario of MDR
The first reported outbreak of chloramphenicol resistant S. Typhi in India was in 1972. Over the next two decades, the incidence of resistant strains, including MDR ones, increased in many parts of the country. Multidrug resistance was initially reported as outbreaks in the northern and eastern parts of the country, following which it became established in those regions. In peninsular India, the spread of MDR strains was more gradual, though outbreaks were reported from time to time. In a study of isolates from all over India during 1990-1992, 64.5% of S. Typhi were found to be MDR. The maximum number of MDR isolates was seen in central India (71.32%), whereas it was least in the south (55.2%).  In west India, MDR among S. Typhi isolates in Mumbai was estimated to have increased from 6.2% in 1988 to 68% in 1990.  In a recent report from north Karnataka (Gulbarga), 10% of the isolates were found to be MDR. 
In Pondicherry, between 2002 and 2003 , 38.8% were MDR and a decline in the number of MDR isolates was noted.  Since 1989, following the emergence of strains with resistance to ampicillin, chloramphenicol and trimethoprim, ciprofloxacin has become the first-line drug in both developing and developed countries. In a prospective study in Pondicherry, during 2005-2009, a total of 338 S. Typhi isolates were recovered from two hospitals. Of these isolates, 222 (66%) were fully susceptible to ampicillin, chloramphenicol and cotrimoxazole; and 74 (22%) were MDRST. The following resistance pattern of S. Typhi observed: chloramphenicol, 22%; ampicillin, 24%; and cotrimoxazole, 30%. When compared, our present observations with those from our previous years, there was a steady decline in the number of MDRST isolates over the study period, as well as a parallel increase in NARST (non-MDR) isolates. A remarkable decrease over the years in resistance to chloramphenicol, ampicillin, and cotrimoxazole was noticed. ,
The beginning of a new era - fluoroquinolones
In 1962, a quinolone derivative, nalidixic acid, was discovered. It had adequate activity against Gram-negative aerobes, but it could not be used to treat systemic infections. This hurdle was overcome with the discovery of the FQs. Ciprofloxacin, discovered in 1981, and contained a cyclopropyl group on position 1 of the quinolones ring.
Quinolones are highly active against salmonellae in vitro. Ciprofloxacin (500 mg twice daily for 10 days) was superior to chloramphenicol in the treatment of S. Typhi infection (50 mg/kg per day divided into four doses for 14 days).  Short course therapy with ofloxacin (10-15 mg/kg divided twice daily for 2 -3 days) was found to be simple, safe and effective in the treatment of uncomplicated MDR typhoid fever when the strain was susceptible to nalidixic acid.  This is an especially valuable attribute, because it decreases the economic burden of the patients who are often of the low income strata.
Quinolone targets are different in Gram-negative and Gram-positive microorganisms. In Gram-negative bacteria the primary target is DNA gyrase, whereas in Gram-positive bacteria it is topoisomerase IV. DNA gyrase is a tetrameric enzyme composed of two A subunits and two B subunits (A 2 B 2 ), encoded by gyrA and gyrB, respectively. Topoisomerase IV is an A 2 B 2 enzyme as well, encoded by parC and parE.
Challenge for FQs
The wide distribution and high prevalence of MDR among Salmonella species led to FQs (e.g. ciprofloxacin, ofloxacin) assuming a primary role in the therapy for invasive Salmonellosis More Details, including typhoid fever.
Isolates fully susceptible to ciprofloxacin by disc testing typically have a ciprofloxacin MIC of less than 0·03 μg/ml and are invariably also susceptible to the first generation quinolone, nalidixic acid. In the late 1980s and early 1990s, fluoroquinolones like ciprofloxacin were found to be highly useful for the treatment of typhoid fever.  A few years after the introduction of fluoroquinolones as therapy for typhoid fever, treatment failure was reported with ciprofloxacin. In 1992, from the United Kingdom, Rowe et al. reported a case of typhoid fever (apparently contracted in India) in a child who did not respond to treatment. S. Typhi isolated from this patient was subsequently shown to be NAR and had a ciprofloxacin MIC of 0.6 μg/ml.  Treatment failure is lack of defervescence even after seven days of treatment with ciprofloxacin. 
It was soon observed that a population of isolates exists with an MIC of 0.125-1.0 μg/ml that seems to be susceptible to ciprofloxacin by disc testing but is associated with clinical failure and is resistant to nalidixic acid (NAR strains).
The response of NAR isolates to short course regimens is poor.  Treatment failures are more likely with standard regimens. Patients with NAR strains require a higher dose of ciprofloxacin (10 mg/kg twice daily for 10 days) or ofloxacin (10-15 mg/kg divided twice daily for 7-10 days). 
Nalidixic acid resistance and decreased ciprofloxacin susceptibility
Among salmonellae isolates that are resistant to ciprofloxacin by disc testing have an MIC higher than 2.0 μg/ml and are resistant to nalidixic acid. However, many workers have found that salmonellae with lower MICs, falling within the CLSI sensitive range may also be NAR.  Salmonella strains isolated from animals in Canada from 1998 to 1999 showing DCS (MIC 0.125 - 0.5 mg/ml) were all NAR.  Studies generally show that isolates with DCS exhibit NAR, although there are rare exceptions. The global distribution of MDR and NAR S. Typhi is shown in [Figure 1].
|Figure 1: Global distribution of MDR and NAR Salmonella enterica serovar Typhi (since 1990)|
Click here to view
The widespread use of fluoroquinolones has also been associated with decreased susceptibility and documented resistance to this class of drugs. Patients with enteric fever due to isolates with DCS are more likely to have prolonged fever clearance times and higher rates of treatment failure.  In addition to DCS, ciprofloxacin resistance has been reported among both S. Typhi and S. Paratyphi A.
Quinolone resistance in Salmonella is usually associated with mutations of the target site, DNA gyrase, most commonly in the quinolone resistance-determining region (QRDR) of the A subunit. Plasmid mediated quinolone resistance genes of qnr (qnrA, qnrB, qnrS, and qnrD) and aac(6')-Ib-cr has also been described in quinolone-resistant non-Typhi Salmonella. , Recent report confirms the qnrS1 from S. Typhi, demonstrating the role of plasmid-mediated fluoroquinolone resistance.  The targets for fluoroquinolones are DNA gyrase and topoisomerase IV, whose subunits are encoded by gyrA and gyrB and by parC and parE genes, respectively. The exact mechanism of resistance is not fully understood but various studies have found that single point mutations in the QRDR of gyrA gene (spanning amino acids amino acids 67 to 106) confer resistance to nalidixic acid and reduced susceptibility to fluoroquinolones.  In contrast, high-level ciprofloxacin resistance may be due to either a) the cumulative impact of mutations in many genes, b) decreased membrane permeability, c) active efflux pump, and/or d) the presence of plasmid-encoded qnr genes. 
In 2002, a high-level ciprofloxacin-resistant (MIC >128 μg/ml) S. Paratyphi A was isolated from Japan.  Saha et al., in 2006, reported three strains of highly ciprofloxacin-resistant (MIC, 512 μg/ml) S. Typhi from Bangladesh.  Enteric fever in developed countries mainly occurs in returning travellers and as such gives a snapshot picture of the occurrence of resistance in the countries visited.
The indian scenario of FQ Resistance
In developing countries such as India, ciprofloxacin continues to be the mainstay in the treatment of enteric fever as it is orally effective and economical. The emergence of S. Typhi highly resistant to ciprofloxacin is a cause for worry. Ciprofloxacin though is the first-line drug of choice; there is upsurge in the occurrence of strains resistant to ciprofloxacin. 
There are reports of high-level ciprofloxacin resistant typhoidal salmonellae from many centers in India [Table 1]. Isolate from Pondicherry,  with a ciprofloxacin MIC of 64 μg/ml was still susceptible to most of the first-line antibacterial agents, and this is different from the other cases reported in India where S. Typhi strains are resistant to first-line antibiotics as well as fluoroquinolones. 
|Table 1: Studies reporting high-level ciprofl oxacin resistance in Salmonella enterica serovar Typhi and Paratyphi A in India|
Click here to view
Emergence of resistance to third-generation cephalosporins
As fluoroquinolone use continues to expand and as DCS and fluoroquinolone resistance drives the use of third-generation cephalosporins and other agents for the management of enteric fever, new patterns of antimicrobial resistance can be anticipated. Patterns of antimicrobial resistance seen in non-Typhi Salmonella species and Enterobacteriaceae may emerge in S. Typhi and S. Paratyphi. Although quinolone resistance among Enterobacteriaceae usually arises as the result of mutations in the QRDR of gyrA, plasmid-mediated resistance is increasingly recognized. Plasmid-mediated quinolone resistance (PMQR) is associated with qnr genes that encode a protein that protects DNA gyrase from ciprofloxacin and by aac(6')-Ib-cr, an aminoglycoside modifying enzyme with activity against ciprofloxacin.  Plasmids bearing qnr or aac(6')-Ib-cr may also contain an extended spectrum cephalosporin resistance gene, which would pose a threat to the success of two major antimicrobial classes (fluoroquinolone and cephalosporin) for the management of invasive salmonellosis.
Indeed, there are sporadic reports of high-level resistance to ceftriaxone in typhoidal salmonellae where CTX-M-15 and SHV-12 extended spectrum β- lactamases (ESBLs) have recently been reported.,, Recently, for the first time ACC-1 AmpC β- lactamase producing S. Typhi has been reported.  Spread of broad-spectrum β-lactamases would greatly limit therapeutic options and leave only carbapenems and tigecycline as secondary antimicrobial drugs.
| ~ Conclusions|| |
Prevention of Salmonella infection relies also on the improvement of hygiene measures all along the food chain through the hazard analysis control critical point (HACCP) approach, and by individual education on food hygiene and practices such as the appropriate cooking of meats and eggs, particularly among high-risk groups.
Typhoid prevention measures target hand washing, sanitary disposal of human feces, provision of safe public water supplies, controlling of flies, scrupulous food preparation, and pasteurization of milk and other dairy products.
Immunity against typhoid is conferred after infection or through vaccination. In either case, it is only temporary. Typhoid fever vaccine can be given orally or parenterally, and the efficacy of, and adverse reactions to, each type differ.  Vaccination is often recommended for people travelling to endemic regions, although the cost-effectiveness of this strategy has been questioned.  The effectiveness of mass vaccination in endemic regions is undergoing further study but should be considered in high-risk situations, such as disaster relief sites and refugee camps.
Ideal antimicrobial treatment of patients with enteric fever depends on an understanding of local patterns of antimicrobial resistance and is enhanced by the results of antimicrobial susceptibility testing of the Salmonella isolated from the individual patient. Ciprofloxacin continues to be widely used, but clinicians need to be aware that patients infected with Salmonella with DCS may not respond adequately.  In this circumstance, third-generation cephalosporins, such as ceftriaxone, may be used. However, the cost and route of administration make ceftriaxone less suitable for patient treatment in some low- and middle-income countries, and the oral third-generation cephalosporin cefixime appears to be inferior to other oral agents both in terms of fever clearance time and treatment failure.  In these circumstances, recent clinical trials suggest that azithromycin treatment (500 mg once daily for seven days for adults or 20 mg/kg/day up to a maximum of 1000 mg/day for seven days for children) is useful for the management of uncomplicated typhoid fever.  Because of its pharmacokinetic profile, gatifloxacin has potential as a new agent for treating patients infected with isolates with DCS,  but carries risk for dysglycemia, which may limit its widespread use.
Although the use of azithromycin, tigecycline and carbapenem is not recommended by CLSI, yet it may become crucial, especially in the setting of ciprofloxacin-resistant and ESBL-producing salmonellae in enteric fever. 
Re-emergence of chloramphenicol sensitive strains in previously resistant areas points towards the concept of antibiotic recycling, preserving the use of older antibiotics.  Antibiotic recycling has been used successfully in hospital settings. But, a high relapse rate; a high rate of continued and chronic carriage, and bone marrow toxicity are other concerns with reuse of chloramphenicol for the treatment of typhoid fever.  The spread of fluoroquinolone resistant S. Typhi may necessitate a change towards 'evidence-based' treatment for typhoid fever. In order to better manage and prevent the spread of antimicrobial resistance, both clinicians and governments require accurate information. 
The consequences of antimicrobial resistance not only have a profound impact on healthcare systems as a whole, but also on patients, society and the general economy. When antimicrobial agents are used incorrectly, for too short a time, at too low a dose, at inadequate potency, or for the wrong diagnosis, the likelihood that bacteria will adapt and replicate, rather than be killed, is greatly enhanced. Major factors identified by WHO in initiating and promoting antimicrobial resistance include, a) the unnecessary use of antibiotics by humans; b) the misuse of antibiotics by health professionals; c) over-the-counter availability of antibiotics in many countries; d) patient failure to follow the prescribed course of treatment; and e) the use of antibiotics in animal feeds as growth hormones. Individual education about these aspects would be foremost important in control of salmonellosis.
| ~ Acknowledgement|| |
The authors sincerely thank Indian Council of Medical Research (ICMR), New Delhi, India for the financial assistance for the work on antimicrobial resistance in typhoidal salmonellae during the years 2005-2010.
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