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1Indian Journal of Medical Microbiology, (2011) 29(3): 223-9

*Corresponding author (email:)

Department of Microbiology, Institute of National Importance,

Jawaharlal Institute of Postgraduate Medical Education and

Research (JIPMER), (BNH, GAM) Pondicherry - 605 006, India,

Department of Microbiology, SSR Medical College, (GAM) Belle

Rive, Mauritius and Sree Balaji Medical College & Hospital,

Chennai, India.

Received: 26-06-2011

Accepted: 27-06-2011

Review Article

Antimicrobial resistance in typhoidal salmonellae

*BN Harish, GA Menezes

Abstract

Infections with Salmonellaare an important public health problem worldwide. On a global scale, it has been appraised

that Salmonellais 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. Ciprooxacin has

become the rst-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 ciprooxacin. 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 -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 researchfrom 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.

Key words: -lactamases, cephalosporins, uoroquinolone, quinolone-resistance determining region, typhoidal

salmonellae

Access this article online

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DOI:

10.4103/0255-0857.83904

PMID:

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Introduction

Salmonella 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%.[1]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

trimethoprimsulfamethoxazole (co-trimoxazole), termed as

multidrug resistance has been present for many years. Hence,

the uoroquinolone (FQ), ciprooxacin has become the rst-

line drug for treatment, especially since the global emergence

of S. Typhi isolates that are multidrug resistant (MDR).[2]

Treatment failures have been dened in strains displaying

decreased ciprooxacin susceptibility (DCS) [ciprooxacin

minimum inhibitory concentration (MIC) of 0.1251.0 g/

ml].[3]Nalidixic acid resistance has been a reliable indicator

of such isolates, which has become common in many areas.

However, switch to ciprooxacin has led to a subsequent

increase in the occurrence of typhoidal salmonellae resistant

to this antimicrobial agent.[4] This review re-emphasizes the

past and current problems encountered in the treatment of

enteric fever.

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224 Indian Journal of Medical Microbiology vol. 29, No. 3

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.[5]Since the

emergence of plasmid-mediated chloramphenicol resistance

in the typhoid bacillus in the early 1970s, the effectiveness

of chloramphenicol as a rst-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 ve years, outbreaks occurred

in Vietnam, Indonesia, Korea, Chile and Bangladesh.[6]

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 (nowtermed as HI1).[7]

Resistance to all rst line antimicrobials- ampicillin,

trimethoprim-sulfamethoxazole and chloramphenicol- is

dened as multidrug resistance (MDR).[8]Chloramphenicol

acetyl transferase inactivates the drug by adding two

acetyl groups to it.[9] A second mechanism of resistance

to chloramphenicol is based on the loss of an OMP.[10]

Ampicillin resistance is mediated by the production of

b-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.[9]

The indian scenario of MDR

The rst 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 19901992, 64.5% of S. Typhi werefound 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%).[11] In west India, MDR among S. Typhi

isolates in Mumbai was estimated to have increased from

6.2% in 1988 to 68% in 1990.[12] In a recent report from

north Karnataka (Gulbarga), 10% of the isolates were found

to be MDR.[13]

In Pondicherry, between 2002 and 2003, 38.8% were

MDR and a decline in the number of MDR isolates

was noted.[14] Since 1989, following the emergence of

strains with resistance to ampicillin, chloramphenicol

and trimethoprim, ciprooxacin has become the rst-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.[15,16]

The beginning of a new era - uoroquinolones

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. Ciprooxacin, discovered in 1981, and contained a

cyclopropyl group on position 1 of the quinolones ring.

Quinolones are highly active against salmonellae in

vitro. Ciprooxacin (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).[17]Short course therapy with ooxacin (10-15 mg/kg

divided twice daily for 2 3 days) was found to be simple,

safe and effective in the treatment of uncomplicated MDRtyphoid fever when the strain was susceptible to nalidixic

acid.[18] 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 subunitsand two B

subunits (A2B

2), encoded by gyrA and gyrB, respectively.

Topoisomerase IV is an A2B

2 enzyme aswell, encoded by

parCandparE.

Challenge for FQs

The wide distribution and high prevalence of MDR

among Salmonella species led to FQs (e.g. ciprooxacin,

ooxacin) assuming a primary role in the therapy for

invasive salmonellosis, including typhoid fever.

Isolates fully susceptible to ciprooxacin by disc testing

typically have a ciprooxacin MIC of less than 003 g/ml

and are invariably also susceptible to the rst generation

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225July-September 2011

quinolone, nalidixic acid. In the late 1980s and early 1990s,

uoroquinolones like ciprooxacin were found to be highly

useful for the treatment of typhoid fever.[19]A few years after

the introduction of uoroquinolones as therapy for typhoid

fever, treatment failure was reported with ciprooxacin. 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 fromthis patient was subsequently shown to be NAR and had a

ciprooxacin MIC of 0.6 g/ml.[20]Treatment failure is lack

of defervescence even after seven days of treatment with

ciprooxacin.[18]

It was soon observed that a population of isolates

exists with an MIC of 0.1251.0 g/ml that seems to be

susceptible to ciprooxacin 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.[18]Treatment failures are more likely with standard

regimens. Patients with NAR strains require a higher

dose of ciprooxacin (10 mg/kg twice daily for 10 days)

or ooxacin (10-15 mg/kg divided twice daily for 7-10

days).[21]

Nalidixic acid resistance and decreased ciprooxacin

susceptibility

Among salmonellae isolates that are resistant to

ciprooxacin by disc testing have an MIC higher than 2.0

g/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.[22]

Salmonella strains isolated from animals in Canada from

1998 to 1999 showing DCS (MIC 0.125 - 0.5 mg/ml) were

all NAR.[23]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.

Fluoroquinolone resistance

The widespread use of uoroquinolones has also been

Figure 1:Global distribution of MDR and NAR Salmonella entericaserovar Typhi (since 1990)[51]

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associated with decreased susceptibility and documentedresistance 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.[24] In addition to DCS, ciprooxacin resistance has

been reported among both S. Typhi and S.Paratyphi A.

Quinolone resistance in Salmonellais 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-crhas also been described in quinolone-resistant

non-Typhi Salmonella.[25,26] Recent report conrms the

qnrS1 from S. Typhi, demonstrating the role of plasmid-

mediated uoroquinolone resistance.[27] The targets for

uoroquinolones are DNA gyrase and topoisomerase IV,

whose subunits are encoded by gyrA andgyrB and byparC

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

uoroquinolones.[28] In contrast, high-level ciprooxacinresistance may be due to either a) the cumulative impact

of mutations in many genes, b) decreased membrane

permeability, c) active efux pump, and/or d) the presence

of plasmid-encoded qnrgenes.[29]

In 2002, a high-level ciprooxacin-resistant (MIC >128

g/ml) S. Paratyphi A was isolated from Japan.[30] Saha et

al., in 2006, reported three strains of highly ciprooxacin-

resistant (MIC, 512 g/ml) S. Typhi from Bangladesh.[31]

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, ciprooxacin

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 ciprooxacin is a cause for

worry. Ciprooxacin though is the rst-line drug of choice;

there is upsurge in the occurrence of strains resistant to

ciprooxacin.[4]

Table 1: Studies reporting high-level ciprofoxacin resistance inSalmonella entericaserovar Typhi and Paratyphi A in

India

Serovar No. of isolates Year and place of

isolation

MIC of CIP (g/mL) Year published and

references

S. Typhi 3 2001 - 2003; 32 (2006) [49]

North India

S. Typhi 1 1999 2004; 16 (2006) [50]

North India

S. Paratyphi A 2 2001 - 2003; 8 (2006) [49]

North India

S. Paratyphi A 1 2004; 8 (2004) [48]

South India

S. Typhi 2 2004; 16 (2008) [32]

South India

S. Paratyphi A 4 2004 - 2005; 8 - 32 (2006) [47]

South India

S. Typhi 1 2005; 16 (2005) [46]

North India

S. Typhi, S. Paratyphi A 28 2005 - 2006; 8 - 512 (2007) [45]*

North IndiaS. Typhi 5 2006; >2 (2007) [44]

South India

S. Paratyphi A 6 2006; >2 (2007) [44]

South India

S. Typhi 22 2005 - 2006; 16 - >32 (2008) [43]

North India

S. Typhi 1 2006 2007; 4 (2010) [13]

South India

S. Typhi 1 2007; 64 (2008) [4]

South India

CIP Ciprooxacin. *This report doesnt clearly indicate MIC of S. Typhi and S. Paratyphi A individually.

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Typhoid fever vaccine can be given orally or parenterally,

and the efcacy of, and adverse reactions to, each

type differ.[38] Vaccination is often recommended for

people travelling to endemic regions, although the cost-

effectiveness of this strategy has been questioned.[38] 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 refugeecamps.

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. Ciprooxacin

continues to be widely used, but clinicians need to be

aware that patients infected with Salmonella with DCS

may not respond adequately.[24]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 cexime appears to be inferior to other oral

agents both in terms of fever clearance time and treatment

failure.[39] 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.[40] Because

of its pharmacokinetic prole, gatioxacin has potential as

a new agent for treating patients infected with isolates with

DCS,[41]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 ciprooxacin-

resistant and ESBL-producing salmonellae in enteric

fever.[42]

Re-emergence of chloramphenicol sensitive

strains in previously resistant areas points towards the

concept of antibiotic recycling, preserving the use of

older antibiotics.[16] 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 ofchloramphenicol for the treatment of typhoid fever.[21] The

spread of uoroquinolone 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.[21]

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

There are reports of high-level ciprooxacin resistant

typhoidal salmonellaefrom many centers in India [Table 1].

Isolate from Pondicherry,[4] with a ciprooxacin MIC of

64 g/ml was still susceptible to most of the rst-line

antibacterial agents, and this is different from the other cases

reported in India where S. Typhi strains are resistant to rst-

line antibiotics as well as uoroquinolones.[32]

Emergence of resistance to third-generation cephalosporins

As uoroquinolone use continues to expand and

as DCS and uoroquinolone 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

Enterobacteriaceaeusually 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 ciprooxacin and

by aac(6)-Ib-cr, an aminoglycoside modifying enzyme

with activity against ciprooxacin.[33] 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

(uoroquinolone 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 - lactamases(ESBLs) have recently been reported.[34-36]Recently, for the

rst time ACC-1 AmpC - lactamase producing S.Typhi has

been reported.[37] Spread of broad-spectrum -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 ies, 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.

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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 identied 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 antibioticsin 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 nancial assistance

for the work on antimicrobial resistance in typhoidal salmonellae

during the years 2005-2010.

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Source of Support:Nil, Conict of Interest:None declared.

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