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Published Date: 2011-11-05 16:54:34
Subject: PRO/EDR> Antibiotic resistance, Salmonella typhi - India (02): (Mumbai) fluoroquinolones
Archive Number: 20111105.3296

ANTIBIOTIC RESISTANCE, SALMONELLA TYPHI - INDIA (02): (MUMBAI)
FLUOROQUINOLONES
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Date: Thu 3 Nov 2011
From: Amit Arjyal [edited]
<amitarjyal@yahoo.com>

Re: ProMED-mail post Antibiotic resistance, Salmonella typhi - India:
(Mumbai) fluoroquinolones 20111031.3235
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Doctors from Lilavati and Hinduja hospitals in Mumbai have reported
cases of resistant typhoid that did not respond to treatment for the
1st 10 days with oral drugs (not stated which drug or at what dose)
and the patients needed hospitalization and treatment with intravenous
antibiotics. We are delighted that the contributors have highlighted
this critical issue.

The treatment of enteric fever (caused by _Salmonella enterica_
serovar Typhi, or _Salmonella enterica_ serovar Paratyphi A) is
becoming increasingly difficult in many part of Asia as drug
resistance spreads. Despite this, few countries make use of available
and affordable vaccines or implement the complex public health
measures to reduce the burden of disease.

Typhoid and paratyphoid fever are both restricted to humans and hence
timely treatment of the individual ensures the patients are cured and
at the same time also ensures that the individual cannot continue to
transmit the infection to others in their community. In this setting,
ensuring the optimal use of antibiotics is absolutely crucial. This
means empirically choosing the right antibiotic at the right dose and
for the appropriate duration on presumptive diagnosis with knowledge
of the circulating drug resistance patterns in the locality, and a
willingness to change that if and when a culture result and
sensitivity testing is available. It is also crucial to follow that
patient up to ensure that they adhered to their treatment and that the
treatment cured the patient and prevented secondary transmission.

There has been a great deal of work aimed at providing an evidence
base for the treatment of enteric fever over the last decade and is
summarized in recent Cochrane reviews. In a series of large randomized
controlled trials in enteric fever, gatifloxacin (a newer generation
fluoroquinolone) has proved to be a safe and highly effective oral
drug with median fever clearance time of < 4 days in about 500
patients with culture proven _Salmonella typhi_ or _Salmonella_
Paratyphi A infection of which more than 80 percent were resistant to
nalidixic acid and some also to the older generation fluoroquinolones
(ofloxacin and ciprofloxacin).

This drug has been associated with dysglycaemia in elderly patients in
North America, a feature predicted from the preclinical studies.
However in the patient population at risk for enteric fever
(predominantly young previously healthy patients of normal or low
weight) no dysglycaemia has been observed despite extensive
investigations. The drug remains available in many parts of Asia, can
be given once a day for 7 days and a treatment course costs
approximately USD 2.00.

Drug resistance is becoming a major problem. This is particularly true
in enteric fever. We have few therapeutic options. We should be very
careful about discarding critical antibiotics whose adverse effects
(dysglycemia in the case of gatifloxacin) are rarely seen in the
affected population at risk and which offer effective and safe
treatment for diseases like typhoid fever. We refer the readers to
these recent articles and ongoing trials and the Cochrane reviews.

Published trials
----------------
Arjyal A, Basnyat B, Koirala S, et al. Gatifloxacin versus
chloramphenicol for uncomplicated enteric fever: a open-label,
randomised, controlled trial. Lancet Infect Dis. 2011
Jun;11(6):445-54.

Dolecek C, Tran TP, Nguyen NR, et al. A multi-center randomised
controlled trial of gatifloxacin versus azithromycin for the treatment
of uncomplicated typhoid fever in children and adults in Vietnam. PLoS
ONE. 2008 May 21;3(5):e2188. PMID: 18493312.

Pandit A, Arjyal A, Day JN, et al. An open randomized comparison of
gatifloxacin versus cefixime for the treatment of uncomplicated
enteric fever. PLoS ONE. 2007 Jun 27;2(6):e542.

Recent Cochrane review
----------------------
Effa EE, Lassi ZS, Critchley JA, et al. Fluoroquinolones for treating
typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst
Rev. 2011 Oct 5;(10):CD004530.

--
Dr. Amit Arjyal
Oxford University Clinical Research Unit, Nepal.
<amitarjyal@yahoo.com>

[In contrast to older fluoroquinolones such as ciprofloxacin,
8-methoxy fluoroquinolones, such as gatifloxacin, have similar
activities against both fluoroquinolone enzyme targets, DNA gyrase and
topoisomerase IV, and resistance to 8-methoxy fluoroquinolones
requires mutations in the genes that encode both these fluoroquinolone
enzyme targets. Such an event apparently occurs at extremely low rates
in wild-type strains previously unexposed to fluoroquinolones.

Even in the presence of significant mutations in topoisomerase- and
gyrase-encoding genes, the 8-methoxy fluoroquinolones, such as
gatifloxacin, may retain high levels of in vitro activity. In
addition, overexpression of efflux pumps has a minimal effect on the
MICs of 8-methoxy fluoroquinolones. As a result, there is anticipated
a lower likelihood of selecting resistant strains with antibacterial
agents such as gatifloxacin
(http://cid.oxfordjournals.org/content/31/Supplement_2/S24.full.pdf+html).
However, it will be important to track changes in the prevalence of
resistance to the 8-methoxy fluoroquinolones, such as gatifloxacin, as
a result of the selective pressures imposed by their increased use. -
Mod.ML]

See Also