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Dispatch
Ciprofloxacin Treatment Failure
in Typhoid Fever Case, Pakistan
Tariq Butt,* Rifat Nadeem Ahmad,* Abid Mahmood,* and Sabeen Zaidi*
*Armed Forces Institute of Pathology, Rawalpindi, Pakistan
Suggested citation
for this article:
Butt T, Ahmad RN, Mahmood A, Zaidi S. Ciprofloxacin treatment failure
in typhoid fever case, Pakistan. Emerg Infect Dis [serial online] 2003
Dec [date cited]. Available from: URL: http://www.cdc.gov/ncidod/EID/vol9no12/03-0230.htm
We report a case
of ciprofloxacin treatment failure in a typhoid fever patient at a tertiary
care hospital in Rawalpindi, Pakistan. This case shows not only the
emergence of fluoroquinolone resistance in typhoid salmonellae but also
the inadequacy of the current laboratory guidelines for detection of
this resistance.
Typhoid fever is a major health concern in the developing world; >16
million new cases occur worldwide annually, resulting in approximately
600,000 deaths per year. The last two decades have seen the emergence
and spread of multidrug resistance against the conventional antityphoid
drugs (chloramphenicol, co-trimoxazole, and ampicillin) among the typhoid
salmonellae, especially in South and Southeast Asia, including Pakistan.
These developments had left fluoroquinolones as the antimicrobial agents
of choice for the treatment of typhoid fever (1). Fluoroquinolone
resistance is being reported with increasing frequency from all over the
world (1–5). We report ciprofloxacin treatment failure
in a case of typhoid fever.
Case Report
A previously healthy 14-year-old boy from Rawalpindi, Pakistan, was admitted
in July 2002 to Combined Military Hospital, Rawalpindi, with a 7-day history
of a high fever (>38°C) and vomiting. He had relative bradycardia (heart
rate 84 bpm) and a soft palpable spleen. His total leukocyte count was
3 x 109/L. Malarial parasites were not seen on examination
of thin and thick smears of peripheral blood. The results of a routine
urinalysis and chest radiographs were normal. A blood Widal test showed
a titer of 320 against “O” (somatic) antigen of Salmonella enterica
serovar Typhi. Blood culture yielded the growth of Salmonella Typhi.
The isolate was found to be resistant to the conventional antityphoid
drugs by using modified Kirby-Bauer disk diffusion technique according
to the criteria of the National Committee for Clinical Laboratory Standards
(NCCLS) (6). The disks of antimicrobial drugs used were
chloramphenicol (30 µg), co-trimoxazole (1.25/23.75 µg), ampicillin
(10 µg), ciprofloxacin (5 µg), and ceftriaxone (30 µg).
The isolate appeared susceptible to ciprofloxacin and ceftriaxone.
The patient was given ciprofloxacin, 500 mg, every 12 hours, orally,
on admission but remained febrile after 3 days of treatment. When the
blood culture report was received, and in view of the susceptibility pattern,
intravenous ciprofloxacin, 200 mg every 12 hours, was administered. Despite
8 days of treatment, his fever did not resolve. The isolate was reviewed
and the MIC of ciprofloxacin was determined by Kirby-Bauer broth dilution
technique; it was 0.5 µg/mL; well below the NCCLS recommended break
point value of 1 µg/mL (7). However, in light of
the treatment failure with ciprofloxacin, intravenous ceftriaxone, 1 g
every 12 hours, was administered, and the patient responded within 3 days.
Conclusions
This case highlights two developments: first, the increasing incidence
of reduced susceptibility and resistance of typhoid salmonellae against
fluoroquinolones, and second, the inadequacy of the present laboratory
guidelines for detecting fluoroquinolone resistance in typhoid salmonellae.
The first case of ciprofloxacin-resistant typhoid fever was reported in
1992 in the United Kingdom (8), and the first case of
fluoroquinolone treatment failure in typhoid fever in Pakistan was reported
in 1993 (9). Similar cases have been reported from several
other countries (1–5). Selective pressure on the bacterial
population by uncontrolled use of these antimicrobial drugs has likely
led to the emergence of this resistance (2), which has
been attributed to a single point mutation in the quinolone-resistance–determining
region (QRDR) of the topoisomerase gene gyrA (1,2,5,10).
However, other mechanisms such as decreased permeability and active efflux
of the antimicrobial agent may also be involved (10).
The inadequacy of the current in vitro antimicrobial susceptibility testing
for detecting fluoroquinolone treatment failure in typhoid fever is apparent
in this case. According to NCCLS guidelines, Enterobacteriaceae (including
typhoid salmonellae) are susceptible to the MIC of <1 µg/mL of
ciprofloxacin, while resistant to the MIC of >4 µg/mL (7).
But in our case-patient, treatment failed, even though the MIC was stated
as 0.5 µg/mL. Similar observations have been made in other countries
(2–5,11). Keeping in view this absence
of correlation between MIC of fluoroquinolones and therapeutic response
in typhoid fever, we recommended break point MIC values of ciprofloxacin
in cases of typhoid salmonellae infection as follows: <0.125 µg/mL
as susceptible, 0.125 µg/mL–1 µg/mL as reduced susceptibility,
and >1 µg/mL as resistant. Determination of MIC may not be practicable
in routine laboratory practice, particularly outside of a reference laboratory
in developing countries. Also, disk diffusion criteria with ciprofloxacin
are inadequate to highlight these new recommended MICs, and detecting
mutation in the QRDR of gyrA gene by polymerase chain reaction
(PCR) would not be practical or cost-effective. Several authors have reported
a correlation between resistance to nalidixic acid and reduced susceptibility
to ciprofloxacin and other fluoroquinolones (2,11).
Routine testing of resistance to nalidixic acid with a disk content of
30 µg can serve as a useful screening test for fluoroquinolone resistance
(11). However, revision of the diagnostic criteria for
detecting fluoroquinolone resistance in typhoid salmonellae is needed,
particularly to validate clinically all the laboratory-based anecdotal
studies. Even with adoption of the new recommended MICs of fluoroquinolones
against typhoid salmonellae, MICs would have to be correlated with inhibition
zone size by disk diffusion technique and the clinical response in infection
with typhoid salmonellae depicting reduced susceptibility against quinolones.
To summarize, fluoroquinolones are the most effective antimicrobial agents
for treating enteric fevers (1). Emergence of resistance
against them is of major concern. The spread of this resistance would
leave only the less effective (1,2), but more expensive,
third-generation cephalosporins for treatment of typhoid. Fluoroquinolone
resistance must be identified early, and these drugs must be used judiciously.
Otherwise, society may be faced with the prospect of untreatable typhoid
fever.
Dr. Butt is a consultant
microbiologist and head of the Microbiology Department at the Armed
Forces Institute of Pathology, Rawalpindi, Pakistan. His research interests
include tuberculosis and enteric fevers.
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