Alternatives to ciprofloxacin use for enteric fever, United Kingdom.

To the Editor: In cases of typhoid and paratyphoid fever, it is often necessary to commence treatment before the results of laboratory sensitivity tests are available. It is therefore important to be aware of optional drug therapies available because some organisms may be resistant to key antimicrobial drugs. For typhoid and paratyphoid, ciprofloxacin has become the first-line drug of choice since the widespread emergence and spread of strains resistant to chloramphenicol, ampicillin, and trimethoprim (1).

The Laboratory of Enteric Pathogens (LEP) of the Health Protection Agency of England and Wales is the reference center for Salmonella enterica serovars Typhi and Paratyphi A for the United Kingdom; as such, this laboratory receives isolates from all cases of infection. Isolates are screened by breakpoint for resistance to antimicrobial drugs at the following levels: chloramphenicol, 8 mg/L; ampicillin, 8 mg/L; trimethoprim, 2 mg/L; ciprofloxacin, 0.125 mg/L (decreased susceptibility); and 1.0 mg/L (high-level resistance), ceftriaxone, 1 mg/L, and cefotaxime, 1 mg/L. The levels for testing for resistance to chloramphenicol, ampicillin, trimethoprim, ceftriaxone, and cefotaxime correspond to internationally accepted therapeutic levels for these antimicrobial agents. In contrast, the levels for ciprofloxacin (0.125 and 1.0 mg/L) have been chosen after observations of treatment failures at levels when used at below the expected recommended serum concentrations (2,3). Since 2005, a proportion of isolates exhibiting decreased susceptibility and high-level resistance to ciprofloxacin have been tested for resistance to azithromycin by Etest (AB Biodisk, Solna, Sweden), using drug-sensitive strains of S. Typhi and S. Paratyphi A as controls.

From January 2001 through December 2006, LEP reported 1,215 cases of S. Typhi infection and 1,274 cases of S. Paratyphi A infection. Of these, [approximately equal to] 60% (1,493) reported recent travel abroad; India and Pakistan were the most frequently visited countries (4). Other cases were associated with persons who had a history of such travel, but the numbers involved were difficult to document accurately because of underreporting of foreign travel and other communication problems.

For S. Typhi, the occurrence of isolates resistant to ciprofloxacin at 0.125 mg/L increased from 60 (35%) of 170 in 2001 to 169 (70%) of 240 cases in 2006, with 4.8 (2%) of isolates in 2006 resistant at 1.0 mg/L (Table). The corresponding figures for S. Paratyphi A were 58 (25%) of 232 cases in 2001, rising to 84% in 2004, with an incidence of 73% in 2006; 9% of these were resistant to ciprofloxacin at 1.0 mg/L (Table). Moreover, in 2006, 56 isolates of S. Typhi (23% of total) exhibited resistance to chloramphenicol, ampicillin, and trimethoprim, 54 (96%) were also resistant to ciprofloxacin at 0.125 mg/L. When tested for resistance to ceftriaxone and cefotaxime, none of the isolates (either S. Yyphi or S. Paratyphi A) were resistant at 1.0 mg/L.

Although the levels of resistance to ciprofloxacin were for the most part below that regarded as therapeutic (MIC 0.25-1.0 mg/L), at least 21 treatment failures have been documented since 2005. These findings demonstrate that the efficacy of ciprofloxacin for first-line treatment of enteric fever in the United Kingdom has been seriously jeopardized. In cases of treatment failures, commonly used alternative antimicrobial agents have included third-generation cephalosporins such as ceftriaxone. The macrolide antimicrobial azithromycin is also being increasingly used, particularly for patients with hypersensitivity to penicillins (5). With this in mind, 50 S. Typhi and 40 S. Paratyphi A strains isolated from January 2005 through December 2006, which exhibited resistance to ciprofloxacin at 0.125 mg/L, were tested for resistance to azithromycin by Etest. Results indicated that none of the isolates of S. Typhi exhibited MICs >8 mg/L, which corresponded to the MIC to azithromycin of a drug-sensitive control strain of S. Typhi (range 4-8 mg/L, [MIC.sub.90] 6 mg/L). For S. Paratyphi A, none of the isolates exhibited MICs >12 mg/L, corresponding to that of a drug-sensitive control strain of this serovar (range 6-12 mg/L, [MIC.sub.90] 10 mg/L). Although there are no definitive data on resistance levels for azithromycin in relation to treatment of typhoid and paratyphoid, these findings suggest that resistance to this antimicrobial agent in terms of treatment efficacy has not yet been jeopardized.

These results indicate that the availability of effective antimicrobial agents for the treatment of typhoid and paratyphoid infection is becoming increasingly limited for patients in the United Kingdom. Nevertheless, despite the dramatic upsurge in the occurrence of strains with decreased susceptibility, ciprofloxacin still remains the drug of choice for many physicians. It is reassuring that in cases of treatment failure, third-generation cephalosporins such as ceftriaxone and macrolide antimicrobial agents such as azithromycin appear to be viable alternatives.

References

(1.) Threlfall EJ, Ward LR. Decreased susceptibility to ciprofloxacin in Salmonella enterica serotype Typhi, United Kingdom. Emerg Infect Dis. 2001;7:448-50.

(2.) Rowe B, Ward LR, Threlfall EJ. Ciprofloxacin and typhoid fever. Lancet. 1992;339:740.

(3.) Aarestrup FM, Wiuff C, Molbak K, Threlfall EJ. Is it time to change the break points for fluoroquinolones for Salmonella spp.? Antimicrob Agents Chemother. 2003;47:827-9.

(4.) Health Protection Agency. Foreign travel-associated illness in England, Wales and Northern Ireland-2007 report. London: Health Protection Agency; 2007.

(5.) Threlfall EJ, Day M, De Pinna E, Lewis H, Lawrence J. Drug-resistant enteric fever in the UK. Lancet. 2006;367:1576.

E. John Threlfall, * Elizabeth de Pinna, * Martin Day, * Joanne Lawrence, * and Jane Jones *

* Health Protection Agency, London, UK

Address for correspondence: E. John Threlfall, Health Protection Agency Laboratory of Enteric Pathogens, Centre for Infections, 61 Colindale Ave, London NW9 5EQ, UK; email: [e-mail]

Table. Incidence of resistance/decreased susceptibility to key
antimicrobial agents in isolates of Salmonella enterica serovars
Typhi and Paratyphi A, United Kingdom, 2001-2006 *

                      % S. Typhi resistant to

Year    No. studied   C      A     Tm   [Cp.sub.L]   [Cp.sub.H]

2001        170       24    23     23       35            0
2002        150       18    17     17       35            1
2003        218       20    20     21       43            1
2004        215       23    23     24       47            2
2005        222       29    29     29       62            2
2006        240       23    24     24       68            2

                      % S. Paratyphi A resistant to

Year    No. studied   C      A     Tm   [Cp.sub.L]   [Cp.sub.H]

2001        232       28    27     27       23            2
2002        149       10     9     10       39            3
2003        177       17    18     17       65           12
2004        221        5     5      5       70           14
2005        217        7     7      7       60           12
2006        278        2     3      2       64            9

* C, chloramphenicol; A, ampicillin, Tm, trimethoprim, Cps,
ciprofloxacin MIC 0.25-1.0 mg/L; [Cp.sub.H], ciprofloxacin MIC >
1.0 mg/L. No isolates exhibited resistance to ceftriaxone or
cefotaxime; of 50 S. Typhi and 40 S. Paratyphi A isolated in 2005
and 2006, the MIC to azithromycin by E test (AB Biodisk, Solna,
Sweden) was not greater than 8 mg/L for S. Typhi and 12 mg/L for
S. Paratyphi A, which corresponds to those of drug-sensitive controls
of the respective serotypes.