state public health laboratories receive salmonella isolates from clinical diagnostic laboratories as part of routine surveillance . state and local health department officials report demographic , clinical , and travel information about laboratory - confirmed typhoid fever on a standard form to the centers for disease control and prevention ( cdc , atlanta , ga , usa ) . participating states began submitting all s. enterica serotype typhi isolates to narms in 1999 ; since 2003 , all state public health laboratories have participated . isolates were tested for susceptibility by using broth microdilution ( sensititre ; trek diagnostics , westlake , oh , usa ) . mics were determined for 15 antimicrobial agents and interpreted by using clinical and laboratory standards institute ( clsi ) criteria when available ( table 1 ) ( 7,13 ) . for ciprofloxacin - resistant isolates , subtyping by pulsed - field gel electrophoresis ( pfge ) was performed by using the protocol established by the national molecular subtyping network for foodborne disease surveillance ( pulsenet ) ( 14 ) . pfge pattern similarity was assessed by cluster analysis ( dice , upgma [ unweighted pair group method using arithmetic averages ] ) and band - matching applications of bionumerics software ( applied maths , sint - martens - latem , belgium ) and confirmed by visual comparison ( figure ) . for ciprofloxacin - resistant isolates detected for 19992005 , sequencing of the quinolone resistance  determining region ( qrdr ; defined as amino acids 67106 for gyra ) was performed according to the methods described by crump et al . ( 6 ) , and additional patient information ( e.g. , antimicrobial drug treatment ) was requested by using a questionnaire with institutional review board approval . * classes of antimicrobial agents defined by the clinical and laboratory standards institute ( clsi ) were used to categorize agents ( 7,13 ) . mics were interpreted by using clsi criteria when available ( 7,13 ) : ciprofloxacin ( resistance breakpoint , > 4 g / ml ) ; nalidixic acid ( > 32 ) ; amikacin ( > 64 ) ; gentamicin ( > 16 ) ; kanamycin ( > 64 ) ; amoxicillin - clavulanic acid ( > 32/16 ) ; cefoxitin ( > 32 ) ; ceftiofur ( > 8) ; ceftriaxone ( > 4 ) ; sulfamethoxazole / sulfisoxazole ( > 512 ) ; trimethoprim - sulfamethoxazole ( > 4/76 ) ; ampicillin ( > 32 ) ; chloramphenicol ( > 32 ) ; and tetracycline ( > 16 ) . for streptomycin , resistance was defined as mic > 64 g / ml ( 7 ) . if growth was not inhibited by the highest concentration of the agent in the panel , the mic was reported as above the highest concentration . another isolate was cultured from fecal samples , which had mic < 0.5 g / ml for amikacin and same mics for other agents tested . pulsed - field gel electrophoresis ( pfge ) xbai ( a ) and blni ( b ) patterns of 9 ciprofloxacin - resistant salmonella enterica serotype typhi isolates detected in the national antimicrobial resistance monitoring system , 19992008 . pfge pattern similarity was assessed by cluster analysis ( dice , upgma [ unweighted pair group method using arithmetic average ] ) and band - matching applications of bionumerics software ( applied maths , sint - martens - latem , belgium ) and confirmed by visual comparison . pulsenet only considers band markings found within the scale of the global standard , which are all bands between 20.5 kb and 1,135 kb . the cluster parameters are dice coefficient and upgma with the tolerance of band position of 1.5% and optimization of 1.5% . during 19992005 , we detected 2 ( 0.1% ) cases of ciprofloxacin resistance among 1,690 s. enterica serotype typhi isolates . case reports follow . in 2003 , a 1-year - old girl had onset of fever 1 day before arriving in the united states from india . a blood specimen collected 3 days after fever onset yielded s. enterica serotype typhi . a 2-year - old girl had onset of diarrhea , which was treated with ofloxacin , 2 days before she arrived in the united states from india . seven days later , she continued to have diarrhea , and fever , vomiting , and abdominal cramps developed . blood and fecal specimens collected 3 weeks after illness onset yielded s. enterica serotype typhi . the s. enterica serotype typhi isolates were resistant to ciprofloxacin ( tables 1 , 2 ) and had indistinguishable pfge patterns when restriction enzymes xbai and blni were used : pulsenet - designated xbai pattern jppx01.0026 and blni pattern jppa26.0110 ( table 2 ; figure ) . qrdr sequencing showed gyra mutations resulting in a serine to tyrosine substitution at codon 83 and an aspartic acid to asparagine substitution at codon 87 , and a parc mutation conferring a serine to isoleucine substitution at codon 80 . state / local public health laboratories that submitted isolates : ma , massachusetts ; ca , california ; tx , texas ; az , arizona ; nyc , new york city ; nj , new jersey ; lac , los angeles county , california . resistance to antimicrobial agents other than ciprofloxacin : cot , trimethoprim  sulfamethoxazole ; fis , sulfamethoxazole or sulfisoxazole ; nal , nalidixic acid ; tet , tetracycline ; amp , ampicillin ; chl , chloramphenicol ; str , streptomycin .  national molecular subtyping network for foodborne disease surveillance ( pulsenet)designated pfge patterns using restriction enzyme xbai ( data as of 2009 oct 21 ) : jppx01.0026 , the most common xbai pattern among 3,233 isolates with reported xbai pattern in pulsenet , was detected in 486 ( 15.0% ) ; jppx01.0465 and jppx01.0506 each were detected in 12 ( 0.4% ) isolates . pulsenet - designated pfge patterns using restriction enzyme blni ( data as of 2009 oct 21 ) : jppa26.0002 , the most common blni pattern among 409 isolates with reported blni pattern in pulsenet , was detected in 61 ( 14.9% ) isolates ; jppa26.0110 was detected in 5 ( 1.2% ) , jppa26.0187 was detected in 3 ( 0.7% ) , and jppa26.0170 was detected in 1 ( 0.2% ) .   travel outside the united states reported in the 30 d before illness onset ; patient 4 also traveled to bangladesh and the united arab emirates . seven ( 0.6% ) ciprofloxacin - resistant infections were detected among patients from whom 1,131 s. enterica serotype typhi isolates were submitted during 20062008 ( table 2 ) . patients were a median of 22 years of age ( range 548 years ) ; 5 ( 71% ) were male . all 6 patients with known travel histories reported travel to india in the 30 days before illness onset . in addition to xbai jppx01.0026 and blni jppa26.0110 , 3 different xbai and blni pattern combinations were detected in the 7 isolates ( table 2 ; figure ) . we describe ciprofloxacin - resistant s. enterica serotype typhi isolates from 9 patients in the united states . the first 5 cases were reported previously in aggregated form , without molecular characterization of the isolates ( 5 ) . the first 2 patients were young children apparently infected in india in 2003 and 2005 . six additional patients , who were detected in 2006 and 2007 , also reported travel to india . resistant s. enterica serotype typhi infection ; however , ciprofloxacin - resistant infections are rarely reported by using current clsi criteria ( 4,5,11 ) . other resistance patterns were first described in southern asia , where the incidence of typhoid fever is high and antimicrobial agents are widely available without prescription , providing the opportunity for the development and selection of resistant strains ( 8) . other than reports by 8 patients of travel to india , we have no information about possible shared exposures , such as specific locations visited , sources of food or water , or contact with carriers of s. enterica serotype typhi . however , the indistinguishable pfge xbai and blni patterns and identical gyra and parc mutations of isolates from the first 2 patients suggest that , although typhoid fever occurred nearly 2 years apart , the same ciprofloxacin - resistant strain is likely to have been involved . after 2005 , different xbai and blni patterns have been identified in ciprofloxacin - resistant isolates , indicating independent selection of ciprofloxacin resistance in different strains . the gyra and parc mutations of isolates from the first 2 patients were reported in ciprofloxacin - resistant s. enterica serotype typhi in india ( 11 ) . the 2 gyra mutations are well characterized and known to be associated with quinolone resistance ; 2 point mutations in gyra and 1 in parc confer fluoroquinolone resistance ( 8,1012 ) . further studies , including characterization of other resistance mechanisms , are needed to track the evolution of fluoroquinolone - resistant s. enterica serotype typhi . although the ciprofloxacin resistance we detected using current clsi criteria is rare in s. enterica serotype typhi , nalidixic acid resistance , which correlates with decreased susceptibility to ciprofloxacin , has increased ( 7 ) . clinicians should be aware that infection with salmonella spp . with decreased susceptibility to ciprofloxacin may not respond satisfactorily to this agent ( 6,8,9,13,15 ) . in addition , identification of ciprofloxacin - resistant cases has been increasing . in the presence of quinolone resistance , third - generation cephalosporins , such as ceftriaxone , recent clinical trials suggest that azithromycin might be useful for treating uncomplicated typhoid fever ( 2,8,9,15 ) . recommendations for empiric treatment of typhoid fever in the united states are best developed by using information about antimicrobial resistance trends in isolates from countries where the infection was acquired .
we report 9 ciprofloxacin - resistant salmonella enterica serotype typhi isolates submitted to the us national antimicrobial resistance monitoring system during 19992008 . 
 the first 2 had indistinguishable pulsed - field gel electrophoresis patterns and identical gyra and parc mutations . 
 eight of the 9 patients had traveled to india within 30 days before illness onset .