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Antimicrobial Agents and Chemotherapy, March 2009, p. 1221-1224, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01260-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activity of Prulifloxacin Tested against a Worldwide Collection of Gastroenteritis-Producing Pathogens, Including Those Causing Traveler's Diarrhea{triangledown}

Thomas R. Fritsche,1 Douglas J. Biedenbach,1 and Ronald N. Jones1,2*

JMI Laboratories, North Liberty, Iowa 52317,1 Tufts University School of Medicine, Boston, Massachusetts 021112

Received 19 September 2008/ Returned for modification 13 November 2008/ Accepted 22 December 2008


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ABSTRACT
 
Prulifloxacin, the prodrug of ulifloxacin (active component), is a newer fluoroquinolone with broad activity against enteric and nonenteric gram-negative bacilli. Ulifloxacin and other oral comparator agents were tested for activity against 582 gastroenteritis strains from global surveillance studies. Ulifloxacin was highly active against Escherichia coli, Salmonella spp., Shigella spp., Yersinia spp., Vibrio spp., Aeromonas spp., and Plesiomonas spp. (MIC50s and MIC90s, ≤0.03 µg/ml and ≤0.06 µg/ml, respectively). Only rare Aeromonas spp., Campylobacter spp., and E. coli displayed elevated MIC results (≥4 µg/ml). Ciprofloxacin exhibited similar activity but was two- to fourfold less potent. Presently approved for clinical use in certain European countries and Japan, ulifloxacin was the most active of the antimicrobial agents tested against these gastroenteritis-causing pathogens.


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INTRODUCTION
 
Leading bacterial pathogens associated with acute gastroenteritis and traveler's diarrhea include Escherichia coli, Salmonella spp., Shigella spp., Yersinia spp., Vibrio spp., Campylobacter spp., Aeromonas spp., and Plesiomonas shigelloides. Although the most common manifestation of gastrointestinal infection is diarrhea, serious and invasive infections related to these bacterial species can occur, particularly among the young, elderly, and immunocompromised patient populations (1, 10). The presentation of illness and the overall outcome can also differ depending upon the causative agent. Gastroenteritis-producing E. coli can cause diverse symptoms and disease processes depending upon the toxins produced or the invasive characteristics of the offending organism. Enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroaggregative (EAEC), and Shiga toxin-producing (enterohemorrhagic [EHEC]) strains of E. coli can cause uncomplicated diarrheagenic symptoms (watery stool) or more serious problems such as hemolytic-uremic syndrome, malnutrition, and life-threatening extraintestinal infection. Campylobacter spp., Vibrio spp., Salmonella spp., and Shigella spp. are well-known pathogens associated with bacillary dysentery causing significant morbidity and mortality worldwide. Yersinia enterocolitica, P. shigelloides, and Aeromonas spp. are less-common causes of gastroenteritis but can also cause serious invasive disease (1, 10).

Due to the numerous bacterial, viral, and parasitic causes of acute diarrhea, directed therapy is often initiated only upon confirmation of the etiologic agent, severity of symptoms, and underlying risk factors. Traveler's diarrhea is one circumstance where empirical therapies are commonly recommended without the aid of laboratory testing and are usually directed against ETEC among other bacterial pathogens including Salmonella spp., Shigella spp., and Campylobacter spp. Such therapy, usually a fluoroquinolone for adults and trimethoprim-sulfamethoxazole (TMP-SMX) for children, is known to reduce the duration of illness (10).

Among newer orally administered fluoroquinolones, pruli-floxacin has potent in vitro activity against commonly occurring gram-positive and -negative pathogens and has been approved for use in the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in several European countries, and gastroenteritis including infectious diarrheas in Japan (3, 4, 8, 9, 14, 17). Prulifloxacin is converted to its active form, ulifloxacin, following oral administration and intestinal absorption (2, 11, 15, 16). This fluoroquinolone is administered orally as a 600-mg tablet once daily and has been shown to maintain high concentrations within the gastrointestinal tract (12, 16). One phase 3 clinical trial assessing the safety and efficacy of prulifloxacin for therapy of infectious diarrhea has recently been completed (in analysis), and another similar trial is ongoing (data on file, Optimer Pharmaceuticals). The objective of this study was to profile and assess the activity of prulifloxacin's active metabolite, ulifloxacin, and other orally administered antimicrobial agents tested in vitro against a global collection of the eight major pathogen groups that are among known causes of bacterial gastroenteritis and traveler's diarrhea.

(This work was presented in part at the 47th ICAAC held in Chicago, IL, 17 to 20 September 2007.)

Isolates were collected from medical centers as part of international antimicrobial surveillance programs as follows (total; North America/Europe/Latin America): Aeromonas spp. (101; 38/45/18), Campylobacter spp. (109; 45/64/0), Salmonella spp. (101; 46/41/14), Shigella spp. (101; 35/33/33), Yersinia spp. (46; 6/39/1), E. coli (100; 40/34/16), Vibrio spp. (20; 18/2/0), and P. shigelloides (4; 4/0/0). The collection of pathogenic E. coli strains included characterized EHEC (21 isolates), EPEC (20 isolates), ETEC (20 isolates), and EAEC (19 isolates) strains and was kindly provided by James P. Nataro (University of Maryland School of Medicine). The numbers of tested species within each of the listed pathogen groups can be found in the footnotes of Table 2.


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  		TABLE 2. In vitro activities of ulifloxacin and comparator antimicrobial agents tested against 582 isolates of gram-negative pathogens associated with traveler's diarrhea

Testing was performed in cation-adjusted Mueller-Hinton broth using broth microdilution reference methods recommended by the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) (5). Campylobacter spp. were also tested using broth microdilution in cation-adjusted Mueller-Hinton broth supplemented with 3 to 5% lysed horse blood using the inoculum and incubation recommendations of the CLSI (6, 7). Interpretive criteria for susceptibility were those of the CLSI (6). Ulifloxacin breakpoint criteria are those suggested by Montanari et al., with susceptibility at ≤1 µg/ml and resistance defined at ≥4 µg/ml (13). Quality control strains utilized E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Campylobacter jejuni ATCC 33560. All quality control results for the tested agents (ciprofloxacin, nalidixic acid, ampicillin, erythromycin, azithromycin, doxycycline, and TMP-SMX) were found to be in control (6, 7).

Ulifloxacin was highly active against all tested Enterobacteriaceae isolates (MIC50, ≤0.008 µg/ml; MIC90, ≤0.03 µg/ml; Tables 1 and 2). While elevated ulifloxacin MICs (≥2 µg/ml) were observed for rare strains of E. coli (two blood-borne and one EHEC), all Salmonella spp., Shigella spp., and Yesinia spp. and 97.0% of E. coli isolates were susceptible to ulifloxacin (Tables 2 and 3). Ciprofloxacin and ulifloxacin displayed similar spectra of activity against all species tested, but ciprofloxacin generally was two- to fourfold less potent (MIC90s, 0.016 to 0.12 µg/ml versus 0.008 to 0.03 µg/ml, respectively [Table 2]).


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  		TABLE 1. Activity of ulifloxacin tested against 582 isolates of gastroenteritis-producing pathogens


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  		TABLE 3. Ulifloxacin activity tested against 100 strains of E. coli listed by pathogenicity group or site of infection

Among Aeromonas spp. and Vibrio spp., susceptibility to ulifloxacin was ≥98.0%, with slightly lower potency (MIC90, 0.03 to 0.06 µg/ml) than that against the enteric bacilli (MIC90, 0.008 to 0.03 µg/ml; Table 2). Rifaximin was most active against Vibrio isolates (MIC50, 0.5 µg/ml) but was markedly less active than ulifloxacin against the Enterobacteriaceae strains, Aeromonas spp., P. shigelloides, and Campylobacter spp. Doxycycline was most active against Yersinia spp., Aeromonas spp., P. shigelloides, and Vibrio spp. (>95% susceptible) and least active against the Enterobacteriaceae (34.7 to 82.2%). While fluoroquinolone and doxycycline resistance was detected among Campylobacter spp. (14.7 to 16.5% and 33.9%, respectively), all isolates remained susceptible to erythromycin.

Ulifloxacin was the most active of all orally administered antimicrobial agents tested overall and exhibited a spectrum of activity against this global collection of gastroenteritis pathogens that was most similar to that of ciprofloxacin, but ulifloxacin was two- to fourfold more potent than ciprofloxacin. Although it was a rare phenomenon, ulifloxacin-resistant strains of Aeromonas spp. (2.0%) and E. coli (3.0%) were identified. Campylobacter spp. displayed a higher resistance rate to ulifloxacin (14.7% of isolates at ≥2 µg/ml), similar to that observed for ciprofloxacin (16.5%). Except for these two Campylobacter strains, ulifloxacin and ciprofloxacin had complete cross-susceptibility (Table 2). Isolates of E. coli, Aeromonas spp., Salmonella spp., Shigella spp., and Yersinia spp. displaying resistance to nalidixic acid and susceptibility to ciprofloxacin were a worrisome finding, being indicative of first-step mutations in the quinolone resistance-determining region. However, prulifloxacin levels in the bowel remain higher than those of other peer drugs due to 50% absorption (11, 12, 16).

The goal of therapy for traveler's diarrhea is to limit the duration of symptoms, prevent disease complications, and improve the patient's activity level while ensuring compliance through simplified treatment regimens. Ulifloxacin, the active metabolite of prulifloxacin, displays potent in vitro activity against the most commonly isolated gastroenteritis-producing bacterial pathogens as demonstrated here and currently is under investigation in two phase 3 studies as a 3-day therapy (600-mg tablets once a day) for gastroenteritis, including traveler's diarrhea (1, 10, 12, 18).


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ACKNOWLEDGMENTS
 
This investigation was supported by an educational/research grant from Optimer Pharmaceuticals.

Technical support was provided by J. Streit and P. Rhomberg.


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FOOTNOTES
 
* Corresponding author. Mailing address: JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty Iowa 52317. Phone: (319) 665-3370. Fax: (319) 655-3371. E-mail: ronald-jones{at}jmilabs.com Back

{triangledown} Published ahead of print on 29 December 2008. Back


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REFERENCES
 
    1
  1. Adachi, J. A., L. Ostrosky-Zeichner, H. L. DuPont, and C. D. Ericsson. 2000. Empirical antimicrobial therapy for traveler's diarrhea. Clin. Infect. Dis. 31:1079-1083.[CrossRef][Medline]
    2. 2
  2. Araake, M., T. Hara, H. Watabe, and T. Nishino. 2002. In vitro antibacterial activity of prulifloxacin, a new oral fluoroquinolone. Jpn. J. Antibiot. 55:778-790.[Medline]
    3. 3
  3. Carmignani, G., A. F. De Rose, L. Olivieri, E. Salvatori, M. T. Rosignoli, and P. Dionisio. 2005. Prulifloxacin versus ciprofloxacin in the treatment of adults with complicated urinary tract infections. Urol. Int. 74:326-331.[CrossRef][Medline]
    4. 4
  4. Cazzola, M., E. Salvatori, P. Dionisio, and L. Allegra. 2006. Prulifloxacin: a new fluoroquinolone for the treatment of acute exacerbation of chronic bronchitis. Pulm. Pharmacol. Ther. 19(Suppl. 1):30-37.[CrossRef][Medline]
    5. 5
  5. Clinical and Laboratory Standards Institute. 2006. M7-A7. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—7th ed. Clinical and Laboratory Standards Institute, Wayne, PA.
    6. 6
  6. Clinical and Laboratory Standards Institute. 2006. M45-A. Methods for antimicrobial dilution and disk susceptibility testing of infrequently isolated or fastidious bacteria. Clinical and Laboratory Standards Institute, Wayne, PA.
    7. 7
  7. Clinical and Laboratory Standards Institute. 2008. M100-S18. Performance standards for antimicrobial susceptibility testing, 18th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA.
    8. 8
  8. Giannarini, G., A. Mogorovich, F. Valent, G. Morelli, M. De Maria, F. Manassero, F. Barbone, and C. Selli. 2007. Prulifloxacin versus levofloxacin in the treatment of chronic bacterial prostatitis: a prospective, randomized, double-blind trial. J. Chemother. 19:304-308.[Medline]
    9. 9
  9. Gualco, L., A. M. Schito, G. C. Schito, and A. Marchese. 2007. In vitro activity of prulifloxacin against Escherichia coli isolated from urinary tract infections and the biological cost of prulifloxacin resistance. Int. J. Antimicrob. Agents 29:679-687.[CrossRef][Medline]
    10. 10
  10. Guerrant, R. L., T. Van Gilder, T. S. Steiner, N. M. Thielman, L. Slutsker, R. V. Tauxe, T. Hennessy, P. M. Griffin, H. DuPont, R. B. Sack, P. Tarr, M. Neill, I. Nachamkin, L. B. Reller, M. T. Osterholm, M. L. Bennish, and L. K. Pickering. 2001. Practice guidelines for the management of infectious diarrhea. Clin. Infect. Dis. 32:331-351.[CrossRef][Medline]
    11. 11
  11. Keam, S. J., and C. M. Perry. 2004. Prulifloxacin. Drugs 64:2221-2234.[CrossRef][Medline]
    12. 12
  12. Matera, M. G. 2006. Pharmacologic characteristics of prulifloxacin. Pulm. Pharmacol. Ther. 19(Suppl. 1):20-29.[CrossRef][Medline]
    13. 13
  13. Montanari, M. P., L. Ferrante, E. Tili, I. Cochetti, V. Rossi, and P. E. Varaldo. 2005. Interpretive criteria for disk diffusion susceptibility testing of ulifloxacin, the active metabolite of prulifloxacin. J. Chemother. 17:138-142.[Medline]
    14. 14
  14. Montanari, M. P., M. Mingoia, and P. E. Varaldo. 2001. In vitro antibacterial activities of AF 3013, the active metabolite of prulifloxacin, against nosocomial and community Italian isolates. Antimicrob. Agents Chemother. 45:3616-3622.[Abstract/Free Full Text]
    15. 15
  15. Prats, G., C. Roig, E. Miro, F. Navarro, and B. Mirelis. 2002. In vitro activity of the active metabolite of prulifloxacin (AF 3013) compared with six other fluoroquinolones. Eur. J. Clin. Microbiol. Infect. Dis. 21:328-334.[CrossRef][Medline]
    16. 16
  16. Prats, G., V. Rossi, E. Salvatori, and B. Mirelis. 2006. Prulifloxacin: a new antibacterial fluoroquinolone. Expert Rev. Anti-Infect. Ther. 4:27-41.[CrossRef]
    17. 17
  17. Roveta, S., A. M. Schito, A. Marchese, and G. C. Schito. 2005. Microbiological rationale for the utilisation of prulifloxacin, a new fluoroquinolone, in the eradication of serious infections caused by Pseudomonas aeruginosa. Int. J. Antimicrob. Agents 26:366-372.[CrossRef][Medline]
    18. 18
  18. Steffen, R., D. A. Sack, L. Riopel, Z. D. Jiang, M. Sturchler, C. D. Ericsson, B. Lowe, P. Waiyaki, M. White, and H. L. DuPont. 2003. Therapy of travelers' diarrhea with rifaximin on various continents. Am. J. Gastroenterol. 98:1073-1078.[CrossRef][Medline]

Antimicrobial Agents and Chemotherapy, March 2009, p. 1221-1224, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01260-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.




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