1 Institute for Medical Microbiology and Virology, Universitätsklinikum Düsseldorf, Universitätsstraße 1, Geb. 22.21, 40225 Düsseldorf, Germany; 2 Eijkman-Winkler Institute for Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
Sir,
In a recent leading article by Giamarellou,1 the prescribing guidelines for Pseudomonas aeruginosa infections were discussed. It was stated that the anti-pseudomonal drugs available for the clinician include the aminoglycosides, ureidopenicillins, ceftazidime, the carbapenems and ciprofloxacin. Given the propensity for this organism to become drug resistant, a worrying question for the clinician arises: what alternatives exist if one of these major anti-pseudomonal drugs fails?
Recent surveillance studies with P. aeruginosa have not differentiated between imipenem-susceptible and -resistant isolates.2,3 In the present study, we investigated the antibiotic susceptibility of 86 unrelated imipenem-resistant P. aeruginosa strains, by broth microdilution using NCCLS recommendations.4 These organisms were isolated in 19981999 from European hospitals as part of the SENTRY antimicrobial surveillance programme. We also tested these isolates against some of the new fluoroquinolones. The MIC data are summarized in Table 1.
|
Resistance to ampicillin was found in all isolates, and with the exception of one isolate was also seen with co-trimoxazole. Amongst the cephalosporins, ceftazidime was more active than ceftriaxone, with 35 (40.7%) versus 20 (23.3%) susceptible isolates, respectively. This greater potency of ceftazidime has been reported previously by Fluit et al.;2 however, they found ceftriaxone resistance rates to be over three-fold greater than those for ceftazidime (65.2% and 18.5%, respectively). Cross-resistance between these drugs was not found.
Jones et al.3 have reported that resistance rates to ciprofloxacin, levofloxacin and gatifloxacin are almost identical, whereas we found that ciprofloxacin and levofloxacin had higher activity. Moxifloxacin and gatifloxacin were the least active in this drug class. Trovafloxacin was at least one dilution step less potent than ciprofloxacin. Sitafloxacin and clinafloxacin recorded the lowest MIC50 and MIC90 values of the fluoroquinolones. These drugs do not have established breakpoints; however, 44 (51.1%) and 48 (55.8%) of the isolates, respectively, had MICs 2 mg/L, suggesting that they may be of therapeutic value against low-level ciprofloxacin-resistant P. aeruginosa. This value decreases to 29 and 30 isolates (34%), respectively, if a breakpoint of
1 mg/L is used. Cross-resistance between the fluoroquinolones was not seen with any of the isolates. For example, some moxifloxacin-resistant isolates were still susceptible to ciprofloxacin. A number of organisms recorded ciprofloxacin MICs > 32 mg/L but their sitafloxacin and clinafloxacin MICs remained relatively low at 24 mg/L. This phenotype was associated with higher MICs of non-fluoroquinolones, suggesting the effect of drug efflux. This resistance mechanism is associated with increased expression of the MexAB-OprM and MexCD-OprJ efflux systems. These pumps have a broad specificity and extrude a wide range of unrelated drugs out of the cell. The emergence of multidrug-resistant P. aeruginosa in vivo has been described by Ziha-Zarifi et al.6 In their study, ß-lactam resistance was associated with either an increase in AmpC ß-lactamase or increased expression of OprM. Those isolates exhibiting increased efflux had raised MICs of non-ß-lactam antibiotics, including quinolones. This antimicrobial phenotype was found in the most fluoroquinolone-resistant organisms within our study, and further investigation into the mechanism of resistance needs to be performed. Isolates with sitafloxacin and clinafloxacin MICs that were similar to ciprofloxacin were generally more susceptible to the non-fluoroquinolones, suggesting that their resistance was due primarily to target site alterations.
This study has shown that imipenem resistance does not necessarily mean blanket resistance to all available drugs. However, it appears that imipenem resistance is associated with higher rates of resistance not only to ß-lactams, but also to unrelated drugs. The high incidence of resistance to the ureidopenicillin piperacillin, even when combined with the ß-lactam inhibitor tazobactam, is worrying. However, the aminoglycoside amikacin still retains a level of potency and thus may be used empirically to treat imipenem-resistant Pseudomonas infections.
Footnotes
* Corresponding author. Tel/Fax: +49-21-3272040; E-mail: Paul.Higgins{at}uni-duesseldorf.de
References
1
.
Giamarellou, H. (2002). Prescribing guidelines for severe Pseudomonas infections. Journal of Antimicrobial Chemotherapy 49, 22933.
2 . Fluit, A. C., Verhoef, J., Schmitz, F.-J. & the European SENTRY participants. (2000). Antimicrobial resistance in European isolates of Pseudomonas aeruginosa. European Journal of Clinical Microbiology and Infectious Diseases 19, 3704.[ISI][Medline]
3 . Jones, R. N., Beach, M. L. & Pfaller, M. A. (2001). Spectrum and activity of three contemporary fluoroquinolones tested against Pseudomonas aeruginosa isolates from urinary tract infections in the SENTRY antimicrobial surveillance program (Europe and the Americas; 2000): more alike than different! Diagnostic Microbiology and Infectious Disease 41, 1613.[ISI][Medline]
4 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA.
5
.
MacGowan, A. P. & Wise, R. (2001). Establishing MIC breakpoints and the interpretation of in vitro susceptibility tests. Journal of Antimicrobial Chemotherapy 48, Suppl. S1, 1728.
6
.
Ziha-Zarifi, I., Llanes, C., Köhler, T., Pechere, J.-C. & Plesiat, P. (1999). In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa overexpressing the active efflux system MexA-MexB-OprM. Antimicrobial Agents and Chemotherapy 43, 28791.