Previous Article | Next Article 
Journal of Clinical Microbiology, July 2001, p. 2748-2750, Vol. 39, No. 7
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.7.2748-2750.2001
LETTERS TO THE EDITOR
Trends in Ciprofloxacin Nonsusceptibility and Levofloxacin
Resistance among Streptococcus pneumoniae Isolates in
North America
 |
LETTER |
Jones and Pfaller recently reported on macrolide and
fluoroquinolone resistances among Streptococcus pneumoniae
isolates from 36 North American laboratories participating in the
SENTRY Antimicrobial Surveillance Program from 1997 to 1999 (3). Their report is one of several recent publications
claiming to support the observations of Canadian investigators Chen et
al. (1), who found associations between ciprofloxacin
nonsusceptibility (MIC 
4 µg/ml) and penicillin resistance in
elderly patients (age 65 years) and increased fluoroquinolone
prescription volumes (1). The work of Chen et al.
(1) has met with considerable response from the medical community and is now commonly cited by authors of studies describing fluoroquinolone activities against pneumococci. A closer examination of
the Jones and Pfaller study, however, demonstrates why care must be
exercised when comparing data from disparate surveillance studies.
The Jones and Pfaller study found that among pneumococcal isolates,
ciprofloxacin nonsusceptibility was essentially unchanged between
1997-1998 (mean nonsusceptibility, 1.9%; range, 1.7 to 2.4%) and 1999 (mean nonsusceptibility, 2.0%; P = 0.82;
2 analysis), while levofloxacin resistance increased
significantly, from 0.2 to 0.3% in 1997-1998 to 0.9% in 1999 (P = 0.002) (3). Although Chen et al.
reported similar rates of ciprofloxacin nonsusceptibility in 1997 (1.7%) and 1998 (1.8%) (1), Jones and Pfaller's finding that ciprofloxacin nonsusceptibility and levofloxacin resistance are
evolving at different rates is perplexing and may not correlate with
the data of Chen et al., which showed that of 75 isolates with reduced
susceptibility to ciprofloxacin, only one-third were levofloxacin-resistant (MIC 8 µg/ml), a resistance rate of
0.3% (25 of 7,551 isolates) (1). Chen et al. did not
discuss yearly trends in levofloxacin resistance for isolates included
in their study (1). One possible explanation for the
above-mentioned disparity may be the low numbers of
levofloxacin-resistant isolates (<15 isolates/year) in the Jones and
Pfaller study, which may make meaningful analysis difficult and
certainly requires some caution in its interpretation.
A major finding of Chen et al. was the association between
ciprofloxacin nonsusceptibility and fluoroquinolone prescription volumes based on IMS prescription rate data (1). The Jones and Pfaller report cannot support this finding, as it did not contain
any usage data. Nor can two other publications cited by Jones and
Pfaller in support of Chen et al. (based on a trovafloxacin surveillance study conducted in 1997-1998 and 1998-1999 in the United
States) (3; R. N. Jones, D. J. Biedenbach,
D. M. Johnson, and The Trovafloxacin Study Group, Abstr. 99th Gen.
Meet. Am. Soc. Microbiol., abstr. C-421, p. 191, 1999), as these also
provide no usage data. Moreover, these studies appear to report only
four ciprofloxacin MICs for the 3,049 isolates tested in 1997-1998 (4) and none for the 4,588 isolates from 1998-1999 (Jones
et al., Abstr. 99th Gen. Meet. Am. Soc. Microbiol., 1999). It should also be noted that the fluoroquinolone prescription data described by
Chen et al. (1) did not include levofloxacin, as it was not marketed in Canada during the period in which the data were collected (1988-1997) (1). The effects (if any) of these
inconsistencies on meaningful analysis and comparison are unclear;
however, the value of Jones and Pfaller's contribution would be
greatly enhanced if these differences were noted and explained.
Another problem arises in comparing a wholly Canadian study like that
of Chen et al. with a study that combines Canadian and U.S. data like
the Jones and Pfaller study. There is evidence to suggest that clear
differences may exist between pneumococcal isolates from Canada and the
United States (1, 6, 7), as Pfaller et al. were careful to
point out for other pathogens in a previous publication
(5). It would have been interesting to see the Jones and
Pfaller data from Canada and the United States analyzed separately, as
well as together, as this conflation could have contributed to some of
the inconsistencies in the study.
The Chen et al. study itself has been challenged recently. In a
1997-1998 surveillance study, it was found that among 5,640 pneumococcal isolates collected from across the United States, only
0.3% had ciprofloxacin MICs of 4 µg/ml (6), and
ciprofloxacin MIC distributions appeared essentially unchanged compared
to those reported in the 1980s (6). A second Canadian
surveillance study conducted during 1997-1998 found that 1% of
isolates (12 of 1,180 isolates) were ciprofloxacin nonsusceptible (a
finding similar to that of Chen et al.) but did not identify
differences in fluoroquinolone activities against S. pneumoniae stratified into penicillin-susceptible, -intermediate, and -resistant groups; in fact, levofloxacin
resistance was not identified among penicillin-resistant or
-intermediate isolates (7). The results of both of these
studies contrast sharply with those of Chen et al. The suggestion by
Jones and Pfaller that this second Canadian study supports the Chen et
al. observation that elevated quinolone resistance rates occur among older patients also appears unfounded. Further inconsistencies identified in the analysis of Chen et al. (5), as well as
their acknowledgment by the Canadian investigators, have been
previously published (2).
As we seek to improve our understanding of antibiotic resistance
mechanisms and trends, researchers must be willing to examine preceding
reports critically, avoid the assumption that all new data will follow
earlier observations and trends, and appreciate that subtly or overtly
overstating resistance may have as negative an impact as understating
it. This is especially important in the complex and often misunderstood
area of the antipneumococcal activities of fluoroquinolones.
| |
FOOTNOTES |
*
Phone: (703)
480-2500
Fax: (703) 480-2670
E-mail: jkarlowsky{at}focusanswers.com
| |
REFERENCES |
| 1.
|
Chen, D. K.,
A. McGeer,
J. C. De Azavedo, and D. E. Low for the Canadian Bacterial Surveillance Network..
1999.
Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada.
N. Engl. J. Med.
341:233-239[Abstract/Free Full Text].
|
| 2.
|
Jones, R. N., and M. A. Pfaller.
2000.
Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY Antimicrobial Surveillance Program (North America, 1997-1999).
J. Clin. Microbiol.
38:4298-4299[Free Full Text].
|
| 3.
|
Jones, R. N.,
M. A. Pfaller, and G. V. Doern.
1998.
Comparative antimicrobial activity activity of trovafloxacin tested against 3049 Streptococcus pneumoniae isolates from the 1997-1998 respiratory infection season.
Diagn. Microbiol. Infect. Dis.
32:119-126[CrossRef][Medline].
|
| 4.
|
Peterson, D. E., and D. F. Sahm.
1999.
Fluoroquinolone resistance in Streptococcus pneumoniae.
N. Engl. J. Med.
341:1546-1548[Free Full Text].
|
| 5.
|
Pfaller, M. A.,
R. N. Jones,
G. V. Doern,
K. Kugler, and The SENTRY Participants Group.
1998.
Bacterial pathogens isolated from patients with bloodstream infection: frequencies of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997).
Antimicrob. Agents Chemother.
42:1762-1770[Abstract/Free Full Text].
|
| 6.
|
Sahm, D. F.,
D. E. Peterson,
I. A. Critchley, and C. Thornsberry.
2000.
Analysis of ciprofloxacin activity against Streptococcus pneumoniae after 10 years of use in the United States.
Antimicrob. Agents Chemother.
44:2521-2524[Abstract/Free Full Text].
|
| 7.
|
Zhanel, G. G.,
J. A. Karlowsky,
L. Palatnick,
L. Vercaigne,
D. E. Low,
The Canadian Respiratory Infection Study Group, and D. J. Hoban.
1999.
Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study.
Antimicrob. Agents Chemother.
43:2504-2509[Abstract/Free Full Text].
|
| | | | |
James A. Karlowsky*
Leigh Nealy
Daniel
F. Sahm
Focus Technologies, Inc. (formerly MRL)
13665 Dulles Technology Dr., Suite 200
Herndon, Virginia 20171-4603
|
| | | | |
Clyde Thornsberry
Focus Technologies, Inc.
Brentwood, Tennessee 37027
|
| | | | |
Mark E. Jones
Focus Technologies, Inc.
Utrecht, The Netherlands
|
| |
AUTHORS' REPLY |
We agree with the concerns of Karlowsky et al. that surveillance data
must be analyzed critically and that resistance trends should not be
overstated. However, we do not agree with their (over) analysis of our
recent report (4). Simply stated, we presented data
representing consecutive isolates of Streptococcus pneumoniae, all of which were from the same participant sites each
year and tested in a central laboratory using reference methods (6). Our data regarding resistance rates for ciprofloxacin and levofloxacin and the relationship with levels of penicillin susceptibility do in fact parallel those of Chen et al.
(1). Furthermore, we confirmed the levofloxacin-resistant
phenotype by identifying specific point mutations in the
quinolone-resistance determining region of the isolates genome. We
chose to report our results as North American data (United States and
Canada combined), but the same trend was noted upon further
stratification and steady trends toward resistance were observed in all
SENTRY-monitored hospitals in the Western Hemisphere from 1997 to 2000 (8,364 strains), although the numbers of isolates were modest
(3). It is curious that Karlowsky et al. criticized our
report for comparing combined U.S. and Canadian data with strictly
Canadian data and then state that a U.S. study (performed by Sahm et
al., i.e., a study of which several of them were coauthors) (7,
8) does not support the emerging fluoroquinolone resistance
trends described by Chen et al. (1). In fact, their
publication (7) clearly demonstrates a statistically
significant increase in levofloxacin resistance (0.1 to 0.6%;
P < 0.05) from the 1997-1998 season to the 1998-1999 season. Also, the data presented by Zhanel and colleagues
(8) principally illustrated that ciprofloxacin resistance
among S. pneumoniae had emerged in Canada in their sample,
confirming the work of Chen et al. (1), who also noted the
well-recognized association with older patients (2).
Further, their analysis of two trovafloxacin surveillance studies
(1997-1998 and 1998-1999; more than 6,000 strains from the same
sites (more than 200 sites in the United States) was not correct
(6; R. N. Jones, D. J. Biedenbach, D. M. Johnson, and The Trovafloxacin Study Group, Abstr. 99th Gen.
Meet. Am. Soc. Microbiol., abstr. C-421, p. 191, 1999). In this trial
only trovafloxacin-resistant strains were referred for molecular
analysis and the trovafloxacin resistance among S. pneumoniae increased from <0.2% (four strains; mutations in gyrA and parC) to 0.5% (14 strains) in only 1 year.
It is true that our study and most of the other studies demonstrating
increased resistance rates of any drug class did not have antimicrobial
use data, but this does not invalidate the resistance rates that were
observed. This is especially true if the study sites are kept stable
over the longitudinal sampling intervals; few studies have accomplished
this task (3-5; Jones et al., Abstr.
99th Gen. Meet. Am. Soc. Microbiol.). It is well known that fluoroquinolone usage has increased markedly (in the United
States and Canada) because of the broad-spectrum applicability and
potency of these drugs against pathogens causing community-acquired respiratory tract infections. Usage of these drugs has been escalated by the recent introduction of agents highly active against S. pneumoniae (gatifloxacin, moxifloxacin, and trovafloxacin). It is
not a far stretch to suggest that there may be a relationship between
usage and resistance, as was implied by the Canadian study (1) and by several studies in the United States
(3-5; Jones et al., Abstr. 99th Gen. Meet. Am. Soc.
Microbiol.).
The bottom line here is that fluoroquinolone resistance data from
surveillance studies in addition to that of Chen et al. (1) have also documented fluoroquinolone resistance creep. The fact (if true?) that other studies might fail to show this same
trend is worth noting and deserving of further analysis. The crux of
antimicrobial resistance surveillance is the observance of what happens
over time (i.e., trends), so continued efforts using reference-quality
testing methods (not less-controllable commercial system results),
validation of reported quantitative resistance data, and molecular
confirmation of phenotypic resistance must continue, with cooperation
among the monitoring networks. This should lead to the rapid sharing of
derived information with the interested parties in clinical practice
(4), federal agencies, professional societies, and industry.
| |
FOOTNOTES |
*
Phone: (319)
665-3370
Fax: (319) 665-3371
E-mail: ronald-jones{at}jonesgr.com
| |
REFERENCES |
| 1.
|
Chen, D. K.,
A. McGeer,
J. C. de Azavedo, and J. C. Low.
1999.
Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada.
N. Engl. J. Med.
341:233-239.
|
| 2.
|
Ho, P. L.,
W. S. Tse,
K. W. T. Tsange,
T. K. Kwok,
T. K. Ng,
V. C. C. Cheng, and R. M. T. Chan.
2001.
Risk factors for acquisition of levofloxacin-resistant Streptococcus pneumoniae: a case-control study.
Clin. Infect. Dis.
32:701-707[CrossRef][Medline].
|
| 3.
|
Jones, R. N., and M. A. Pfaller.
2000.
In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: data from the SENTRY Antimicrobial Surveillance Program.
Clin. Infect. Dis.
31(Suppl. 2):S16-S23.
|
| 4.
|
Jones, R. N., and M. A. Pfaller.
2000.
Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY Antimicrobial Surveillance Program (North America, 1997-1999).
J. Clin. Microbiol.
38:4298-4299.
|
| 5.
|
Jones, R. N.,
M. A. Pfaller, and G. V. Doern.
1998.
Comparative antimicrobial activity of trovafloxacin tested against 3,049 Streptococcus pneumoniae isolates from the 1997-1998 respiratory infection season.
Diagn. Microbiol. Infect. Dis.
32:119-126.
|
| 6.
|
National Committee for Clinical Laboratory Standards.
2000.
Performance standards for antimicrobial susceptibility testing. M7-A5.
NCCLS, Wayne, Pa.
|
| 7.
|
Sahm, D. F.,
J. A. Karlowsky,
L. J. Kelly,
I. A. Critchley,
M. E. Jones,
C. Thornsberry,
Y. Mauriz, and J. Kahn.
2001.
Need for annual surveillance of antimicrobial resistance in Streptococcus pneumoniae in the United States: two-year longitudinal analysis.
Antimicrob. Agents Chemother.
45:1037-1042[Abstract/Free Full Text].
|
| 8.
|
Zhanel, G. G.,
J. A. Karlowsky,
L. Palatnick,
L. Vercaigne,
D. E. Low,
The Canadian Respiratory Infection Study Group, and D. J. Hoban.
1999.
Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study.
Antimicrob. Agents Chemother.
43:2504-2509.
|
| | | | |
Michael A. Pfaller
University of Iowa College of Medicine
Iowa City, Iowa
|
| | | | |
Ronald N. Jones*
University of Iowa College of Medicine
Iowa City, and The JONES Group/JMI Laboratories,
345 Beaver Creek Centre, Suite A
North Liberty, Iowa 52317
|
Journal of Clinical Microbiology, July 2001, p. 2748-2750, Vol. 39, No. 7
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.7.2748-2750.2001
This article has been cited by other articles:
-
Hsueh, P.-R., Teng, L.-J., Wu, T.-L., Yang, D., Huang, W.-K., Shyr, J.-M., Chuang, Y.-C., Wan, J.-H., Yan, J.-J., Lu, J.-J., Wu, J.-J., Ko, W.-C., Chang, F.-Y., Yang, Y.-C., Lau, Y.-J., Liu, Y.-C., Lee, C.-M., Leu, H.-S., Liu, C.-Y., Luh, K.-T.
(2003). Telithromycin- and Fluoroquinolone-Resistant Streptococcus pneumoniae in Taiwan with High Prevalence of Resistance to Macrolides and {beta}-Lactams: SMART Program 2001 Data. Antimicrob. Agents Chemother.
47: 2145-2151
[Abstract]
[Full Text]
