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Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999–2000
International Journal of Antimicrobial Agents 19 (2002) 33 – 37 www.ischemo.org
Original article
Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999–2000 Laura M. Koeth a,*, Michael R. Jacobs b, Saralee Bajaksouzian b, Anne Zilles b, Gengrong Lin c, Peter C. Appelbaum c b
a Laboratory Specialists, Inc., 1651 A Crossings Parkway, Westlake, OH 44145, USA Department of Pathology, Case Western Reser6e Uni6ersity and Uni6ersity Hospitals of Cle6eland, Cle6eland, OH 44106, USA c Department of Pathology, Hershey Medical Center, Hershey, PA 17033, USA
Received 17 July 2001; accepted 25 July 2001
Abstract This study was undertaken to assess the in vitro activity of gemifloxacin, five other fluoroquinolone antimicrobial agents (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin and ofloxacin) and other non-quinolone comparator agents (ampicillin, erythromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulphamethoxazole) against Streptococcus pneumoniae collected in the United States. Susceptibility testing of 550 S. pneumoniae, 290 Haemophilus influenzae and 205 Moraxella catarrhalis showed that 38.2% of pneumococci were penicillin nonsusceptible, while 26.2 and 95.6% of H. influenzae and M. catarrhalis, respectively, produced b-lactamase. Overall new fluoroquinolones were the most active agents. The in vitro activity (based on MIC90 in mg/l) of the six fluoroquinolones was gemifloxacin \ moxifloxacin\gatifloxacin\levofloxacin\ ciprofloxacin and ofloxacin. © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Fluoroquinolone antimicrobial agents; Streptococcus pneumoniae; Gemifloxacin
1. Introduction The majority of bacterial community acquired respiratory tract infections (RTI) are caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis [1,2]. As a result of increases in resistance of these key respiratory pathogens, physicians have been advised to modify their treatment practices [1,3,4]. Recent empirical first-line recommendations include the newer fluoroquinolones, macrolides and doxycycline for community acquired pneumonia (CAP), and amoxycillin, amoxycillin/clavulanate, cef* Corresponding author. Tel.: + 1-440-835-4458; fax: +1-440-8355786. E-mail address: [email protected] (L.M. Koeth).
podoxime, cefuroxime and newer fluoroquinolones for acute bacterial sinusitis [3,4].
2. Methods This study was performed to determine the activity of agents used to treat RTI against contemporary isolates of S. pneumoniae, H. influenzae and M. catarrhalis. A total of 550 S. pneumoniae, 290 H. influenzae and 205 M. catarrhalis were collected from 16 hospitals in the United States (33.8% northeast, 8.7% northwest, 13.5% north central, 12.7% southeast, 14.4% southwest and 16.9% south central). Isolates were recovered from cultures of blood (17.2%), sputum (62.4%), bronchoalveolar lavage (2.3%), middle ear fluid (6.9%),
0924-8579/02/$ - $20 © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 1 ) 0 0 4 3 1 - 9
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L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
nasopharynx (4.4%), sinus (4.9%), and other (1.9%) performed between May 1999 and 2000. Isolates were collected from outpatients or hospitalized patients within 48 h of admission with RTI. S. pneumoniae and M. catarrhalis were collected from children and adults (15.3% B2 years, 10.5% 2–10 years, 1.9% 11– 16 years and 72.3% \16 years). H. influenzae were collected from adult patients only (\ 16 years). Broth microdilution MICs were performed in custom dried 96-well microdilution trays (TREK Diagnostic Systems, Inc., Westlake, OH) following NCCLS guidelines and according to the microdilution tray manufacturer as described previously [5,6]. S. pneumoniae was tested in Mueller Hinton broth (TREK) supplemented with 5% lysed horse blood (Cleveland Scientific, Bath, OH), and H. influenzae and M. catarrhalis in HTM broth (PML, Tualatin, OR.). Repeat testing of S. pneumoniae strains with ciprofloxacin MICs \ 4 mg/l was performed in custom frozen trays containing higher ciprofloxacin and levofloxacin concentrations (PML, Tualatin, OR) following NCCLS guidelines. H. influenzae and M. catarrhalis isolates were also tested for b-lactamase production using the nitrocefin disk method (Cefinase; Becton Dickinson Laboratories, Spark, MD). MICs were interpreted according to NCCLS breakpoints [6] and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints where NCCLS breakpoints were not available [2,5].
3. Results Results of the MICs of non-fluoroquinolones are shown in Table 1 and to quinolone antibiotics in Table 2.
for these six strains were also elevated and are shown in Table 3. Gemifloxacin was the most active agent against these ‘quinolone-resistant’ strains.
3.2. Haemophilus influenzae The proportion of b-lactamase producing isolates was 26.2%. Erythromycin and doxycycline showed poor activity against H. influenzae at PK/PD breakpoints. However, 81.7% of isolates were susceptible to trimethoprim/sulphamethoxazole. All fluoroquinolones were highly active against H. influenzae (100% susceptible). No MICs exceeded 0.12 mg/l for any of the quinolone agents and gemifloxacin was the most active agent. MIC90 values (in mg/l) were gemifloxacin (0.008), ciprofloxacin (0.015), gatifloxacin (0.015), levofloxacin (0.015), moxifloxacin (0.03) and ofloxacin (0.06).
3.3. Moraxella catarrhalis Nearly all of the M. catarrhalis (95.6%) were b-lactamase positive. The majority of the isolates (98.5%) were susceptible to erythromycin using PK/PD breakpoints. A total of 99.5% of M. catarrhalis strains were susceptible to doxycycline. In contrast, only 38.0% were susceptible to trimethoprim/sulphamethoxazole. All six fluoroquinolones were extremely active (100% susceptible), with gemifloxacin being the most active agent. The MIC90 for gemifloxacin was 0.015 mg/l, followed by gatifloxacin at 0.03 mg/l, ciprofloxacin, levofloxacin and moxifloxacin at 0.06 mg/l and ofloxacin at 0.12 mg/l.
4. Discussion
3.1. Streptococcus pneumoniae Of the 550 S. pneumoniae isolates tested, 61.8% were susceptible, 12.2% were intermediate and 26% were resistant to penicillin. Clindamycin was one of the more active, non-fluoroquinolone agents tested (92.4% susceptible). Doxycycline was slightly less active (82.0% susceptible, based on PK/PD breakpoint) and was followed in activity by erythromycin (71.5% susceptible) and trimethoprim/sulphamethoxazole (58.9% susceptible). MIC90 values (in mg/l)/% susceptible of the six fluoroquinolones were: gemifloxacin (0.03/99.8%), moxifloxacin (0.25/99.1%), gatifloxacin (0.5/98.9%), levofloxacin (1/99.1%), ciprofloxacin (2/82.9%) and ofloxacin (2/94.0%) (Table 2). There were six strains with ciprofloxacin MICs \4 mg/l. These strains were retested with trays containing higher fluoroquinolone concentrations and ciprofloxacin MICs ranged from 8 to 128 mg/l. The MICs for the other fluoroquinolones
This study has shown that the primary RTI pathogens are susceptible to the new quinolones. Agents that were inactive against at least one of the three bacterial species tested included erythromycin, doxycycline and trimethoprim/sulphamethoxazole. There were no major changes in susceptibilities of S. pneumoniae to fluoroquinolones compared with 1997 surveillance data [5,7–9]. S. pneumoniae susceptibility to erythromycin was similar to that reported for azithromycin in 1997 by Jacobs et al. [5] (69.2%) but lower than the erythromycin resistant rate reported in 1997 by Doern et al. [10] (84.5%), in 1996–1997 by Thornsberry et al. [9] (clarithromycin susceptibility rate of 80.9%) or in 1997–1998 by Thornsberry et al. [8] (azithromycin and clarithromycin resistant rates of 77.1%). The susceptibility to trimethoprim/sulphamethoxazole was also lower than in recent studies, e.g. 68.1% by Thornsberry et al. [8] and 74.4% by Doern et al [10]. Six isolates of the total 550 S. pneumo-
Table 1 MIC summary of five antimicrobial agents against S. pneumoniae, H. influenzae, and M. catarrhalis Test agent
– – 0.25 – 0.25 –
Streptococcus pneumoniae (n =550)
Haemophilus influenzae (n = 290)
Moraxella catarrhalis (n=205)a
NCCLS Susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
NCCLS Susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
PK/PD (%S)
MIC50/90 (mg/l)
0.06/1b NAc 0.25 0.25 NAc 0.5
61.8/12.2b NAc 71.5 92.4 NAc 58.9
– – 71.7 – 82.0 –
0.03/4 NAc 0.06/8 0.06/0.06 0.25/8 0.25/8
NAc 2 NAc NAc NAc 0.5
NAc 73.4 NAc NAc NAc 81.7
– – 0 – 36.6 –
NAc 0.25/32 4/8 \2/\2− 0.5/0.5 0.06/8
NAc – 98.5 – 99.5 38
NAc 8/32 0.12/0.25 \2/\2− 0.25/0.25 1/2
a
NCCLS susceptibility interpretations are not available for M. catarrhalis. Susceptible/intermediate values. c Not available. b
Table 2 MIC summary of six fluoroquinolone antimicrobial agents against S. pneumoniae, H. influenzae, and M. catarrhalis Test agent
Ciprofloxacin Gatifloxacin Gemifloxacin Levofloxacin Moxifloxacin Ofloxacin a
PK/PD susceptible breakpoint
1 1 0.25 2 1 2
Streptococcus pneumoniae (n =550)
Haemophilus influenzae (n = 290)
Moraxella catarrhalis (n= 205)a
NCCLS susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
NCCLS susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
PK/PD (%S)
MIC50/90 (mg/l)
NAa 1 NAa 2 1 2
NAa 98.9 NAa 99.1 99.1 94.0
82.9 98.9 99.8 99.1 99.1 94.0
1/2 0.25/0.5 0.015/0.03 1/1 0.12/0.25 2/2
1 1 NAa 2 1 2
100 100 NAa 100 100 100
100 100 100 100 100 100
0.015/0.015 0.008/0.015 0.004/0.008 0.015/0.015 0.015/0.03 0.03/0.06
100 100 100 100 100 100
0.03/0.06 0.03/0.03 0.015/0.015 0.03/0.06 0.06/0.06 0.12/0.12
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
Penicillin Ampicillin Erythromycin Clindamycin Doxycycline Trimethoprim/ sulphamethoxazole
PK/PD susceptible breakpoint
Not available.
35
36
Strain number
2000-145-024S 2000-148-004S 2000-148-010S 2000-148-042S 2000-153-017S 2000-154-003S
State
CA WA WA WA IN OH
Ciprofloxacin
Gatifloxacin
Gemifloxacin
Levofloxacin
Moxifloxacin
Initial
Retest
Initial
Retest
Initial
Retest
Initial
Retest
Initial
Retest
\8 \8 8 \8 \8 \8
32 64 8 128 32 64
\1 \1 \1 \1 \1 \1
4 8 1 8 4 8
0.12 0.25 0.06 0.5 0.25 0.12
0.25 0.5 0.12 0.5 0.5 0.25
\2 \2 2 \2 \2 \2
16 32 4 32 16 16
\1 \1 0.25 \1 \1 \1
4 4 0.5 4 4 4
Ofloxacin
Penicilllin
\8 \8 4 \8 \8 \8
50.015 50.015 50.015 50.015 50.015 50.015
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
Table 3 Fluoroquinolone and penicillin MICs (mg/l) of S. pneumoniae with ciprofloxacin MICs of \4 mg/l
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
niae strains tested (1.1%) had ciprofloxacin MICs of \4 mg/l. These data are consistent with other recent studies that have shown low rates of quinolone resistance in the USA [9,11– 13]. Other studies have also shown that gemifloxacin remains the most active fluoroquinolone against quinolone-resistant S. pneumoniae [7,14]. b-lactamase production by H. influenzae and M. catarrhalis was also similar to other recent studies [5,8,11,15]. No b-lactamase negative, ampicillin-resistant H. influenzae were isolated in this study. There were also no significant MIC differences found in H. influenzae and M. catarrhalis with the antimicrobial agents tested when compared to other studies [5,8,9]. Overall, the fluoroquinolones were very active against all three RTI pathogens with gemifloxacin showing superior in vitro activity. Therefore, when prescribing initial empirical therapy for community acquired RTI, the clinician must consider the changing susceptibility patterns of the major pathogens and choose a therapy that has activity against the suspected pathogens. Gemifloxacin, with minimal resistance occurring in all three major bacterial RTI pathogens, is a promising agent for empirical treatment of RTIs in adults. The clinician should be aware that the presence of b-lactam, macrolide and quinolone resistance in S. pneumoniae may increase as a result of use of less active antibiotics, including the less potent quinolones.
Acknowledgements This work was GlaxoSmithKline.
supported
by
a
grant
from
References [1] The Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group, Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM, Rakowsy A, Schwartz B. Acute otitis media: management and surveillance in an era of pneumococcal resistance —a report from the drug-resistant Streptococcus pneumoniae therapeutic working group. Pediatric Infectious Disease Journal 1999;18:1 –9. [2] Drusano GL, Craig WA. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. Journal of Chemotherapy 1997;9(Suppl. 3):38 – 44.
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[3] Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ. Practice guidelines for the management of community acquired pneumonia in adults. Clinical Infectious Disease 2000;31:347 – 82. [4] Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngology — Head and Neck Surgery 2000;123:S1 – S32. [5] Jacobs MR, Bajaksouzian S, Zilles A, Lin G, Pankuch GA, Appelbaum PC. Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance Study. Antimicrobial Agents and Chemotherapy 1999;43:1901 – 8. [6] NCCLS. Performance standards for antimicrobial susceptibility testing. 2000; M100-S11. NCCLS, Wayne, PA. [7] Chen DK, McGerr A, deAzavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Journal of American Medical Association 1999;341:233 – 9. [8] Thornsberry C, Jones ME, Hickey ML, Mauriz Y, Kahn J, Sahm DF. Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolated in the United States, 1997 – 1998. Journal of Antimicrobial Chemotherapy 1999;44:749 – 59. [9] The Laboratory Investigator Group, Thornsberry C, Ogilvie P, Kahn J, Mauriz Y. Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996 – 1997 respiratory season. Diagnostic Microbiology and Infectious Disease 1997;29:249 – 57. [10] Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN. Prevalence of Antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clinical Infectious Diseases 1998;27:764 – 70. [11] Barry AL, Pfaller MA, Fuchs PC, Packer RR. In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from U.S. medical centers in 1992 and 1993. Antimicrobial Agents and Chemotherapy 1994;38:2419 – 25. [12] The Alexander Project Group, Felmingham D, Gru¨ neberg RN. A multicentre collaborative study of the antimicrobial susceptibility of community-acquired, lower respiratory tract pathogens 1992 – 1993: the Alexander Project. Journal of Antimicrobial Chemotherapy 1996;38(Suppl. A):1 – 57. [13] Jones RN, Pfaller MA. In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: data from the SENTRY antimicrobial surveillance program. Clinical Infectious Diseases 2000;31(Suppl. 2):S16 – 23. [14] Jorgensen J.H., Weigel L.M., Swenson J.M., Whitney C.G., Ferraro M.J., Tenover F.C. Activities of clinafloxacin, gatifloxacin, gemifloxacin and trovafloxacin against recent clinical isolates of levofloxacin-resistant Streptococcus pneumoniae, AAC, November 2000;2962 – 68. [15] Jorgensen JH, Doern GV, Maher LA, Howell AW, Redding JS. Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States. Antimicrobial Agents and Chemotherapy 1990;34:2075 – 80.
Original article
Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999–2000 Laura M. Koeth a,*, Michael R. Jacobs b, Saralee Bajaksouzian b, Anne Zilles b, Gengrong Lin c, Peter C. Appelbaum c b
a Laboratory Specialists, Inc., 1651 A Crossings Parkway, Westlake, OH 44145, USA Department of Pathology, Case Western Reser6e Uni6ersity and Uni6ersity Hospitals of Cle6eland, Cle6eland, OH 44106, USA c Department of Pathology, Hershey Medical Center, Hershey, PA 17033, USA
Received 17 July 2001; accepted 25 July 2001
Abstract This study was undertaken to assess the in vitro activity of gemifloxacin, five other fluoroquinolone antimicrobial agents (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin and ofloxacin) and other non-quinolone comparator agents (ampicillin, erythromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulphamethoxazole) against Streptococcus pneumoniae collected in the United States. Susceptibility testing of 550 S. pneumoniae, 290 Haemophilus influenzae and 205 Moraxella catarrhalis showed that 38.2% of pneumococci were penicillin nonsusceptible, while 26.2 and 95.6% of H. influenzae and M. catarrhalis, respectively, produced b-lactamase. Overall new fluoroquinolones were the most active agents. The in vitro activity (based on MIC90 in mg/l) of the six fluoroquinolones was gemifloxacin \ moxifloxacin\gatifloxacin\levofloxacin\ ciprofloxacin and ofloxacin. © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Fluoroquinolone antimicrobial agents; Streptococcus pneumoniae; Gemifloxacin
1. Introduction The majority of bacterial community acquired respiratory tract infections (RTI) are caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis [1,2]. As a result of increases in resistance of these key respiratory pathogens, physicians have been advised to modify their treatment practices [1,3,4]. Recent empirical first-line recommendations include the newer fluoroquinolones, macrolides and doxycycline for community acquired pneumonia (CAP), and amoxycillin, amoxycillin/clavulanate, cef* Corresponding author. Tel.: + 1-440-835-4458; fax: +1-440-8355786. E-mail address: [email protected] (L.M. Koeth).
podoxime, cefuroxime and newer fluoroquinolones for acute bacterial sinusitis [3,4].
2. Methods This study was performed to determine the activity of agents used to treat RTI against contemporary isolates of S. pneumoniae, H. influenzae and M. catarrhalis. A total of 550 S. pneumoniae, 290 H. influenzae and 205 M. catarrhalis were collected from 16 hospitals in the United States (33.8% northeast, 8.7% northwest, 13.5% north central, 12.7% southeast, 14.4% southwest and 16.9% south central). Isolates were recovered from cultures of blood (17.2%), sputum (62.4%), bronchoalveolar lavage (2.3%), middle ear fluid (6.9%),
0924-8579/02/$ - $20 © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 1 ) 0 0 4 3 1 - 9
34
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
nasopharynx (4.4%), sinus (4.9%), and other (1.9%) performed between May 1999 and 2000. Isolates were collected from outpatients or hospitalized patients within 48 h of admission with RTI. S. pneumoniae and M. catarrhalis were collected from children and adults (15.3% B2 years, 10.5% 2–10 years, 1.9% 11– 16 years and 72.3% \16 years). H. influenzae were collected from adult patients only (\ 16 years). Broth microdilution MICs were performed in custom dried 96-well microdilution trays (TREK Diagnostic Systems, Inc., Westlake, OH) following NCCLS guidelines and according to the microdilution tray manufacturer as described previously [5,6]. S. pneumoniae was tested in Mueller Hinton broth (TREK) supplemented with 5% lysed horse blood (Cleveland Scientific, Bath, OH), and H. influenzae and M. catarrhalis in HTM broth (PML, Tualatin, OR.). Repeat testing of S. pneumoniae strains with ciprofloxacin MICs \ 4 mg/l was performed in custom frozen trays containing higher ciprofloxacin and levofloxacin concentrations (PML, Tualatin, OR) following NCCLS guidelines. H. influenzae and M. catarrhalis isolates were also tested for b-lactamase production using the nitrocefin disk method (Cefinase; Becton Dickinson Laboratories, Spark, MD). MICs were interpreted according to NCCLS breakpoints [6] and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints where NCCLS breakpoints were not available [2,5].
3. Results Results of the MICs of non-fluoroquinolones are shown in Table 1 and to quinolone antibiotics in Table 2.
for these six strains were also elevated and are shown in Table 3. Gemifloxacin was the most active agent against these ‘quinolone-resistant’ strains.
3.2. Haemophilus influenzae The proportion of b-lactamase producing isolates was 26.2%. Erythromycin and doxycycline showed poor activity against H. influenzae at PK/PD breakpoints. However, 81.7% of isolates were susceptible to trimethoprim/sulphamethoxazole. All fluoroquinolones were highly active against H. influenzae (100% susceptible). No MICs exceeded 0.12 mg/l for any of the quinolone agents and gemifloxacin was the most active agent. MIC90 values (in mg/l) were gemifloxacin (0.008), ciprofloxacin (0.015), gatifloxacin (0.015), levofloxacin (0.015), moxifloxacin (0.03) and ofloxacin (0.06).
3.3. Moraxella catarrhalis Nearly all of the M. catarrhalis (95.6%) were b-lactamase positive. The majority of the isolates (98.5%) were susceptible to erythromycin using PK/PD breakpoints. A total of 99.5% of M. catarrhalis strains were susceptible to doxycycline. In contrast, only 38.0% were susceptible to trimethoprim/sulphamethoxazole. All six fluoroquinolones were extremely active (100% susceptible), with gemifloxacin being the most active agent. The MIC90 for gemifloxacin was 0.015 mg/l, followed by gatifloxacin at 0.03 mg/l, ciprofloxacin, levofloxacin and moxifloxacin at 0.06 mg/l and ofloxacin at 0.12 mg/l.
4. Discussion
3.1. Streptococcus pneumoniae Of the 550 S. pneumoniae isolates tested, 61.8% were susceptible, 12.2% were intermediate and 26% were resistant to penicillin. Clindamycin was one of the more active, non-fluoroquinolone agents tested (92.4% susceptible). Doxycycline was slightly less active (82.0% susceptible, based on PK/PD breakpoint) and was followed in activity by erythromycin (71.5% susceptible) and trimethoprim/sulphamethoxazole (58.9% susceptible). MIC90 values (in mg/l)/% susceptible of the six fluoroquinolones were: gemifloxacin (0.03/99.8%), moxifloxacin (0.25/99.1%), gatifloxacin (0.5/98.9%), levofloxacin (1/99.1%), ciprofloxacin (2/82.9%) and ofloxacin (2/94.0%) (Table 2). There were six strains with ciprofloxacin MICs \4 mg/l. These strains were retested with trays containing higher fluoroquinolone concentrations and ciprofloxacin MICs ranged from 8 to 128 mg/l. The MICs for the other fluoroquinolones
This study has shown that the primary RTI pathogens are susceptible to the new quinolones. Agents that were inactive against at least one of the three bacterial species tested included erythromycin, doxycycline and trimethoprim/sulphamethoxazole. There were no major changes in susceptibilities of S. pneumoniae to fluoroquinolones compared with 1997 surveillance data [5,7–9]. S. pneumoniae susceptibility to erythromycin was similar to that reported for azithromycin in 1997 by Jacobs et al. [5] (69.2%) but lower than the erythromycin resistant rate reported in 1997 by Doern et al. [10] (84.5%), in 1996–1997 by Thornsberry et al. [9] (clarithromycin susceptibility rate of 80.9%) or in 1997–1998 by Thornsberry et al. [8] (azithromycin and clarithromycin resistant rates of 77.1%). The susceptibility to trimethoprim/sulphamethoxazole was also lower than in recent studies, e.g. 68.1% by Thornsberry et al. [8] and 74.4% by Doern et al [10]. Six isolates of the total 550 S. pneumo-
Table 1 MIC summary of five antimicrobial agents against S. pneumoniae, H. influenzae, and M. catarrhalis Test agent
– – 0.25 – 0.25 –
Streptococcus pneumoniae (n =550)
Haemophilus influenzae (n = 290)
Moraxella catarrhalis (n=205)a
NCCLS Susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
NCCLS Susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
PK/PD (%S)
MIC50/90 (mg/l)
0.06/1b NAc 0.25 0.25 NAc 0.5
61.8/12.2b NAc 71.5 92.4 NAc 58.9
– – 71.7 – 82.0 –
0.03/4 NAc 0.06/8 0.06/0.06 0.25/8 0.25/8
NAc 2 NAc NAc NAc 0.5
NAc 73.4 NAc NAc NAc 81.7
– – 0 – 36.6 –
NAc 0.25/32 4/8 \2/\2− 0.5/0.5 0.06/8
NAc – 98.5 – 99.5 38
NAc 8/32 0.12/0.25 \2/\2− 0.25/0.25 1/2
a
NCCLS susceptibility interpretations are not available for M. catarrhalis. Susceptible/intermediate values. c Not available. b
Table 2 MIC summary of six fluoroquinolone antimicrobial agents against S. pneumoniae, H. influenzae, and M. catarrhalis Test agent
Ciprofloxacin Gatifloxacin Gemifloxacin Levofloxacin Moxifloxacin Ofloxacin a
PK/PD susceptible breakpoint
1 1 0.25 2 1 2
Streptococcus pneumoniae (n =550)
Haemophilus influenzae (n = 290)
Moraxella catarrhalis (n= 205)a
NCCLS susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
NCCLS susceptible breakpoint
NCCLS (%S)
PK/PD (%S)
MIC50/90 (mg/l)
PK/PD (%S)
MIC50/90 (mg/l)
NAa 1 NAa 2 1 2
NAa 98.9 NAa 99.1 99.1 94.0
82.9 98.9 99.8 99.1 99.1 94.0
1/2 0.25/0.5 0.015/0.03 1/1 0.12/0.25 2/2
1 1 NAa 2 1 2
100 100 NAa 100 100 100
100 100 100 100 100 100
0.015/0.015 0.008/0.015 0.004/0.008 0.015/0.015 0.015/0.03 0.03/0.06
100 100 100 100 100 100
0.03/0.06 0.03/0.03 0.015/0.015 0.03/0.06 0.06/0.06 0.12/0.12
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
Penicillin Ampicillin Erythromycin Clindamycin Doxycycline Trimethoprim/ sulphamethoxazole
PK/PD susceptible breakpoint
Not available.
35
36
Strain number
2000-145-024S 2000-148-004S 2000-148-010S 2000-148-042S 2000-153-017S 2000-154-003S
State
CA WA WA WA IN OH
Ciprofloxacin
Gatifloxacin
Gemifloxacin
Levofloxacin
Moxifloxacin
Initial
Retest
Initial
Retest
Initial
Retest
Initial
Retest
Initial
Retest
\8 \8 8 \8 \8 \8
32 64 8 128 32 64
\1 \1 \1 \1 \1 \1
4 8 1 8 4 8
0.12 0.25 0.06 0.5 0.25 0.12
0.25 0.5 0.12 0.5 0.5 0.25
\2 \2 2 \2 \2 \2
16 32 4 32 16 16
\1 \1 0.25 \1 \1 \1
4 4 0.5 4 4 4
Ofloxacin
Penicilllin
\8 \8 4 \8 \8 \8
50.015 50.015 50.015 50.015 50.015 50.015
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
Table 3 Fluoroquinolone and penicillin MICs (mg/l) of S. pneumoniae with ciprofloxacin MICs of \4 mg/l
L.M. Koeth et al. / International Journal of Antimicrobial Agents 19 (2002) 33–37
niae strains tested (1.1%) had ciprofloxacin MICs of \4 mg/l. These data are consistent with other recent studies that have shown low rates of quinolone resistance in the USA [9,11– 13]. Other studies have also shown that gemifloxacin remains the most active fluoroquinolone against quinolone-resistant S. pneumoniae [7,14]. b-lactamase production by H. influenzae and M. catarrhalis was also similar to other recent studies [5,8,11,15]. No b-lactamase negative, ampicillin-resistant H. influenzae were isolated in this study. There were also no significant MIC differences found in H. influenzae and M. catarrhalis with the antimicrobial agents tested when compared to other studies [5,8,9]. Overall, the fluoroquinolones were very active against all three RTI pathogens with gemifloxacin showing superior in vitro activity. Therefore, when prescribing initial empirical therapy for community acquired RTI, the clinician must consider the changing susceptibility patterns of the major pathogens and choose a therapy that has activity against the suspected pathogens. Gemifloxacin, with minimal resistance occurring in all three major bacterial RTI pathogens, is a promising agent for empirical treatment of RTIs in adults. The clinician should be aware that the presence of b-lactam, macrolide and quinolone resistance in S. pneumoniae may increase as a result of use of less active antibiotics, including the less potent quinolones.
Acknowledgements This work was GlaxoSmithKline.
supported
by
a
grant
from
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