Activity of gatifloxacin tested against isolates from pediatric patients: report from the SENTRY Antimicrobial Surveillance Program (North America, 1998–2003)

Diagnostic Microbiology and Infectious Disease 55 (2006) 157 – 164 www.elsevier.com/locate/diagmicrobio

Surveillance

Activity of gatifloxacin tested against isolates from pediatric patients: report from the SENTRY Antimicrobial Surveillance Program (North America, 1998–2003) Kelley A. Fedler a,4, Ronald N. Jones a,b, Helio S. Sader a, Thomas R. Fritsche a b

a JMI Laboratories, North Liberty, IA 52317, USA Tufts University School of Medicine, Boston, MA 02111, USA Received 30 November 2005; accepted 3 January 2006

Abstract The SENTRY Antimicrobial Surveillance Program has monitored the activity of antimicrobial agents worldwide since 1997. The increasing number of clinical failures with established anti-infectives (penicillins, other h-lactams, macrolides) among pediatric patients has stressed the importance for alternative therapeutic options. Ciprofloxacin has been recently approved for expanded use as treatment of complicated urinary tract infections in children, and gatifloxacin has been used successfully in clinical trials in selected children with severe or refractory otitis media. We evaluated the activity of gatifloxacin against strains isolated from children b 7 years of age and compared this to the general patient population using the SENTRY Program database. A total of 59 826 North American isolates were collected, of which 4641 were from children ( b 7 years old); all isolates were tested using reference broth microdilution methods. In contrast to the general population (GP), gatifloxacin resistance rates were very low among isolates from this younger patient group. Gatifloxacin susceptibility rates were N 84% for all pathogens evaluated in younger patients. All Streptococcus pneumoniae strains from children b 7 years old were susceptible to gatifloxacin, and susceptibility among the Enterobacteriaceae species was N 98%. The greatest difference in susceptibility rates between the younger children and the GP was observed among nonfermentative Gram-negative bacilli (95.0–100% versus 64.8 – 83.7%, respectively) and Enterococcus faecalis (94.7% versus 58.4%). Gatifloxacin susceptibilities of Pseudomonas aeruginosa and Acinetobacter spp. isolates from the pediatric population were z 95% ( N 97% for ciprofloxacin) compared to the GP at only 64.8 – 69.1%. In conclusion, gatifloxacin remains very active against bacterial isolates from children b 7 years, indicative of the limited exposure of this population to fluoroquinolones. Continued resistance surveillance will be necessary to monitor the activity of the fluoroquinolone class as they are introduced for specific clinical indications into the pediatric age groups, especially if re-studied against S. pneumoniae (refractory otitis media) and P. aeruginosa (cystic fibrosis associated pneumonia). D 2006 Elsevier Inc. All rights reserved. Keywords: Pediatrics; Resistance; Fluoroquinolone; Gatifloxacin; SENTRY; North America

1. Introduction Antimicrobial activity of early quinolones was directed primarily against Gram-negative organisms as such agents possess a high probability of producing adverse events among treated patients. These side effects included rash, crystalluria, central nervous system irritation, phototoxicity, arthropathy, and the most frequently reported problem, gastrointestinal disturbance (Domagala, 1994; Tarshis et al., 2001). Subsequent modifications to side chains of the basic molecular structures have resulted in a broader spectrum of 4 Corresponding author. Tel.: +1-319-665-3370; fax: +1-319-665-3371. E-mail address: [email protected] (K.A. Fedler ). 0732-8893/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2006.01.005

activity while reducing the risk and severity of adverse events. Concern about irreversible damage to the weightbearing joints of children and birth defects in babies with prenatal exposure to quinolones has limited utilization of the class in the pediatric population (Stahlmann et al., 2000; Takizawa et al., 1999). Although several studies found an absence of correlation between prenatal exposure and increased bone malformation rates or irreversible arthropathies, prudent utilization has limited fluoroquinolone use in children to compassionate use (Burkhardt et al., 1997; Grady, 2003; Schaad, 1999; Schaefer et al., 1996; Wogelius et al., 2005). The introduction of the new fluoroquinolones is characterized by enhanced spectrum and increased potency

158

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164

for the class. Among recently licensed fluoroquinolones, gatifloxacin is a broad-spectrum agent with excellent activity against many clinically significant Gram-positive, Gram-negative, and select anaerobic organisms (Ednie et al., 1998; Fung-Tomc et al., 2000; Goldstein et al., 1999). The C-8 methoxy side chain and other characteristics of the gatifloxacin chemical structure are known to minimize the rate at which indicated bacteria acquire resistance (Zhao et al., 1997; Zhao et al., 1998). DNA gyrase and topoisomerase IV are 2 enzymes needed for bacterial replication that are targeted by these fluoroquinolones (dual action) (Ferrero et al., 1994; Janoir et al., 1996). Resistance occurs in a stepwise manner, and at least 2 mutations of the quinolone resistance-determining region (QRDR) of the parC and gyrA genes are usually necessary for high-level gatifloxacin resistance to occur. Streptococcus pneumoniae strains with parC and gyrA mutations, or efflux mutations, can have gatifloxacin MIC values (MIC90) that are 16- to 32-fold higher and 2- to 4-fold higher than wild-type strains, respectively (Boswell et al., 2002). Resistance rates of common pathogens to such commonly used antimicrobial agents such as amoxicillin/clavulanate, other oral h-lactams, and macrolides are on the rise. Among S. pneumoniae, the macrolide susceptibility rate was noted to decrease from a high of 89.3% to 75.4% in just 1 year as the use of this class accelerated (Jones and Pfaller, 2000). The rapid escalation of penicillin and erythromycin resistance in S. pneumoniae has dramatized the need for increased availability of agents such as fluoroquinolones for younger pediatric patients. However, fluoroquinolone therapy in children has been prescribed as a last resort only after traditional therapy fails if a multidrug-resistant (MDR) organism has been identified. Ciprofloxacin has been recently approved by the United States Food and Drug Administration (US-FDA) for the treatment of complicated urinary tract infection in children and gatifloxacin has been successfully used in clinical trials of selected children with severe otitis media failing therapy with the commonly used agent, amoxicillin/clavulanate, but the NDA was withdrawn by the sponsor in 2004 (Echols et al., 2005; Pichichero et al., 2005). Currently, reported S. pneumoniae resistance to fluoroquinolones in pediatrics is believed to be extremely low. However, as fluoroquinolones are introduced into the pediatric population, selective pressures can be expected to result in a progressive increase of acquired resistance as has occurred with penicillins, macrolides, and fluoroquinolones in adult patient populations. A limited number of studies have observed that fluoroquinolone resistance rates increase with age as well as increased use (Bhavnani et al., 2005; Jones et al., 2003). If fluoroquinolone resistance does emerge, it can be expected to spread (clonal MDR organisms) rapidly in children and pose a global threat (Klugman, 2003; Mandell et al., 2002). The purpose of this study was to systematically evaluate the activity of gatifloxacin tested against a large collection of Gram-

positive and Gram-negative pathogens isolated in North American medical centers from children less than 7 years of age and to compare these results with those of the larger patient population (all ages included) using results generated as part of the longitudinal SENTRY Antimicrobial Surveillance Program (1998 –2003).

2. Materials and methods 2.1. Bacterial isolates studied A total of 59 826 isolates with gatifloxacin susceptibility test results were collected according to protocols of the SENTRY Program in North America from 1998 to 2003. Demographic data collected on each isolate contained the patient’s sex, age, prior antimicrobial test results, and site of infection. The vast majority (85%) of specimens were isolated from bloodstream infections (34 292 isolates; 57.3%); community-acquired respiratory tract infection caused by S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis (6507; 10.9%), and from patients hospitalized with pneumonia (10 343; 17.3%). Isolates were forwarded to the central monitor (JMI Laboratories North Liberty, IA) for susceptibility testing. Upon arrival, all isolates were subcultured to the appropriate media to insure culture purity and viability. Species identification confirmation was performed as necessary, and all isolates were stored as stock cultures at 708C or below in tryptic soy broth with 10% glycerol, defibrinated rabbit blood, or for Pseudomonas spp. in sterile distilled water at room temperature. 2.2. Antimicrobial susceptibility tests Susceptibility tests were performed utilizing Clinical Laboratory Standards Institute (CLSI, 2005; formerly National Committee for Clinical Laboratory Standards [NCCLS, 2003]) reference broth microdilution methods. All isolates were tested against a variety of commonly used antimicrobial agents, including 3 fluoroquinolones (gatifloxacin, levofloxacin, and ciprofloxacin). Three to five isolated colonies were taken from a 16- to 24h-old subculture plate and suspended in cation-adjusted Mueller–Hinton broth to a turbidity equal to that of a 0.5 McFarland standard. A 1:200 dilution of the inoculum was made into cation-adjusted Mueller–Hinton broth (with added 3–5% lysed horse blood for testing of Streptococcus spp.), and 100 AL of this dilution was dispensed into wells of commercially prepared validated dry-form panels (TREK Diagnostics, Cleveland, OH) using an autoinoculator. Panels were incubated in an ambient air environment at 358C for 20– 24 h for Gram-positive and fastidious organisms and for 16 –20 h for Gram-negative organisms. Panels were read manually and an end point of no visible growth was used to record the MIC per NCCLS (2003) recommendations. MIC values were interpreted using current CLSI (2005) M100-S15 criteria.

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164 Table 1 Rank order of the 10 most frequently isolated pathogens from the general patient population (59 826 strains) and from children b 7 years of age (4641 strains) in the SENTRY Program (North America, 1998 – 2003) Organism (no. all ages/ b 7 years)

All ages b 7 (rank order (rank order [% isolated]) [% isolated])

S. aureus (17 260/747) 1 E. coli (10 356/513) 2 S. pneumoniae (9248/1382) 3 P. aeruginosa (5517/338) 4 CoNS (4951/749) 5 K. pneumoniae (4251/272) 6 E. faecalis (3514/244) 7 Enterobacter spp. (2838/258) 8 Acinetobacter spp. (1044/84) 9 S. maltophilia (847/54) 10

(28.9) (17.3) (15.5) (9.2) (8.3) (7.1) (5.9) (4.7) (1.7) (1.4)

2 4 1 5 2 6 8 7 9 10

(16.1) (11.1) (29.8) (7.3) (16.1) (5.9) (5.3) (5.6) (1.8) (1.2)

Quality control (QC) tests and inoculum colony counts were routinely performed with Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, H. influenzae ATCC 49247, Escherichia coli ATCC 25922 and 35218, Pseudomonas aeruginosa ATCC 27853, and S. pneumoniae ATCC 49619. All QC results were within published CLSI (2005) ranges.

3. Results 3.1. Occurrences of pathogens The rank order of isolates collected from the 2 patient populations is listed in Table 1. A total of 59 826 isolates (1998 – 2003) were collected, of which 4641 (7.8%) were from children b 7 years of age. The frequency of occurrence among certain organisms differed markedly between the general population (GP, all ages included) and the younger children. In the GP, S. aureus (28.9%) was the most commonly isolated organism and was followed by E. coli (17.3%) and S. pneumoniae (15.5%). In contrast, in children b 7 years old, S. pneumoniae (29.8%) was the most common organism isolated ranking ahead of coagulasenegative staphylococci (CoNS, 16.1%) and S. aureus (16.1%). Gram-positive pathogens clearly predominate in young children (67.3%) compared to the adult patients (58.6%). Among both patient populations, Klebsiella pneumoniae, Acinetobacter spp., and Stenotrophomonas maltophilia remained 6th, 9th, and 10th in rank, respectively. 3.2. Antibiograms of common Gram-positive pathogens The in vitro activity and potency of gatifloxacin tested against the 10 most frequently isolated pathogens isolated from children b7 years old are summarized in Table 2. Among children b7 years old, penicillin-nonsusceptible S. pneumoniae was more prevalent (45.1% of strains) than among the larger patient population (Table 3), and elevated resistance rates of 10.4% and 33.8% were documented in children for clindamycin and erythromycin, respectively. All S. pneumoniae strains from younger children were sus-

159

ceptible to gatifloxacin, whereas 0.7% resistance was observed in the GP. A ciprofloxacin MIC result of z 4 Ag/mL, which indicates the presence of first-step QRDR mutations (Chen et al., 1999), was observed in 1.4% and 3.0% of the S. pneumoniae strains isolated from children b 7 years old and the GP, respectively. Among the staphylococci, 19.0% (S. aureus) to 82.9% (CoNS) oxacillin resistance was observed in younger children compared to 37.0% (S. aureus) to 76.2% (CoNS) in the GP. Generally, fluoroquinolone resistance rates mirror oxacillin resistance rates in staphylococci, but in pediatricaged patients a significant difference between agents was documented (see Tables 2 and 3). Gatifloxacin was at least 2-fold more potent than either ciprofloxacin or levofloxacin against the staphylococci regardless of age; however, the susceptibility rate was N 80.6% for all fluoroquinolones tested in younger patients. This was significantly different than the fluoroquinolone susceptibility rates among the GP where only 47.0– 63.0% of staphylococci were found to be susceptible. Among E. faecalis, there was uniform susceptibility to ampicillin, vancomycin, and linezolid. A small number of vancomycin-resistant E. faecalis (3.5%) were recovered in the GP, whereas no resistance was observed in pediatric patients. Among the fluoroquinolones, significant differences between populations were again documented; susceptibility rates for E. faecalis ranged from 85.2% to 94.7% in children b7 years old compared to only 48.7% to 58.4% susceptibility in the GP. 3.3. Antibiograms of common Gram-negative pathogens Among the Enterobacteriaceae, potency was generally identical between populations for all agents tested with the exception of gatifloxacin, which was 2-to 4-fold more potent in children b7 years old (MIC90, 0.06– 0.12 Ag/mL) when compared to the GP (MIC90, 0.12– 0.5 Ag/mL). Fluoroquinolone resistance rates among the enteric bacilli increased with age, from V 0.6% and V 1.4% in younger children versus z 2.9% and z 4.6% in GP for gatifloxacin and ciprofloxacin, respectively. Phenotypic ESBL rates (z 2 Ag/mL for ceftazidime or ceftriaxone) among E. coli (2.3% in pediatric patients and 2.9% in the GP) and K. pneumoniae (7.4% in pediatric patients and 7.3% in the GP) were comparable between age groups. Fluoroquinolone (gatifloxacin) resistance rates among P. aeruginosa (MIC90, V 2 Ag/mL) and Acinetobacter spp. (MIC90, V 0.5 Ag/mL) were relatively low and ranged from 1.2% to 2.4% in children b7 years old; however, a dramatic increase in fluoroquinolone resistance (19.0– 37.7%) was reported in isolates from the GP (MIC90 values, N2 Ag/mL). An increase in the activity of the h-lactam drugs versus P. aeruginosa and Acinetobacter spp. was also documented among the younger children. Gatifloxacin was 2-fold more potent (100% susceptible; MIC90, 2 Ag/mL) than ciprofloxacin (50.0% susceptible; MIC90, 4 Ag/mL) against S. maltophilia isolated from

160

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164

Table 2 In vitro activity of gatifloxacin tested against isolates from children b7 years of age Organism (rank; no. tested)/ antimicrobial

MIC (Ag/mL)

Interpretive categorya

50%

% Susceptible

90%

S. pneumoniae (1; 1382) Gatifloxacin 0.25 Levofloxacin 1 Penicillin 0.03 Ceftriaxone V 0.25 Erythromycin V 0.25 Clindamycin V 0.25 Tetracycline V4 Trimethoprim– V 0.5 sulfamethoxazole Vancomycin 0.25 CoNS (2; 749) Gatifloxacin Levofloxacin Ciprofloxacin Oxacillin Erythromycin Clindamycin Vancomycin Linezolid S. aureus (3; 747) Gatifloxacin Levofloxacin Ciprofloxacin Oxacillin Erythromycin Clindamycin Vancomycin Linezolid E. faecalis (8; 244) Gatifloxacin Levofloxacin Ciprofloxacin Ampicillin Vancomycin Linezolid Gentamicin (HL)e E. coli (4; 513) Gatifloxacin Ciprofloxacin Ceftazidime Ceftriaxone Cefepime Piperacillin/ tazobactam Imipenem Gentamicin

0.12 0.25 0.25 N2 N8 0.25 2 1

0.06 0.12 0.25 0.5 0.5 0.12 1 2

0.5 1 1 V2 1 2 V 500

0.5 1 2 1 N8 N2 N8 N1 0.5

% Resistant (% ESBL phenotype)

100.0 99.9 54.9 92.8 65.7 89.6 80.0b 54.6

0.0 0.1 26.0 3.6 33.8 10.4 20.0 37.8

100.0

–c

2 N4 N2 N2 N8 N8 2 2

84.4 80.6 83.7 17.1 14.6 52.6 100.0 100.0

12.0 15.4 15.8 82.9 84.8 46.9 0.0 –c

0.25 2 1 N2 N8 0.5 1 4

91.3 89.4 90.4 81.0 61.8 91.0 100.0 100.0

8.4 10.0 8.8 19.0 36.3 8.4 0.0 –c

0.5 2 2 2 2 2 V 500

d

94.7 92.8 85.2 99.6 100.0 96.7 –c

V 0.03 V 0.25 V2 V 0.25 V 0.12 2

0.06 V 0.25 V2 V 0.25 V 0.12 4

98.8 98.6 98.8 99.4 99.8 98.4

V 0.5 V2

V 0.5 V2

100.0 95.5

0.12 V 0.25 V2 V 0.25 0.25

99.3 98.9 94.9 95.6 99.3

4.1 6.6 6.6 0.4 0.0 0.4 –c

d

0.6 1.4 0.6 (2.3) 0.2 (1.0) 0.2 0.6

Table 2 (continued) Organism (rank; no. tested)/ antimicrobial

K. pneumoniae (6; 272) Gatifloxacin 0.06 Ciprofloxacin V 0.25 Ceftazidime V2 Ceftriaxone V 0.25 Cefepime V 0.12

0.4 0.7 4.8 (7.4) 1.5 (7.0) 0.0

Interpretive categorya

50%

% Susceptible

Piperacillin/ tazobactam Imipenem Gentamicin

90%

P. aeruginosa (5; 338) Gatifloxacin Ciprofloxacin Cefepime Piperacillin/ tazobactam Imipenem Amikacin Polymyxin B

8

94.4

2.6

V 0.5 V2

V 0.5 V2

99.6 94.1

0.4 3.3

0.12 V 0.25 N 16 N 32 1 64

99.2 98.4 76.4 79.8 99.2 80.9

0.4 0.8 19.4 10.5 0.4 9.4

100.0 93.4

0.0 5.0

0.5 V 0.25 2 4 1 4 V1

Acinetobacter spp. (9; 84) Gatifloxacin 0.06 Ciprofloxacin V 0.25 Ceftazidime 4 Cefepime 2 Piperacillin/ 2 tazobactam Imipenem V 0.5 Amikacin 2 Polymyxin B V1 S. maltophilia (10; 54) Gatifloxacin 0.5 Ciprofloxacin 1 Ceftazidime 4 Cefepime 16 Imipenem N8 Piperacillin/ N 64 tazobactam Trimethoprim– V 0.5 sulfamethoxazole Polymyxin B 2 a b

d e

% Resistant (% ESBL phenotype)

4

Enterobacter spp. (7; 258) Gatifloxacin V 0.03 Ciprofloxacin V 0.25 Ceftazidime V2 Ceftriaxone V 0.25 Cefepime V 0.12 Piperacillin/ 2 tazobactam Imipenem V 0.5 Gentamicin V2

c

0.0 3.1

MIC (Ag/mL)

1 V2

2 0.5 8 64

95.0d 97.9 92.0 93.2

1.2d 1.5 1.2 6.8

2 8 2

95.6 99.4 97.6

0.9 0.6 2.4

97.6d 97.6 86.9 92.9 85.5

1.2d 2.4 3.6 2.4 4.8

0.12 0.5 16 8 32 V 0.5 8 2

2 N2 N 16 N 16 N8 N 64 V 0.5 N8

98.8 97.6 100.0

1.2 1.2 0.0

100.0d 50.0 53.7 35.2 1.9 18.5

0.0d 29.6 38.9 37.0 98.1 55.6

100.0

0.0

51.7

48.3

Breakpoints those of CLSI (2005). Includes susceptible and intermediate values. No CLSI breakpoints established. Breakpoint applies to urinary tract isolates only. HL = high-level resistance.

children b 7 years of age. Although no trimethoprim– sulfamethoxazole resistant S. maltophilia isolates were observed in the younger population, 2.2% resistance was noted in isolates from the GP.

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164 Table 3 In vitro activity of gatifloxacin tested against isolates from the GP for all ages Organism (rank; no. tested)/ antimicrobial

S. aureus (1; 17 260) Gatifloxacin Levofloxacin Ciprofloxacin Oxacillin Erythromycin Clindamycin Vancomycin Linezolid S. pneumoniae (3; 9248) Gatifloxacin Levofloxacin Penicillin Ceftriaxone Erythromycin Clindamycin Tetracycline Trimethoprim– sulfamethoxazole Vancomycin CoNS (5; 4951) Gatifloxacin Levofloxacin Ciprofloxacin Oxacillin Erythromycin Clindamycin Vancomycin Linezolid E. faecalis (7; 3514) Gatifloxacin Levofloxacin Ciprofloxacin Ampicillin Vancomycin Linezolid Gentamicin (HL)e E. coli (2; 10 356) Gatifloxacin Ciprofloxacin Ceftazidime Ceftriaxone Cefepime Piperacillin/tazobactam Imipenem Gentamicin K. pneumoniae (6; 4251) Gatifloxacin Ciprofloxacin Ceftazidime Ceftriaxone Cefepime Piperacillin/tazobactam

MIC (Ag/mL)

Interpretive categorya

50%

% Susceptible

90%

0.12 0.25 0.5 0.5 4 N8 1 2

N4 N4 N2 N2 N8 N8 1 4

0.25 1 V 0.03 V 0.25 V 0.25 V 0.25 V4 V 0.5

0.5 1 2 1 8 V 0.25 N8 N1

0.5

0.5

0.25 2 1 N2 N8 0.12 2 1

0.5 2 2 V2 1 2 V 500

4 N4 N2 N2 N8 N8 2 2

N4 N4 N2 2 2 2 N 1000

63.0 59.4 61.7 63.0 48.5 69.4 100.0 100.0

99.2 99.2 69.9 96.5 76.6 92.7 85.9c 70.0 100.0

51.1 47.0 50.4 23.8 28.6 60.0 99.9 100.0

58.4d 55.0 48.7 99.2 96.1 98.5 –b

% Resistant (%ESBL phenotype) 36.3 39.8 37.2 37.0 50.0 30.4 0.0 –b

0.7 0.7 15.2 1.5 22.5 7.0 14.1 23.7 –b

40.9 46.3 48.0 76.2 70.8 39.5 0.0 –b

40.6d 44.5 43.2 0.8 3.5 0.1 –b

Table 3 (continued) MIC (Ag/mL)

Interpretive categorya

50%

90%

% Susceptible

V 0.5 V2

V 0.5 V2

99.9 94.3

0.1 4.3

Enterobacter spp. (8; 2838) Gatifloxacin V 0.03 Ciprofloxacin V 0.25 Ceftazidime V2 Ceftriaxone V 0.25 Cefepime V 0.12 Piperacillin/tazobactam 2 Imipenem V 0.5 Gentamicin V2

0.5 0.5 N 16 32 2 64 1 V2

95.5 93.6 79.1 82.3 99.0 83.5 99.9 93.7

2.9 4.6 17.5 9.3 0.4 6.7 0.1 5.0

P. aeruginosa (4; 5517) Gatifloxacin 1 Ciprofloxacin V 0.25 Cefepime 4 Piperacillin/tazobactam 8 Imipenem 1 Amikacin 4 Polymyxin B V1

N4 N2 16 N 64 8 8 2

69.1d 75.2 85.2 89.1 86.9 96.2 98.4

21.6d 19.0 5.5 10.9 7.6 2.0 1.6

Acinetobacter spp. (9; 1044) Gatifloxacin 0.12 Ciprofloxacin V 0.25 Ceftazidime 8 Cefepime 4 Piperacillin/tazobactam 8 Imipenem V 0.5 Amikacin 4 Polymyxin B V1

N4 N2 N 16 N 16 N 64 4 N 32 2

64.8d 60.8 62.2 63.1 63.2 92.4 85.2 97.4

28.7d 37.7 28.0 22.5 20.3 4.7 9.7 2.6

4 N2 N 16 N 16 N 64 N8 V 0.5

83.7d 27.2 55.6 30.5 17.1 0.9 97.8

6.7d 43.0 32.9 37.3 53.4 98.0 2.2

8

63.4

36.6

Organism (rank; no. tested)/ antimicrobial

Imipenem Gentamicin

S. maltophilia (10; 847) Gatifloxacin 1 Ciprofloxacin 2 Ceftazidime 8 Cefepime 16 Piperacillin/tazobactam N 64 Imipenem N8 Trimethoprim– V 0.5 sulfamethoxazole Polymyxin B 2 a

V 0.03 V 0.25 V2 V 0.25 V 0.12 2 V 0.5 V2

0.06 V 0.25 V2 V 0.25 V 0.12 2

0.12 V 0.25 V2 V 0.25 V 0.12 4 V 0.5 V2

0.5 0.5 V2 V 0.25 0.25 8

93.5 93.1 98.5 98.9 99.7 97.2 100.0 96.0

95.5 93.9 94.3 96.1 99.3 95.3

5.2 6.7 1.0 (2.9) 0.4 (1.8) 0.2 1.1 0.0 3.3

2.9 4.7 5.2 (7.3) 1.2 (6.4) 0.4 2.6

161

b c d e

% Resistant (%ESBL phenotype)

Breakpoints those of CLSI (2005). No CLSI breakpoints established. Includes susceptible and intermediate values. Breakpoint applies to urinary tract isolates only. HL = high-level resistance.

3.4. Summary of age differences on susceptibility to gatifloxacin Table 4 lists the 10 most frequently isolated pathogens indexed by patients age, b 7 years (0– 6 years) and all ages (GP). At the published gatifloxacin breakpoints (CLSI, 2005), dramatic differences were not apparent in the wildtype MIC population distributions between age groups. When the V 2 Ag/mL breakpoint was applied for Enterobacteriaceae, nonfermentative Gram-negative bacilli and

162

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164

Table 4 Antimicrobial activity of gatifloxacin tested against all organisms submitted as part of the SENTRY Program (North America; 1998–2003) compared with those for younger pediatric patients ( b 7 years old) Organism (no. tested)

Cumulative % at MIC (Ag/mL) V 0.03

0.06

0.12

0.25

0.5

1

2

4

N4

S. pneumoniae 0 – 6 years (1382) All ages (9248)

0.2 0.3

0.9 0.8

9.4 8.1

89.2 84.9

99.8 98.9

100.0 99.2

– 99.3

– 99.8

– 100.0

S. aureus 0 – 6 years (747) All ages (17 260)

9.5 6.9

60.9 42.5

88.6 61.1

90.8 62.6

91.3 63.0

91.6 63.7

94.1 72.0

98.3 86.5

100.0 100.0

CoNS 0 – 6 years (749) All ages (4951)

0.5 0.5

24.2 16.8

79.2 45.8

83.3 50.4

84.4 51.1

88.0 59.1

97.2 85.4

99.1 91.9

100.0 100.0

E. faecalis 0 – 6 years (244) All ages (3514)

0 0

0 0.1

0.8 1.2

32.4 19.5

91.8 53.6

93.9 57.5

94.7 58.4

95.9 59.4

100.0 100.0

E. coli 0 – 6 years (513) All ages (10 356)

89.9 83.8

95.3 89.1

96.3 90.4

97.9 92.0

98.4 92.9

98.4 93.2

98.8 93.5

99.4 94.8

100.0 100.0

K. pneumoniae 0 – 6 years (272) All ages (4251)

32.7 32.3

80.5 74.2

90.4 82.1

95.6 86.4

97.8 90.3

98.9 93.9

99.3 95.5

99.6 97.1

100.0 100.0

Enterobacter spp. 0 – 6 years (258) All ages (2838)

66.7 54.0

88.4 77.0

91.9 82.1

96.1 87.6

98.1 90.5

98.4 93.3

99.2 95.5

99.6 97.1

100.0 100.0

Acinetobacter spp. 0 – 6 years (84) All ages (1044)

40.5 22.6

83.3 47.7

94.0 56.7

96.4 59.6

96.4 61.0

97.6 63.1

97.6 64.8

98.8 71.3

100.0 100.0

P. aeruginosa 0 – 6 years (338) All ages (5517)

0 0.3

0 0.8

1.2 2.1

16.6 9.8

63.6 39.2

85.2 56.8

95.0 69.1

98.8 78.4

100.0 100.0

S. maltophilia 0 – 6 years (54) All ages (847)

1.9 0.4

1.9 0.8

18.5 6.3

35.2 19.4

57.4 40.9

83.3 65.6

100.0 83.7

– 93.3

– 100.0

enterococci, the isolates from the pediatric population were clearly more susceptible ranging from a low of 94.7% (E. faecalis) to 100.0% (S. maltophilia) compared to rates of 58.4 – 95.5% for GP isolates. Dramatic differences in susceptibility rates for gatifloxacin were also noted for the staphylococci using the recently modified breakpoint of V 0.5 Ag/mL (susceptible) at 84.4– 91.3% susceptible for children b 7 years and 51.1–63.0% susceptible for the GP. Lastly, the differences were more subtle for S. pneumoniae, but the remarkable lack of gatifloxacin resistance in younger children is in stark contrast to emerging resistances in drugexposed adult populations. 4. Discussion The US-FDA has approved various fluoroquinolones for use in the adult population for therapy of respiratory tract,

urinary tract (cystitis and pyelonephritis), and skin infections. Gatifloxacin, a newer so-called brespiratory fluoroquinoloneQ, is a broad-spectrum antimicrobial and has good pharmacokinetic features with rapid absorption, good bioavailability, excellent tissue and intracellular penetration, suitability for oral and parenteral dosing, an acceptable safety profile, and has been proven to be metabolically stable (Capparelli et al., 2005; Domagala, 1994; Grasela, 2000). Several studies have reported that between 65% and 88% of the administered drug is excreted unchanged in urine (Boy et al., 2004; Capparelli et al., 2005; Nakashima et al., 1995). Gatifloxacin demonstrated potency and activity (N 84.0% susceptibility rates) among all pathogens isolated from children b7 years of age. Gatifloxacin was routinely 2- to z 4-fold more active than ciprofloxacin and levofloxacin against the Gram-positive species and S. maltophilia, and

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164

possessed comparable potency and activity to ciprofloxacin versus the Enterobacteriaceae, Acinetobacter spp., and P. aeruginosa. Also, our findings confirm previous publications which demonstrated that gatifloxacin (MIC50 and MIC90, 1 and 4 Ag/mL, respectively) had superior potency compared to other fluoroquinolones against S. maltophilia isolates. Against P. aeruginosa, however, gatifloxacin (MIC50, 2 Ag/mL) was 2- to 4-fold less active than ciprofloxacin (MIC50, 0.5 Ag/mL) (Fung-Tomc et al., 2000). Patient age has a pronounced influence on the activity and potency of fluoroquinolones against certain groups of pathogenic organisms. The greatest difference in susceptibility rates of gatifloxacin between children and the larger patient population was detected among enterococci and some nonfermentative Gram-negative bacilli. However, these pathogens represent only 15–16% of all isolates recovered from children. Overall, gatifloxacin had markedly superior activity as indicated by differences in the GP resistance rates (increases) against the listed Enterobacteriaceae (+2.5 to 4.6%; Tables 2 and 3), the nonfermenting Gram-negative bacilli (+6.7 to 27.5%), E. faecalis (+36.5%), S. aureus (+11.8%), and S. pneumoniae (+0.7%). These latter results demonstrate that S. pneumoniae resistance rates to penicillin, other h-lactam agents, macrolides, and trimethoprim–sulfamethoxazole were significantly increased in the younger children; however, fluoroquinolone-resistant S. pneumoniae was not as prevalent in this young patient population compared to noted increases in prevalence with age (Jones et al., 2003). Gatifloxacin (MIC90, 0.5 Ag/mL) is known to be one of the most potent agents tested against the S. pneumoniae, and N99.0% of isolates studied here were susceptible to gatifloxacin, regardless of age. A previous study conducted in the United States from 1994 to 2000 also demonstrated that N 99% of S. pneumoniae isolates were susceptible to gatifloxacin and levofloxacin (Brueggemann et al., 2002). Currently, fluoroquinolone-resistant S. pneumoniae remains rare, with only 0.7% of the studied strains demonstrating resistance to gatifloxacin or levofloxacin in the overall population; however, no resistance to gatifloxacin was identified in children b 7 years of age. The limited use of fluoroquinolones in children appears to be a major factor influencing the low resistance rates observed in this patient population. However, as new indications for the use of fluoroquinolones in pediatric patients emerge, selective pressure may be placed on this class of drug as has occurred with adult patients having respiratory tract infections and resistance will likely increase. Bhavnani et al. (2005) demonstrated not only an increase in levofloxacin MIC values for S. pneumoniae, but also a correlation between increasing levofloxacin use and increasing bwild-typeQ MIC values, commonly called a bMIC creepQ. In conclusion, gatifloxacin remains highly active against bacterial strains isolated from children who, as a population, are largely naive to fluoroquinolone therapy. Gatifloxacin

163

remains very active against S. pneumoniae and other pathogens (H. influenzae, M. catarrhalis; data not shown) isolated from children with acute otitis media and may be expected to adequately cover such isolates initially, should pediatric indications be forthcoming. Continued surveillance will be necessary however to monitor the activity of the fluoroquinolones as they are introduced into the pediatric age groups for a variety of medical indications, and as a component of a comprehensive risk management plan, given the recognized potential for rapid emergence of resistance with this class. Acknowledgments At the time this study was conducted, the SENTRY Antimicrobial Surveillance Program was supported by an educational/research grant from Bristol-Meyers Squibb. We thank M.G. Stilwell and D.J. Biedenbach for their technical support and N. O’Mara-Morrissey in the preparation of the manuscript.

References Bhavnani SM, Hammel JP, Jones RN, Ambrose PG (2005) Relationship between increased levofloxacin use and decreased susceptibility of Streptococcus pneumoniae in the United States. Diagn Microbiol Infect Dis 51:31 – 37. Boswell FJ, Andrews JM, Jevons G, Wise R (2002) Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance. J Antimicrob Chemother 50:495 – 502. Boy D, Well M, Kinzig-Schippers M, Sorgel F, Ankel-Fuchs D, Naber KG (2004) Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose. Int J Antimicrob Agents 23(Suppl 1):6 – 16. Brueggemann AB, Coffman SL, Rhomberg P, Huynh H, Almer L, Nilius A, Flamm R, Doern GV (2002) Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994–1995. Antimicrob Agents Chemother 46:680 – 688. Burkhardt JE, Walterspiel JN, Schaad UB (1997) Quinolone arthropathy in animal versus children. Clin Infect Dis 25:1196 – 1204. Capparelli EV, Reed MD, Bradley JS, Kearns GL, Jacobs RF, Damle BD, Blumer JL, Grasela DM (2005) Pharmacokinetics of gatifloxacin in infants and children. Antimicrob Agents Chemother 49:1106 – 1112. Chen DJ, McGreer A, de Azavedo JC, Low DE (1999) Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med 341:233 – 239. Clinical and Laboratory Standards Institute (2005) Performance standard for antimicrobial susceptibility testing, 15th informational supplement (Document M100-S15). Wayne, PA7 NCCLS. Domagala JM (1994) Structure–activity and structure–side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother 33: 685 – 706. Echols R, Hamed K, Arguedas A, Dagan R, Sher L, Saez-Llorens X, Pichichero ME (2005) Gatifloxacin therapy for children: turn on the light. Clin Infect Dis 41:1824 – 1825. Ednie LM, Jacobs MR, Appelbaum PC (1998) Activities of gatifloxacin compared to those of seven other agents against anaerobic organisms. Antimicrob Agents Chemother 42:2459 – 2462.

164

K.A. Fedler et al. / Diagnostic Microbiology and Infectious Disease 55 (2006) 157–164

Ferrero L, Cameron B, Manse B, Lagneaux D, Crouzet J, Famechon A, Blanche F (1994) Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol 13:641 – 653. Fung-Tomc J, Minassian B, Koelek B, Washo T, Huczko E, Bonner D (2000) In vitro antibacterial spectrum of a new broad-spectrum 8methoxy fluoroquinolone, gatifloxacin. J Antimicrob Chemother 45:437 – 446. Grady R (2003) Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis 22:1128 – 1132. Grasela DM (2000) Clinical pharmacology of gatifloxacin, a new fluoroquinolone. Clin Infect Dis 31(Suppl 2):S51 – S58. Goldstein EJC, Citron DM, Merriam CV, Tyrell K, Warren Y (1999) Activity of gatifloxacin compared to those of five other quinolones versus aerobic and anaerobic isolates from skin and soft tissue samples of human and animal bite wound infections. Antimicrob Agents Chemother 43:1475 – 1479. Janoir C, Zeller V, Kitzis M, Moreau NJ, Gutmann L (1996) High-level fluoroquinolone resistance in Streptococcus pneumoniae requires mutations in parC and gyrA . Antimicrob Agents Chemother 40:2760 – 2764. Jones RN, Pfaller MA (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. Jones RN, Biedenbach DJ, Beach ML (2003) Influence of patient age on the susceptibility patterns of Streptococcus pneumoniae isolates in North America (200–2001): report from the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis 46:77 – 80. Klugman KP (2003) The role of clonality in the global spread of fluoroquinolones-resistant bacteria. Clin Infect Dis 36:783 – 785. Mandell LA, Peterson LR, Wise R, Hooper D, Low DE, Schaad UB, Klugman KP, Courvalin P (2002) The battle against emerging antibiotic resistance: should fluoroquinolones be used to treat children? Clin Infect Dis 35:721 – 727. Nakashima M, Uematsu T, Kosuge K, Kusajima H, Ooie T, Masuda Y, Ishida R, Uchida H (1995) Single- and multiple-dose pharmacokinetics

of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans. Antimicrob Agents Chemother 39:2635 – 2640. National Committee for Clinical Laboratory Standards (2003) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard M7-A6. Wayne, PA7 NCCLS. Pichichero ME, Arguedas A, Dagan R, Sher L, Saez-Llorens X, Hamed K, Echols R (2005) Safety and efficacy of gatifloxacin therapy for children with recurrent acute otitis media (AOM) and/or AOM treatment failure. Clin Infect Dis 41:470 – 478. Schaad UB (1999) Pediatric use of quinolones. Pediatr Infect Dis J 18:469 – 470. Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P (1996) Pregnancy outcome after prenatal quinolone exposure evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Biol 69:83 – 89. Stahlmann R, Kuhner S, Shakibaei M, Schwabe R, Flores J, Evander SA, van Sickle DC (2000) Chondrotoxicity of ciprofloxacin in immature beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations. Arch Toxicol 73:564 – 572. Takizawa T, Hashimoto K, Minami T, Yamashita S, Owen K (1999) The comparative arthropathy of fluoroquinolones in dogs. Hum Exp Toxicol 18:392 – 399. Tarshis GA, Miskin BM, Jones TN, Champlin J, Wingert KJ, Breen JD, Brown MJ (2001) Once-daily oral gatifloxacin versus oral levofloxacin in treatment of uncomplicated skin and soft tissue infections: double blind, multicenter, randomized study. Antimicrob Agents Chemother 45:2358 – 2362. Wogelius P, Norgaard M, Gislum M, Pedersen L, Schonheyder HC, Sorensen HT (2005) Further analysis of the risk of adverse birth outcome after maternal use of fluoroquinolones. Int J Antimicrob Agents 26:323 – 326. Zhao X, Xu C, Domagala J, Drlica K (1997) DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance. Proc Natl Acad Sci U S A 94:13991 – 13996. Zhao X, Wang JY, Xu C, Dong Y, Zhou J, Drlica K (1998) Killing of Staphylococcus aureus by C-8-methoxy fluoroquinolones. Antimicrob Agents Chemother 42:956 – 958.