Antimicrobial activity against Streptococcus pneumoniae and Haemophilus influenzae collected globally between 2004 and 2008 as part of the Tigecycline Evaluation and Surveillance Trial

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Diagnostic Microbiology and Infectious Disease 67 (2010) 78 – 86 www.elsevier.com/locate/diagmicrobio

Antimicrobial activity against Streptococcus pneumoniae and Haemophilus influenzae collected globally between 2004 and 2008 as part of the Tigecycline Evaluation and Surveillance Trial☆ Ali Darabia , Didier Hocquetb,⁎, Michael J. Dowzickyc a

WPAHS, Core Lab., Pittsburgh, PA 15212, USA b University Hospital, 25030 Besançon, France c Pfizer Inc., Collegeville, PA 19424, USA Received 16 June 2009; accepted 6 December 2009

Abstract We report here on the in vitro activity of tigecycline and comparators against a global collection of Streptococcus pneumoniae and Haemophilus influenzae collected between 2004 and 2008 as part of the Tigecycline Evaluation and Surveillance Trial. A total of 6785 S. pneumoniae and 6642 H. influenzae isolates were collected, most from North America. The percentages of penicillin-intermediate resistance and penicillin resistance among S. pneumoniae in North America were 27.8% and 14.3%, respectively. Penicillin resistance ranged from 9.3% in Europe to 25.1% in the Asia-Pacific Rim. The rate of β-lactamase–producing H. influenzae was 25.8% in North America, and among the other regions, it ranged from 8.7% in South Africa to 26.8% in the Asia-Pacific Rim. Tigecycline MIC90's were 0.03 to 0.12 mg/L and 0.5 to 2 mg/L, depending on the region considered, against S. pneumoniae and H. influenzae, respectively. Tigecycline had low MIC90's against S. pneumoniae and H. influenzae, irrespective of resistance to β-lactams. © 2010 Elsevier Inc. All rights reserved. Keywords: Streptococcus pneumoniae; Haemophilus influenzae; Tigecycline; Antimicrobial surveillance; Resistance

1. Introduction Streptococcus pneumoniae and Haemophilus influenzae are common causes of respiratory tract infections, including community-acquired pneumonia (CAP) and exacerbation of chronic obstructive pulmonary disease (COPD), and both pathogens are associated with some antimicrobial resistance. Resistance of S. pneumoniae to penicillins and other β-lactams arises from alteration of penicillin-binding proteins (PBPs), which are responsible for maintenance of the bacterial cell wall, via acquisition of PBP fragments from other streptococci. The degree of resistance depends on ☆ TEST is funded by Wyeth Pharmaceuticals. Writing and data management services were also funded by Wyeth Pharmaceuticals. ⁎ Corresponding author. Laboratoire de Bactériologie, Hôpital Jean Minjoz, University of Franche-Comté, 25030 Besançon Cedex, France. Tel.: +33-3-81668286; fax: +33-3-81668914. E-mail address: [email protected] (D. Hocquet).

0732-8893/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2009.12.009

which PBPs are involved and the affinity of the β-lactams to the PBP. Penicillin-intermediate and penicillin-resistant isolates of S. pneumoniae are commonly reported, with penicillin resistance shown to be associated with resistance to other antimicrobial agents (Wimmerstedt and Kahlmeter, 2008). In H. influenzae, β-lactam resistance is primarily mediated by β-lactamase production. However, ampicillin resistance can also occur secondary to membrane permeability modification in β-lactamase–negative ampicillinresistant (BLNAR) isolates. Rare isolates possess both β-lactamases and altered PBPs, resulting in β-lactamase– positive amoxicillin–clavulanic acid-resistant (BLPACR) H. influenzae (Tristram et al., 2007). Hospitalized patients with CAP represent a health care burden and a challenge for appropriate antimicrobial management (Rello, 2008). Currently, antimicrobial treatment guidelines in the United States for CAP recommend empiric therapy based on a respiratory fluoroquinolone or a β-lactam plus a macrolide for non-intensive care unit

A. Darabi et al. / Diagnostic Microbiology and Infectious Disease 67 (2010) 78–86

(ICU) patients or a β-lactam (cefotaxime, ceftriaxone, or ampicillin–sulbactam) plus either azithromycin or a respiratory fluoroquinolone for ICU patients (Mandell et al., 2007). Emerging resistance among the common respiratory pathogens to these classes of antimicrobial agents, however, has led to the need for new therapeutic agents such as tigecycline, which are stable to the common resistance mechanisms. Tigecycline, a glycylcycline, is approved for the treatment of complicated skin and skin structure as well as complicated intra-abdominal infections in patients 18 years and older (Wyeth Pharmaceuticals, 2009). Tigecycline phase III trials for the treatment of CAP (Bergallo et al., 2009; Tanaseanu et al., 2008) have been completed, and it has recently been approved by the Food and Drug Administration (FDA) for the treatment of community-acquired bacterial pneumonia (CABP) caused by penicillin-susceptible S. pneumoniae and β-lactamase–negative H. influenzae (Wyeth Pharmaceuticals, 2009). Tigecycline has been shown in a number of in vitro studies to be active against a broad spectrum of Gram-negative and Gram-positive organisms, including S. pneumoniae and H. influenzae (McKeage and Keating 2008). The Tigecycline Evaluation and Surveillance Trial (TEST) began in 2004 to chart the activity of tigecycline and comparators against bacterial isolates collected globally. The aim of this article is to report the in vitro activity of tigecycline and comparator agents against S. pneumoniae and H. influenzae collected, as part of the TEST program, from North America, Europe, the AsiaPacific Rim, Latin America, South Africa, and the Middle East between 2004 and 2008. 2. Materials and methods 2.1. Isolate collection Isolates of S. pneumoniae and H. influenzae were submitted to the TEST surveillance study between 2004 and 2008 (2008 data not complete) from 428 teaching hospitals globally. Regions contributing to the study were North America (212 centers), Europe (117 centers), AsiaPacific Rim (44 centers), Latin America (36 centers), South Africa (11 centers), and the Middle East (8 centers). Isolates were collected consecutively from patients with a documented infection where the isolate was identified as the probable causative organism; causality was determined using center-defined criteria. One isolate per patient was accepted with inclusion independent of medical history, antimicrobial use, age, and sex. Isolate identification was carried using local methodologies. Collection sources included blood, respiratory tract, urine (limited to not more than 25% of isolates from any center), skin, wound, and fluids other than blood. All isolates collected form cardiovascular sources were blood derived. S. pneumoniae isolates were collected from 61 identified body sites, the most common being sputum (30.3% of all isolates), cardiovascular blood (29.6%), bronchial (7.0%),

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trachea (4.8%), ears (4.5%), eyes (4.0%), nose (3.4%), sinuses (3.4%), throat (1.9%), cerebrospinal fluid (1.8%), respiratory (other) (1.3%), and respiratory (undefined) (1.2%); all other isolate sources provided b1% of all isolates. The most common body sites for H. influenzae were as follows: sputum (46.3%), bronchials (10.2%), trachea (7.3%), eyes (6.9%), cardiovascular blood (4.7%), nose (4.0%), sinuses (3.8), ears (3.4%), throat (3.1%), other respiratory sites (2.3%), and undefined respiratory sites (1.6%); in total, H. influenzae isolates were collected from 64 body sites. Banked, stored, or duplicate isolates were not acceptable, and centers were requested to submit 15 S. pneumoniae and 15 H. influenzae isolates per year. The reference laboratory (International Health Management Associates [IHMA], Schaumburg, IL) coordinated organism collection, identity confirmation, and transport, as well as the development and management of a centralized database. Quality control testing was performed on each day of testing at each center using S. pneumoniae ATCC 49619, H. influenzae ATCC 49247, and H. influenzae ATCC 49766 when appropriate. MICs and isolate identification quality control checks were carried out by the central laboratory on approximately 10% to 15% of strains (Clinical and Laboratory Standards Institute [CLSI], 2006). 2.2. Antimicrobial susceptibility testing MICs for a panel of antimicrobial agents were determined at each center using the broth microdilution methodology of the CLSI (2008), using either MicroScan® panels (Dade Behring, West Sacramento, CA) or Sensititre® plates (TREK Diagnostic Systems, West Sussex, England). The panel of antimicrobials included the following (with their dilution ranges, in mg/L): amikacin (0.5–64), amoxicillin– clavulanic acid (0.12/0.06–32/16), ampicillin (0.5–32 [Gram negative], 0.06–16 [Gram-positive]), cefepime (0.5–32), ceftriaxone (0.06–64), imipenem (0.06–16), meropenem (0.06–16), linezolid (0.5–8), levofloxacin 0.008–8), minocycline (0.5–16), tigecycline (0.008–16), penicillin (0.06–8), piperacillin–tazobactam (0.06/4–128/4), and vancomycin (0.12–32). Susceptibility was determined according to CLSI breakpoints (CLSI, 2008), with the exception of tigecycline, for which CLSI breakpoints are not yet available. The FDA has recently assigned tigecycline susceptibility breakpoints for S. pneumoniae (≤0.06 mg/L) and H. influenzae (≤0.25 mg/L) (Wyeth Pharmaceuticals, 2009). Imipenem was removed from the TEST study and replaced with meropenem in 2006 because of imipenem stability issues. 2.3. Antimicrobial resistance determinations Penicillin-intermediate resistance in S. pneumoniae was defined as an MIC for penicillin of between 0.12 and 1 mg/L. Penicillin-resistant S. pneumoniae (PRSP) was defined as isolates with an MIC of ≥2 mg/L. β-lactamase production among isolates of H. influenzae was determined at each

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center using local methodology. Confirmatory tests were performed by the central laboratory only when data were missing or were questionable (i.e., if the ampicillin result did not match the β-lactamase result) or if the isolate failed the quality control checks for any reason.

Table 2 Rates of penicillin-intermediate and PRSP and β-lactamase–producing H. influenzae, by region and globally, collected as part of the TEST between 2004 and 2008 Geographic region

3. Results Of a total of 6785 isolates of S. pneumoniae and 6642 H. influenzae, more than half were collected from North America (57.1% and 52.7%, respectively) and from male patients (58.0% and 57.2%, respectively). More than 40% of each S. pneumoniae and H. influenzae were collected from patients aged 18 to 64 years (44.6% and 42.7%, respectively), with the other isolates equally split between patients aged ≤17 years and those aged ≥65 years old. Respiratory sources were the most common culture sources for both S. pneumoniae and H. influenzae (48.7% and 73.0%, respectively), although a high number of S. pneumoniae isolates (29.8%) were also collected from the cardiovascular system (mainly blood) (Table 1). 3.1. S. pneumoniae Globally, the ratio of penicillin-intermediate to penicillinresistant strains among S. pneumoniae was 2:1 (25.3% and 13.8% respectively), reflecting the relative distribution Table 1 Geographic distribution and demographic parameters of S. pneumoniae and H. influenzae isolates collected as part of the TEST between 2004 and 2008 S. pneumoniae

Geographic region North America Europe Asia-Pacific Rim Latin America South Africa Middle East Sexa Male Female Age (years)a 0–17 18–64 ≥65 Culture sourcea Bodily fluids Cardiovascular system HEENT Respiratory Otherb

H. influenzae

n

%

n

%

3871/6785 1725/6785 522/6785 464/6785 135/6785 68/6785

57.1 25.4 7.7 6.8 2.0 1.0

3499/6642 1874/6642 559/6642 447/6642 138/6642 125/6642

52.7 28.2 8.4 6.7 2.1 1.9

3894/6716 2822/6716

58.0 42.0

3760/6569 2809/6569

57.2 42.8

1769/6714 2996/6714 1949/6714

26.3 44.6 29.0

1886/6567 2802/6567 1879/6567

28.7 42.7 28.6

321/6760 2014/6760 971/6760 3295/6760 159/6760

4.7 29.8 14.4 48.7 2.4

129/6601 320/6601 1200/6601 4817/6601 135/6601

2.0 4.8 18.2 73.0 2.0

Percentages are rounded to 1 decimal place and may therefore not add up to 100 in each category. HEENT = head, ears, eyes, nose, mouth, throat. a Sex, age, and culture source information was not available for all isolates; therefore, n values vary between parameters. b Other includes sources representing b1.5% of isolates collected.

North America Europe Asia-Pacific Rim Latin America South Africa Middle East Global

Penicillinintermediate S. pneumoniae

Penicillinresistant S. pneumoniae

β-lactamase producing H. influenzae

n

%

n

%

n

%

1077/3871 321/1725 116/522 130/464 58/135 16/68 1718/6785

27.8 18.6 22.2 28.0 43.0 23.5 25.3

555/3872 160/1725 131/522 46/464 31/135 14/68 937/6786

14.3 9.3 25.1 9.9 23.0 20.6 13.8

904/3499 269/1874 150/559 94/447 12/138 24/125 1453/6642

25.8 14.3 26.8 21.0 8.7 19.2 21.9

of these phenotypes in North America, Europe, and South Africa. In Latin America, the ratio was 3:1, and in the Asia-Pacific Rim and Middle East, the proportions were similar (Table 2). Among the S. pneumoniae isolates overall, susceptibility to amoxicillin–clavulanic acid varied from 88.1% for South Africa to 98.0% for Europe. In North America, 92.1% of S. pneumoniae isolates collected were susceptible to amoxicillin–clavulanic acid. Similar or higher rates of susceptibility were recorded for ceftriaxone. Susceptibility rates to amoxicillin–clavulanic acid and to ceftriaxone were lower among the subset of penicillin-resistant isolates than overall, although the difference was markedly greater for amoxicillin–clavulanic acid than ceftriaxone (Table 3). Levofloxacin remained largely active (N97% susceptibility) against isolates of S. pneumoniae, including penicillin-resistant isolates (susceptibility N92%). The area with the lowest reported levofloxacin susceptibility among penicillin-resistant isolates was the Middle East (92.9%), although this is based on only 14 isolates. The only region where 100% of S. pneumoniae isolates collected were susceptible to levofloxacin was South Africa. In North America, 99.2% of S. pneumoniae were susceptible to levofloxacin (Table 3). All isolates of S. pneumoniae were susceptible to linezolid and vancomycin (Table 3). S. pneumoniae susceptibility to tigecycline ranged from 87.5% (MIC90 0.12 mg/L) in Latin America to 97.1% (MIC90, 0.3 mg/L) in the Middle East. Susceptibility was unaffected by penicillin resistance mechanisms with susceptibility of PRSP similar to that of all S. pneumoniae isolates, ranging from 86.3% (Europe) (MIC90, 0.12 mg/L) to 100% (Middle East) (MIC90, 0.3 mg/L) (Table 3). No CLSI breakpoint values are yet available to determine susceptibility to tigecycline; however, the lowest MIC90 values (≤0.12 mg/L) for S. pneumoniae were associated with this compound. MIC90 values of b1 mg/L were also obtained for imipenem and vancomycin, irrespective of penicillin susceptibility. Small variations in MIC90 values (1 or 2 doubling dilutions) were recorded among the regions for all the antimicrobial agents tested (Table 3).

Table 3 Regional antimicrobial susceptibility (MIC90 [mg/L] and % susceptibility [%S]) among S. pneumoniae isolates collected as part of the TEST between 2004 and 2008 North America MIC90

Europe %S

MIC90

Asia-Pacific Rim %S

MIC90

Latin America %S

MIC90

South Africa %S

MIC90

Middle East %S

MIC90

%S

n = 3871 (2200/1671)a 2 92.1 4 1 97.3 0.5 70.8 1 99.2 1 100 1 80.1 4 87.2 2 57.8 2 0.06 90.4 0.5 100

n = 1725 (886/839)a 1 98.0 2 0.5 98.2 0.25 84.5 1 99.5 1 100 0.5 84.0 4 84.9 1 72.1 1 0.12 88.3 0.5 100

n = 522 (169/353)a 2 92.1 4 1 93.5 0.5 75.1 1 97.9 1 100 1 65.7 8 62.8 2 52.7 4 0.06 92.0 0.5 100

n = 464 (184/280)a 1 97.4 2 0.5 97.2 0.25 84.2 1 99.4 1 100 0.5 81.1 4 85.8 1 62.1 2 0.12 87.5 0.5 100

n = 135 (52/83)a 4 88.1 4 1 97.0 0.5 50.0 1 100 1 100 1 62.7 4 85.9 2 34.1 4 0.06 95.6 0.5 100

n = 68 (11/570)a 2 95.6 2 1 97.1 0.5 63.6 1 97.1 1 100 1 66.7 2 91.2 2 55.9 2 0.03 97.1 0.5 100

Penicillin-intermediate S. pneumoniae Amoxi–clav Ampicillinb Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin Pip–tazb Tigecycline Vancomycin

n = 1077 (650/427)a

n = 321 (171/150)a

n = 116 (40/76)a

n = 130 (44/86)a

n = 58 (29/29)a

n = 16 (3/13)a

1 2 0.5 0.5 1 1 0.5 8 1 2 0.06 0.5

PRSP Amoxi–clav Ampicillinb Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin Pip–tazb Tigecycline Vancomycin

n = 555 (284/271)a 8 45.6 8 2 82.3 1 1.8 1 98.7 1 100 1 1.8 4 58.0 4 0.0 4 0.06 91.2 0.5 100

99.5 99.3 44.7 98.4 100 84.5 80.1 0.0 90.2 100

1 2 1 0.5 1 1 0.5 8 1 2 0.12 0.5

99.4 97.5 50.3 99.4 100 80.7 64.2 0.0 86.0 100

n = 160 (50/110)a 4 80.0 8 2 85.6 0.5 0.0 1 99.4 1 100 1 4.5 8 61.3 4 0.0 4 0.12 86.3 0.5 100

1 2 0.5 0.5 1 1 0.5 8 1 2 0.06 0.5

99.1 99.1 50.0 100 100 76.3 53.4 0.0 90.5 100

n = 131 (23/108)a 8 69.5 8 2 74.8 1 4.3 1 93.9 1 100 1 4.6 8 39.7 4 0.0 4 0.06 96.2 0.5 100

1 1 0.5 0.25 1 1 0.5 8 1 2 0.12 0.5

100 97.7 72.7 100 100 72.1 78.5 0.0 89.2 100

n = 46 (16/30)a 8 73.9 8 2 78.3 8 0.0 1 97.8 1 100 1 3.3 8 65.2 8 0.0 4 0.12 87.0 0.5 100

1 1 1 0.5 1 1 0.5 8 1 1 0.06 0.5

100 98.3 41.4 100 100 72.4 84.5 0.0 93.1 100

n = 31 (8/23)a 4 48.4 8 1 90.3 N/A N/A 1 100 1 100 1 0.0 8 74.2 4 0.0 4 0.03 96.8 0.5 100

1 2 0.5 N/A 1 1 0.5 0.5 1 2 0.03 0.5

100 93.8 N/A 93.8 100 53.8 93.8 0.0 100 100

n = 14 (1/13)a 4 78.6 4 1 92.9 N/A N/A 1 92.9 1 100 1 0.0 4 78.6 4 0.0 4 0.03 100 0.5 100

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MIC90 = MIC required to inhibit 90% of isolates; %S = percentage of isolates susceptible; amoxi–clav = amoxicillin–clavulanic acid; pip–taz = piperacillin–tazobactam; N/A = data not presented when n b 10. a Not all isolates were tested against the 2 carbapenems. The n values given in parenthesis refer to the number of isolates tested against imipenem and meropenem, respectively. b No breakpoints available.

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S. pneumoniae Amoxi–clav Ampicillinb Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin Pip–tazb Tigecycline Vancomycin

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A. Darabi et al. / Diagnostic Microbiology and Infectious Disease 67 (2010) 78–86

Table 4 Regional antimicrobial susceptibility (MIC90 [mg/L] and % susceptibility [%S]) among H. influenzae isolates collected as part of the TEST between 2004 and 2008 North America MIC50

MIC90

Europe a

Range b

MIC50

Asia-Pacific Rim a

MIC90

Range b

MIC50

H. influenzae Amikacinc Amoxi–clav Ampicillin Cefepime Ceftriaxone Imipenem Levofloxacin Meropenem Minocycline Pip–taz Tigecycline

n = 3499 (2005/1493) 4 8 ≤0.5 to ≥128 0.5 1 ≤0.12 to ≥64 ≤0.5 ≥64 ≤0.5 to ≥64 ≤0.5 ≤0.5 ≤0.5 to ≥64 ≤0.06 ≤0.06 ≤0.06 to 4 0.5 1 ≤0.06 to 4 0.15 0.03 ≤0.008 to 2 ≤0.06 0.25 ≤0.06 to 0.5 ≤0.5 1 ≤0.5 to ≥32 ≤0.06 ≤0.06 ≤0.06 to 4 0.25 0.5 ≤0.008 to 2

n = 1874 (995/879) 4 8 0.5 1 ≤0.5 16 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.25 1 0.015 0.03 ≤0.06 0.12 ≤0.5 1 ≤0.06 ≤0.06 0.25 0.5

≤0.5 to 64 ≤0.12 to 32 ≤0.5 to ≥64 ≤0.5 to 32 ≤0.06 to 32 ≤0.06 to 4 ≤0.008 to 2 ≤0.06 to 0.5 ≤0.5 to ≥32 ≤0.06 to 16 ≤0.008 to 2

n = 559 (225/334) 4 8 0.5 2 ≤0.5 ≥64 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.25 1 0.015 0.03 ≤0.06 0.25 ≤0.5 1 ≤0.06 ≤0.06 0.25 0.5

β-lactamase producing H. influenzae Amikacinc Amoxi–clav Ampicillin Cefepime Ceftriaxone Imipenem Levofloxacin Meropenem Minocycline Pip–taz Tigecyclinec

n = 904 (535/369)b 4 8d 1 2 32 ≥64 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.5 1 0.015 0.03 ≤0.06 0.12 ≤0.5 1 ≤0.06 ≤0.06 0.25 0.5

n = 269 (145/124)b 4 8 1 2 32 ≥64 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.25 1 0.015 0.03 ≤0.06 0.12 ≤0.5 2 ≤0.06 0.12 0.25 0.5

≤0.5 to 64 ≤0.12 to 32 2 to ≥64 ≤0.5 to 8 ≤0.06 to 32 ≤0.06 to 2 ≤0.008 to 1 ≤0.06 to 0.25 ≤0.5 to 16 ≤0.06 to 16 ≤0.008 to 2

n = 150 (54/96)b 4 8 1 4 32 ≥64 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.25 1 0.015 0.03 0.12 0.25 ≤0.5 1 ≤0.06 ≤0.06 0.25 0.5

β-lactamase–negative, ampicillinresistant H. influenzae Amikacinc Amoxi–clav Ampicillin Cefepime Ceftriaxone Imipenem Levofloxacin Meropenem Minocycline Pip–taz Tigecyclinec

n = 34 (13/21)b 8 2 2 ≤0.5 ≤0.06 1 0.015 0.25 1 ≤0.06 0.25

8 4 2 ≤0.5 ≤0.06 1 0.03 0.5 2 0.25 0.5

≤0.5 to 32 ≤0.12 to ≥64 2 to ≥64 ≤0.5 to ≥64 ≤0.06 to 4 ≤0.06 to 4 ≤0.008 to 1 ≤0.06 to 0.5 ≤0.5 to ≥32 ≤0.06 to 2 ≤0.008 to 2

n = 34 (11/23)b 1 to 8 0.25 to 4 2 to 2 ≤0.5 to 1 ≤0.06 to 2 0.25 to 4 ≤0.008 to 0.5 ≤0.06 to 0.5 ≤0.5 to 8 ≤0.06 to 2 0.015 to 2

4 2 2 ≤0.5 ≤0.06 0.25 0.015 0.12 1 ≤0.06 0.25

8 4 2 1 0.12 0.5 0.12 0.5 4 0.25 0.5

Rangea

MIC90 b

≤0.5 to ≥128 ≤0.12 to 16 ≤0.5 to ≥64 ≤0.5 to 4 ≤0.06 to 2 ≤0.06 to 2 ≤0.008 to 2 ≤0.06 to 0.5 ≤0.5 to 8 ≤0.06 to 1 ≤0.008 to 2 ≤0.5 to ≥128 0.25 to 16 2 to ≥64 ≤0.5 to 4 ≤0.06 to 1 ≤0.06 to 2 ≤0.008 to 2 ≤0.06 to 0.5 ≤0.5 to 4 ≤0.06 to 0.5 ≤0.008 to 2

n = 15 (2/13)b, e ≤0.5 to 64 ≤0.12 to 4 2 to 2 ≤0.5 to 2 ≤0.06 to 2 0.12 to 1 ≤0.008 to 0.5 ≤0.06 to 0.5 ≤0.5 to 16 ≤0.06 to 0.5 0.03 to 1

4 0.5 2 ≤0.5 ≤0.06

8 4 2 1 0.12

0.015 ≤0.06 ≤0.5 ≤0.06 0.25

0.03 0.25 1 0.12 1

≤0.5 to 8 0.25 to 4 2 to 2 ≤0.5 to 2 ≤0.06 to 0.25 0.5 to 0.5 ≤0.008 to 0.03 ≤0.06 to 0.25 ≤0.5 to 2 ≤0.06 to 0.25 ≤0.008 to 1

MIC90 = MIC required to inhibit 90% of isolates; %S = percentage of isolates susceptible; amoxi–clav = amoxicillin–clavulanic acid; pip–taz = piperacillin– tazobactam; N/A = data not presented when n b 10; NT = not tested. a MIC range (mg/L). b Not all isolates were tested against the 2 carbapenems. The n values given in parenthesis refer to the number of isolates tested against imipenem and meropenem, respectively. c No breakpoints available. d Nine hundred three isolates tested against amikacin. e MIC50/90 not calculated when n b 10.

3.2. H. influenzae One-quarter of H. influenzae isolates collected from North America and from the Asia-Pacific Rim were identified as βlactamase producers (25.8% and 26.8%, respectively). The lowest percentage of β-lactamase producers was among isolates collected from South Africa (8.7%) (Table 2). By extending the definition of BLNAR to include β-lactamase–negative ampicillin-intermediate isolates (MIC 2 mg/L), a total of 94 (1.4%) BLNAR isolates were

identified globally (Table 4). They were distributed as follows: 34 (36.2%) from North America, 34 (36.2%) from Europe, 15 (16.0%) from the Asia-Pacific Rim, 5 (5.3%) from Latin America, 4 (4.3%) from South Africa, and 2 (2.1%) from the Middle East. Of the 15 BLNAR isolates collected from the Asia-Pacific Rim region, none originated in Japan (Australia, 4; India, 4; Indonesia, 1; Korea, 4; Taiwan, 2). A total of 16 BLPACR isolates were collected: 7 from North America, 6 from Europe, 2 from Asia/Pacific Rim, and 1 from Latin America.

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Latin America

South Africa a

MIC90

Range b

MIC50

83

Middle East MIC90

a

Range

b

MIC50

MIC90

n = 447 (190/257) 4 8 0.5 1 ≤0.5 16 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.5 1 0.015 0.03 ≤0.06 0.12 ≤0.5 1 ≤0.06 ≤0.06 0.25 0.5

≤0.5 to ≥128 ≤0.12 to 8 ≤0.5 to ≥64 ≤0.5 to 8 ≤0.06 to 1 ≤0.06 to 4 ≤0.008 to 2 ≤0.06 to 0.5 ≤0.5 to 16 ≤0.06 to 4 ≤0.008 to 2

n = 138 (47/91) 8 8 0.5 1 ≤0.5 2 ≤0.5 ≤0.5 ≤0.06 ≤0.06 ≤0.06 1 0.015 0.03 0.12 0.25 ≤0.5 1 ≤0.06 ≤0.06 0.12 0.5

≤0.5 to 16 ≤0.12 to 4 ≤0.5 to ≥64 ≤0.5 to 0.5 ≤0.06 to 0.5 ≤0.06 to 2 ≤0.008 to 1 ≤0.06 to 0.5 ≤0.5 to 16 ≤0.06 to 2 0.015 to 2

n = 125 (21/104) 8 16 0.5 2 ≤0.5 ≥64 ≤0.5 ≤0.5 ≤0.06 ≤0.06 1 2 0.015 0.03 ≤0.06 0.25 1 4 ≤0.06 ≤0.06 0.5 2

n = 94 (27/67)b 4 8 1 2 16 ≥64 ≤0.5 ≤0.5 ≤0.06 ≤0.06 0.5 1 0.015 0.03 ≤0.06 0.12 ≤0.5 1 ≤0.06 ≤0.06 0.25 0.5

≤0.5 to 16 ≤0.12 to 8 2 to ≥64 ≤0.5 to 4 ≤0.06 to 0.25 ≤0.06 to 2 ≤0.008 to 0.12 ≤0.06 to 0.25 ≤0.5 to 16 ≤0.06 to 1 ≤0.008 to 2

n = 12 (4/8)b 4 1 32 ≤0.5 ≤0.06 0.5 0.015 0.25 1 ≤0.06 0.12

1 to 16 0.5 to 4 2 to ≥64 ≤0.5 to 0.5 ≤0.06 to 0.06 ≤0.06 to 1 ≤0.008 to 0.25 ≤0.06 to 0.5 ≤0.5 to 2 ≤0.06 to 1 0.12 to 0.5

n = 24 (0/24)b 4 1 ≥64 ≤0.5 ≤0.06 N/A 0.015 ≤0.06 1 ≤0.06 0.5

n = 5 (1/4)b, e

8 4 ≥64 ≤0.5 ≤0.06 N/A 0.015 N/A 1 ≤0.06 0.25

n = 4 (2/2)b, e 4–8 ≤0.12 to 2 2 to 2 ≤0.5 to 2 ≤0.06 to 0.5 ≤0.06 to 0.06 ≤0.008 to 0.03 ≤0.06 to 0.06 ≤0.5 to 1 ≤0.06 to 0.06 0.06 to 0.5

Overall, N99% of H. influenzae isolates in each region were susceptible to amoxicillin–clavulanic acid and piperacillin–tazobactam. Susceptibility to ceftriaxone was almost complete: the exceptions were 1 nonsusceptible isolate each in North America and Europe. Both isolates were identified as β-lactamase producers, with ceftriaxone MICs of 32 mg/ L. All isolates were susceptible to imipenem, meropenem, and levofloxacin (Table 4). MIC90 values for ampicillin ranged from 2 mg/L against H. influenzae from South Africa to ≥64 mg/L against

Rangea

b

8 2 ≥64 ≤0.5 ≤0.06 N/A 0.5 0.12 4 ≤0.06 2

2 to 32 ≤0.12 to 4 ≤0.5 to ≥64 ≤0.5 to 2 ≤0.06 to 0.5 0.5 to 4 ≤0.008 to 1 ≤0.06 to 0.5 ≤0.5 to 8 ≤0.06 to 0.12 0.015 to 2

2 to 16 0.5 to 4 2 to ≥64 ≤0.5 to 1 ≤0.06 to 0.06 ≤0.008 to 0.5 ≤0.06 to 0.25 ≤0.5 to 8 ≤0.06 to 0.12 0.015 to 2

n = 2 (0/2)b, e 4 to 8 0.5 to 4 2 to 2 ≤0.5 to 0.5 ≤0.06 to 0.12 0.5 to 1 ≤0.008 to 1 ≤0.06 to 0.25 ≤0.5 to 4 ≤0.06 to 2 0.03 to 2

4 to 32 0.25 to 2 2 to 2 ≤0.5 to 0.5 ≤0.06 to 0.06 NT 0.015 to 0.5 ≤0.06 to 0.12 2 to 8 ≤0.06 to 0.12 0.5 to 2

isolates from North America, the Asia-Pacific Rim, and the Middle East. For the other antimicrobials in the panel, MIC90 variations were small among the regions (within 1 or 2 doubling dilutions). Ceftriaxone and piperacillin– tazobactam had the lowest MIC90 values (b0.06 mg/L across all regions). Cefepime, levofloxacin, and meropenem displayed MIC90 values of ≤0.5 mg/L across the regions, irrespective of β-lactamase production. MIC90 values for tigecycline were also low (0.5 mg/L) across the regions, except for the Middle East (MIC90 = 2 mg/L).

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Tigecycline efficacy was unaffected by β-lactamase production (Table 4).

4. Discussion Tigecycline's excellent in vitro activity against respiratory pathogens has been reported globally (Casellas et al., 2007; Fritsche et al., 2005; Ko et al., 2006; Lau et al., 2006; Tsao et al., 2008). Like these published works, this study compares tigecycline with, among others, agents used in the treatment of CABP and COPD exacerbation. As multidrug resistance is now widespread, the common resistance phenotypes of the likely pathogens (i.e., PRSP and βlactamase–producing H. influenzae), as well as the overall populations, are considered. It has been reported that in the United States, in particular, penicillin resistance rates in S. pneumoniae may have peaked in 1999 to 2000 and leveled since (Doern et al., 2005). Certainly in our study, we found a lower percentage of penicillin-resistant isolates relative to penicillin-intermediate isolates globally, in contrast with studies before 2004, which reported higher proportions of penicillin-resistant isolates relative to penicillin-intermediate isolates (Adam, 2002; Felmingham et al., 2007). In this study, both ceftriaxone and amoxicillin–clavulanic acid retained good activity against penicillin-intermediate isolates but showed marked deterioration in activity with regional variation among isolates with high-level penicillin resistance. Reported clonal spread of ceftriaxone resistance in Taiwan (Chiu et al., 2007) must raise some concern over the current recommendations for empiric treatment based on these β-lactams, especially in geographic areas of high penicillin resistance, for example, Asia. Concern exists about the use of respiratory fluoroquinolones, such as levofloxacin, and the potential for increasing resistance to these agents among S. pneumoniae. In this study, resistance to levofloxacin was low (b3% overall in each region) and mostly apparent among penicillin-nonsusceptible isolates. For example, among the 19 (0.5%) levofloxacin-resistant isolates from North America, 11 were also penicillin intermediate and 5 were penicillin resistant. Our levofloxacin susceptibility rate for North America was the same as that reported by Doern et al. (2005) for isolates collected in the United States in 2002 to 2003, suggesting that fluoroquinolone resistance is not increasing in the United States. Sahm et al. (2008a) also concluded from their surveillance study that fluoroquinolone resistance remains uncommon among isolates of S. pneumoniae. As expected, tigecycline, linezolid, and vancomycin were unaffected by penicillin susceptibility and demonstrated excellent antipneumococcal activity in our study. Tigecycline susceptibility to S. pneumoniae was slightly lower than that of linezolid or vancomycin, although the MIC90 for tigecycline was the lowest reported of all antimicrobial agents (in most cases, by several dilutions).

The production of β-lactamases is the most common means by which H. influenzae isolates develop resistance to β-lactam antimicrobials (Tristram et al., 2007). Rates of βlactamase production varied widely by region in this study, ranging from 8.7% in South Africa to 26.8% in the AsiaPacific Rim region. Levels of β-lactamase production have previously been shown to vary widely by region among H. influenzae isolates. Hoban and Felmingham (2002) demonstrated regional variation in β-lactamase production ranging from 7.1% in Eastern Europe to 27.7% in Australasia; on a national level, β-lactamase variation ranged from 1.8% in Italy to 64.7% in South Korea. The reasons for such regional variation are currently unknown (Morrissey et al., 2008) but may involve factors such as clonal outbreaks or varying antimicrobial use in different regions. These regional discrepancies highlight the importance of monitoring global resistance patterns through the continuation of surveillance studies such as TEST. Rates of β-lactamase production in H. influenzae have been reported to be stable in recent years (Hoban et al., 2001), and this study supports that finding, with rates in North America similar to those reported by Johnson et al. (2003) for isolates collected between 1997 and 2001 (27.9%) and by Sahm et al. (2008a, 2008b) for isolates collected in the United States between 2001 and 2005 (28.9–27.8%) (2008a) and between 2003 and 2004 (28.5%) (2008b). The rate reported for Europe in this study (14.3%) was similar to those reported by Johnson et al. (2003) and Sahm et al. (2008b) (16.3% and 16.8%, respectively). Results from Sahm et al. (2008b) (29.6% in Asia and 8.7% in South Africa) also correspond with those reported here for the Asia-Pacific Rim and South Africa. Resistance to levofloxacin among H. influenzae has been reported by other researchers (Biedenbach and Jones, 2003; Sahm et al., 2008b); however, in this study, all isolates of H. influenzae were susceptible to levofloxacin. Imipenem- or meropenem-nonsusceptible isolates of H. influenzae are rare but have been reported in Japan, Korea, the United States, and Europe (Brown and Traczewski, 2005; Cerquetti et al., 2007; Kim et al., 2007; Miyazaki et al., 2001; Sanbongi et al., 2006), and such resistance was typically associated with BLNAR isolates. No such isolates have been noted among the 6642 isolates of H. influenzae examined in the TEST study. Tigecycline was highly active against the H. influenzae (including β-lactamase–producing) isolates in this study, with MIC90's of ≤0.5 mg/L in 5 of the 6 regions. These results were comparable with previous published reports (Draghi et al., 2008; Fritsche et al., 2005). The MIC90 of tigecycline (as well as several other antimicrobial agents) was higher against H. influenzae isolates from the Middle East at 2 mg/L. This compares with recently published data from 2 university hospitals in Istanbul, in which a tigecycline MIC90 of 0.5 mg/L was reported among isolates of H. influenzae (Gonullu et al., 2009). This discrepancy could be due to small sample sizes from the

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region in these 2 studies: Gonullu et al. (2009) provided data on 140 isolates of H. influenzae, whereas only 125 isolates were reported here, considerably less than the samples provided from North America (3499) or from Europe (1874) in this study. At such low numbers, even small local outbreaks of isolates with a high MIC90 could have a large impact on regional MICs. This regional variation could also be due to a high prevalence of multidrug-resistant pathogens in the Middle East, as recently described among Acinetobacter baumannii from bacteremic patients (Paul et al., 2005) or multiple Gramnegative pathogens in Turkey (Gür et al., 2008). In recent phase III clinical trials of tigecycline in the treatment of patients with CAP, the in vitro activity of tigecycline against S. pneumoniae and H. influenzae was examined. All 184 strains of S. pneumoniae were inhibited by tigecycline at a concentration of ≤0.12 mg/L (MIC90, 0.06 mg/L), whereas all 39 H. influenzae isolates were inhibited by ≤1 mg/L (MIC90 0.5 mg/L). The breakpoints assigned by the FDA for tigecycline against S. pneumoniae and H. influenzae were based on data from these phase III trials, so these breakpoints have been assigned based on maximum observed MIC values and not on inherent resistance to tigecycline. No truly resistant isolates have yet been identified, reflected by an absence of resistance breakpoints for tigecycline against S. pneumoniae or H. influenzae. Tigecycline resistance in clinical isolates is rare to date for most pathogens. No cross-resistance has been noted between tigecycline and other antimicrobial agents, and tigecycline is not affected by mechanisms that are effective against tetracyclines (Wyeth Pharmaceuticals, 2009). Two pathogens that do have reduced susceptibility to tigecycline are Pseudomonas spp. and Proteus spp.; both genera use chromosomally encoded efflux pumps as the mechanism of tigecycline resistance (Dean et al., 2003; Visalli et al., 2003). Tigecycline nonsusceptible isolates of A. baumannii have recently been identified, demonstrating multidrug resistance efflux mechanisms as primary mode of action against tigecycline (Peleg et al., 2007). As a result of the relatively low susceptibility breakpoints assigned recently by the FDA for tigecycline against S. pneumoniae and H. influenzae, several isolates in this study are classified as nonsusceptible; no resistance breakpoints have been assigned to these pathogens for tigecycline. Results from the PROTEKT study (prospective resistance organism tracking and epidemiology for the ketolide telithromycin) indicate that the genotypes responsible for multidrug resistance among S. pneumoniae and H. influenzae are increasing in prevalence, with corresponding increases in pneumococcal resistance (Marchese and Schito, 2007). One recent report suggests that approximately 40% of pneumococci today are multidrug-resistant (Reinert 2009). In regions where penicillin nonsusceptible S. pneumoniae prevalence is high in the PROTEKT study, for example, parts of Europe (where prevalence ranges from 25% to 50% in some countries), tigecycline retains good activity against

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pneumococci (MIC90, 0.12 mg/L; 88.3% susceptible) regardless of penicillin susceptibility. In conclusion, these data from the TEST program, coupled with those of other researchers, suggest that the global proportion of S. pneumoniae identified as penicillinintermediate and penicillin-resistant may be changing (Richter et al., 2009), whereas the percentage of H. influenzae identified as β-lactamase producing has remained unchanged in recent years (Hoban et al., 2001; Johnson et al., 2003; Sahm et al., 2008a, 2008b). However, continued surveillance is warranted given the emergence of new phenotypes such as carbapenem-nonsusceptible H. influenzae. The MICs for tigecycline in this study demonstrated excellent in vitro activity against all isolates of S. pneumoniae and H. influenzae, irrespective of resistance phenotype (Conte et al., 2005). This, together with the favorable results of the phase III clinical trials in CAP (Bergallo et al., 2009), suggests that this novel antimicrobial agent would offer clinicians a clear option for the treatment of patients with CABP or COPD exacerbation.

Acknowledgments The authors thank the many investigators and center staff who submitted isolates and data to this study and the staff of IHMA for their coordination of TEST. This study was sponsored by Wyeth, which was acquired by Pfizer in October 2009. Medical writing support for this manuscript was provided by Dr Wendy Hartley and Dr Rod Taylor of Micron Research and was funded by Wyeth. Micron Research also provided assistance with data analysis.

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