Antimicrobial resistance among isolates of respiratory tract infection pathogens from the Southern United States: data from the PROTEKT US Surveillance Program 2000/2001.

Background: PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) was established in 2000 to monitor antimicrobial resistance among respiratory tract pathogens across the United States.

Methods: During 2000 to 2001, 75 southern US centers collected 3,867 Streptococcus pneumoniae, 1,455 Streptococcus pyogenes and 1,042 Haemophilus influenzae.

Results: Overall, 46.1% of S. pneumoniae isolates were nonsusceptible to penicillin, 35.8% were resistant to erythromycin, and 0.5% were resistant to fluoroquinolones. Against S. pneumoniae the most active agents were telithromycin (99.7% susceptible), linezolid (99.8%) and the fluoroquinolones (levofloxacin 99.4%, gatifloxacin 99.5%). The prevalence of erythromycin-resistant S. pyogenes isolates was 4.5%. Telithromycin, at concentration of [less than or equal to] 1 mg/L, inhibited 99.9% of S. pyogenes. The prevalence of [beta]-lactamase positive H. influenzae was 26.2%. Telithromyein was active (MI[C.sub.90] 4 mg/L) against H. influenzae, irrespective of [beta]-lactamase production.

Conclusion: The prevalence of penicillin and macrolide resistance among respiratory tract pathogens from the southern United States is high. Fluoroquinolone resistance is low. Telithromycin is highly active against respiratory tract pathogens with reduced susceptibility to [beta]-lactams, macrolides, and fluoroquinolones.

Key Words: PROTEKT US, resistance, respiratory infections, southern United States, telithromycin

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Community-acquired respiratory tract infections (CARTIs), such as community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis and acute otitis media, are caused by a variety of microorganisms. Bacterial pathogens commonly associated with upper and lower respiratory tract infections (RTIs) include Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes. Management of RTIs is generally empirical, with the [beta]-lactam, macrolide, fluoroquinolone and tetracycline (doxycycline) antimicrobial agents being the mainstays of treatment. However, the prevalence of antimicrobial resistance among common respiratory pathogens has increased rapidly worldwide over the last decade, increasing the risk of clinical failures. (1-6)

Data from large surveillance programs show that penicillin-resistant strains of S. pneumoniae have spread rapidly worldwide and their prevalence continues to increase. (7,8) A common theme among a number of surveillance studies, either conducted solely in the United States (9-14) or international studies including US centers (7,8) has been the wide, and often striking, geographic variability in resistance.

In addition to rising penicillin resistance rates, coresistance between the penicillins, cephalosporins and other antimicrobial agents, such as the macrolide-lincosamide-streptogramin (MLS) class of antimicrobials, is a common problem. (7,8) Recent evidence also suggests that pneumococcal resistance to [beta]-lactams, macrolides and fluoroquinolones may be associated with poor clinical outcomes. (15-17) These issues have driven research into improving strategies of antimicrobial usage and the development of new agents that do not induce or select resistance, which are important factors in safeguarding future antimicrobial efficacy. As a result the ketolides, a group of agents within the MLS class, have been developed. Telithromycin is the first ketolide to undergo clinical evaluation. Telithromycin consists of a 14-membered ring with a 3-keto structure replacing the L-cladinose moiety, a methoxy group at C6, and, unlike other ketolides, an N-substituted carbamate side chain at C11/C12. These structural modifications enhance the affinity of telithromycin to the ribosome and reduce the propensity to induce resistance. (18)

Importantly, the development of newer agents, like the ketolides, needs to be complemented by more rational prescribing of antimicrobials to limit the spread of resistance. Hence, continued surveillance of resistance among the bacterial species most commonly associated with CARTIs is essential. The PROTEKT US (Prospective Resistant Organism Tracking for the Ketolide Telithromycin in the United States) surveillance study is longitudinally monitoring the antimicrobial susceptibility of S. pneumoniae, S. pyogenes and H. influenzae isolated from patients with CARTIs across the United States. This paper reports the 2000 to 2001 results for antimicrobial susceptibility among isolates from 75 participating centers in the southern United States.

Methods

Participating Centers

Across the southern United States, 75 centers participated in PROTEKT US in 2000 to 2001. These were distributed across the states of Alabama, Arizona, Arkansas, California, Colorado, Florida, Georgia, Kentucky, Louisiana, Nevada, New Mexico, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Utah, Virginia, and West Virginia.

Collection and Storage of Bacterial Isolates

Isolates were collected from adults and children with different types of community-acquired infections, including acute/chronic sinusitis, acute/chronic otitis media, acute/chronic pharyngitis, pneumonia, acute bacterial exacerbation of chronic bronchitis, or acute exacerbation of chronic obstructive airways disease. Each center recruited to the PROTEKT US study was requested to collect 85 isolates of the following bacterial species: S. pneumoniae (n = 50), S. pyogenes (n = 20) and H. influenzae (n = 15).

The following sources for isolation of RTI pathogens were permitted in the study: blood, sputum, bronchoalveolar lavage, middle ear fluid, nasopharyngeal swab or aspirate, sinus aspirate, and throat (S. pyogenes only). Specimens were accepted if they were the first positive specimen from each patient and had been obtained from patients with CARTIs or from hospitalized patients within 48 hours of admission. Isolates from patients who had been hospitalized for [greater than or equal to]48 hours, who had nosocomial lower respiratory tract infections (RTIs) or cystic fibrosis were excluded, as were duplicate strains, strains originating from existing collections, or isolates from sputum samples with an unacceptable Gram stain indicative of oropharyngeal contamination.

All isolates were stored in Ames Transport medium and shipped to a central laboratory (CMI, Portland, OR) for microbiologic investigation.

Antimicrobial Susceptibility Testing 

Following re-identification of the isolates, minimum inhibitory concentrations (MICs) were determined using the National Committee for Clinical Laboratory Standards broth microdilution method. (19) S. pneumoniae and S. pyogenes were tested with the following antimicrobials: penicillin, amoxicillin clavulanate, cefuroxime, clindamycin, erythromycin, clarithromycin, azithromycin, telithromycin, levofloxacin, gatifloxacin, tetracycline, linezolid, and cotrimoxazole. H. influenzae isolates were tested with: ampicillin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefotaxime, clarithromycin, azithromycin, telithromycin, levofloxacin, gatifloxacin, moxifloxacin, tetracycline, and linezolid. NCCLS breakpoints were used to define susceptibility. (20) For telithromycin the proposed NCCLS breakpoints were applied, S. pneumoniae: susceptible [less than or equal to]1 mg/L, intermediate 2 mg/L, resistant [greater than or equal to]4 mg/L; H. influenzae susceptible [less than or equal to]4 mg/L, intermediate 8 mg/L, resistant [greater than or equal to]16 mg/L. No NCCLS telithromycin breakpoints are currently proposed for S. pyogenes.

[FIGURE 1 OMITTED]

Resistance Mechanism Determination

[beta]-lactamase production was determined for isolates of H. influenzae using the chromogenic cephalosporin (nitrocefin) test (Oxoid, Basingstoke, UK).

Results

S. pneumoniae

A total of 3,867 isolates of S. pneumoniae were submitted from centers in the southern United States (South-Central region, n = 1,455; Southeastern region, n = 1,063; South-western region, n = 1,349). The prevalence of susceptibility to penicillin, macrolides (erythromycin) and fluoroquinolones (levofloxacin) among these isolates is summarized in Table 1.

Penicillin Resistance

Overall, 31.7% (1,224/3,867) of isolates were penicillinresistant (MIC [greater than or equal to]2 mg/L), and a further 14.4% (558/3,867) were intermediately resistant (MIC 0.12-1 mg/L) (Table 1). Nonsusceptibility (intermediate and full resistance) was identified in 46.3% (674/1,455) of isolates in the South-central region, 42.4% (572/1,349) in the Southwest and 50.4% (536/1,063) in the Southeast.

There was considerable variation in the prevalence of penicillin-resistance across the southern states of the United States. Penicillin nonsusceptibility exceeded 60% of isolates in two states (Louisiana and Utah) (Table 2). In contrast, a relatively low rate of nonsusceptibility was found in Kentucky (31.6%), California (32.6%), Colorado (33.9%) and New Mexico (33.9%). Typically, lower rates of resistance were observed in the Southwestern states of the United States than the other southern regions.

Among the [beta]-lactams agents, cefuroxime had the highest level of resistance across the southern regions followed by penicillin (at MIC [greater than or equal to] 2 mg/L) and amoxicillin-clavulanate (Table 1).

Macrolide Resistance

Overall, 35.8% (1,383/3,867) of isolates showed resistance to erythromycin (MIC [greater than or equal to]1 mg/L; South-central 38.6%, Southeastern 40.2%, Southwest, 29.3%) (Table 1). Only six erythromycin intermediate isolates (MIC = 0.5 mg/L) were identified. There were considerable interstate differences in the prevalence of resistance to erythromycin. The highest level of resistance was recorded in Oklahoma (56.2%). In contrast Kentucky had an erythromycin resistance rate of 20%. The prevalence of resistance to azithromycin (South-central 38.7%, Southeast 40.0%, Southwest 29.2%), and clarithromycin (South-central 38.4%, Southeast 39.8%, Southwest 29.0%) was similar to that of erythromycin (Table 1). In total 24.9% (345/1,383) of isolates resistant to the macrolides were also resistance to clindamycin.

Multidrug Resistance 

Overall, 26.2%, 29.2% and 19.6% of pneumococci from South-central, Southeastern and the Southwestern regions, respectively, were resistant to both erythromycin and penicillin (Table 2). The highest incidence of coresistance to both penicillin and erythromycin was in Oklahoma (43.8%) and the lowest rate was in Kentucky (11.7%). Of the 1,224 isolates resistant to penicillin across the southern regions of the United States, 78.0% were also resistant to erythromycin.

Isolates with penicillin resistance also often exhibited resistance to other antimicrobials, particularly cefuroxime, co-trimoxazole, the macrolides and tetracycline. Pneumococcal isolates resistant to erythromycin were also resistant to azithromycin and clarithromycin, but not to telithromycin. Indeed, 98.7% of penicillin-resistant pneumococci isolated in South-Central United States, 99.2% of Southeastern isolates, and 99.5% of Southwestern isolates were susceptible to telithromycin.

Fluoroquinolone Resistance

Rates of fluoroquinolone resistance (levofloxacin MIC [greater than or equal to]8 mg/L) were low (18/3,867, 0.5%) across the southern United States (Table 1). Overall rates for South-central, Southeastern, and Southwestern regions were 0.5% (7/1,455), 0.3% (3/1,063) and 0.6% (8/1,349), respectively. Intermediate resistance (MIC = 4 mg/L) was rare and only detected in the states of Alabama and California. Of the 18 levofloxacin resistant isolates, 14 were also resistant to gatifloxacin (MIC [greater than or equal to]4 mg/L), and four had intermediate resistance to gatifloxacin (MIC = 2 mg/L).

S. pneumoniae isolates resistant to fluoroquinolones were often resistant to other antimicrobials (Fig. 1). Among the 18 levofloxacin-resistant isolates ten were resistant to erythromycin, azithromycin and clarithromycin (one isolate was resistant to erythromycin and azithromycin but intermediate for clarithromycin). Three of the 18 isolates were resistant to clindamycin. The 11 erythromycin resistant isolates were also nonsusceptible to penicillin (seven resistant, four intermediate). In addition three of the fluoroquinolone resistant isolates were resistant to amoxicillin-clavulanate, seven were resistant to cefuroxime and seven resistant to tetracycline. A total of 13 were resistant to cotrimoxazole. All 18 isolates were susceptible to telithromycin (MIC [less than or equal to] 1 mg/L) and linezolid (MIC [less than or equal to]2 mg/L).

S. pyogenes

A total of 1,455 isolates of S. pyogenes (South-central, n = 521; Southeast, n = 433; Southwest, n = 501) were submitted for microbiologic evaluation. All S. pyogenes isolates tested were susceptible to penicillin. The majority of S. pyogenes isolates were fully susceptible to all antimicrobials tested, with the exception of tetracycline (7.4% [108/1,455] of isolates resistant) and the macrolides (Table 3). Telithro mycin had a low MI[C.sub.50] and MI[C.sub.90] (0.03 mg/L), and 99.9% of isolates were inhibited at a MIC of [less than or equal to] 1 mg/L.

Macrolide Resistance

In total 4.5% of S. pyogenes were resistant to erythromycin. Only minor differences in susceptibility were noted between states, with overall erythromycin resistance rates from 3.8% (range 0.0% to 10.5%) in the Southwest to 5.4% (range 0.0% to 8.9%) in the South-central region (Table 4).

Multidrug Resistance

Cross-resistance between erythromycin-resistant S. pyogenes and other macrolides (azithromycin and clarithromycin) was observed. Importantly, 97.0% (64/66) of these macrolide resistant isolates were susceptible to telithromycin.

H. influenzae

In total, 1,042 isolates of H. influenzae were submitted and underwent microbiologic investigation (South-central, n = 390; Southeast, n = 306; Southwest, n = 346).

[beta]-lactamase Production in H. influenzae

The overall rate of [beta]-lactamase production was 26.2% in the southern United States but varied both within and between geographical areas (Table 5). In the southern states of the United States the proportion of [beta]-lactamase positive isolates ranged from 6.7% in Nevada to 44.4% in Louisiana. Eleven [beta]-lactamase negative ampicillin resistant (BLNAR) isolates were identified.

Overall, 30.0%, 25.2% and 25.4% of H. influenzae isolates were resistant to ampicillin in the South-central, -eastern and -western regions, respectively. The bimodal nature of the ampicillin MIC distribution (Fig. 2) demonstrates the incidence of [beta]-lactamase negative and positive isolates.

Resistance to cefuroxime and tetracycline was observed in 0.8% and 1.0% of isolates, respectively. A total of 99.9% (1,041/1,042) of isolates were susceptible to levofloxacin, one isolate (from Alabama) had a levofloxacin MIC of 8 mg/L. This isolate was also nonsusceptible to Gatifloxacinvand moxifloxacin but susceptible to ampicillin, azithromycin and telithromycin. A further isolate though susceptible to levofloxacin and Gatifloxacinvhad a moxifloxacin MIC of 2 mg/L. Telithromycin was active against H. influenzae, irrespective of [beta]-lactamase production, with more potent activity in comparison to clarithromycin (MI[C.sub.90] = 16 mg/L) and equivalent to azithromycin (MI[C.sub.90] = 4 mg/L) (Table 6).

[FIGURE 2 OMITTED]

Discussion

In accordance with other surveillance studies either conducted solely in the United States (9-13) or including US centers as part of an ongoing program, (7,8) the current PROTEKT US results confirm that penicillin resistance (MIC [greater than or equal to]2 mg/L) among pneumococci is common in the southern United States.

The overall rate of penicillin resistance in the current study (31.7%) is considerably higher than found in earlier US-based surveillance programs conducted in 1997 (9) and during the period 1997 to 1999, (8) where rates of 14.5% and 12.7%, respectively, were reported. However, the prevalence of penicillin resistance among S. pneumoniae in each of the southern regions of the United States participating in PROTEKT US (Southwest 27.0%, South-central 32.5%, Southeast 36.4%) are comparable with those from a US surveillance study reported by Jacobs et al, which noted rates of penicillin resistance for the Southwestern, South-central and Southeastern regions of 33.7%, 46.2% and 40.1%, espectively. (12)

As in previous studies, marked intrastate variability was also apparent for the prevalence of penicillin-resistant strains, ranging from 27.3% (Alabama) to 50.0% (Oklahoma) in the South-central region, from 18.3% (Kentucky) to 41.7% (South Carolina) in the Southeastern region, and from 18.8% (California) to 44.5% (Utah) in the Southwestern region. Such findings re-affirm the importance of physicians to be aware of local resistance patterns to ensure the judicious use of antimicrobials for patients with community-acquired RTIs that may be attributable to S. pneumoniae.

An important finding of the PROTEKT US study is the high prevalence (35.8%) of macrolide (erythromycin) resistance among pneumococci, ranging from 29.3% to 40.2% between regions. These values are markedly higher than the 14.3% reported by Doern et al (9) for early 1997, 17.7% from the 1997 to 1999 SENTRY program (8) and 24.0% reported by Jones et al. (21) As with penicillin resistance, marked intrastate variability was also observed. Macrolide resistance either equaled or exceeded penicillin resistance in most of the states participating in the study (MIC [less than or equal to] 1 mg/L).

Perhaps even more concerning is the degree to which penicillin-resistant S. pneumoniae isolates are becoming multiply resistant. Overall, 26.2% of South-central, 29.2% of Southeastern and 19.6% of Southwestern pneumococci were resistant to both erythromycin and penicillin. Isolates with decreasing penicillin susceptibility also demonstrated a trend toward decreased activity of other antimicrobials tested, including cotrimoxazole and tetracycline. However, 98.7% of penicillin-resistant pneumococci isolated in South-Central United States, 99.2% of Southeastern isolates, and 99.5% of Southwestern isolates were susceptible to telithromycin. Penicillin-resistant pneumococci in the southern United States were also highly susceptible to Linezolid and the fluoroquinolones.

The rapid increase in [beta]-lactam and macrolide resistance and associated resistance with other agents among pneumococci may be explained by selective pressure. Since a strong association exists between erythromycin resistance and consumption of the newer macrolides dosed once or twice daily. (22.23) A number of antimicrobial resistance mechanisms exist, although two mechanisms are known to play a key role in S. Pneumoniae resistance to macrolides and other macrolide-lincosamide-streptogramin B (ML[S.sub.B]) antimicrobial. The first involves alterations in antimicrobial transport (efflux), which is encoded by the mef(A) gene (M-phenotype) and generally confers low-level resistance (MIC 1-16 mg/L) to 14- and 15-membered macrolides, but not lincosamides and streptogramin B. (24,25) Secondly, high-level macrolide resistance may result from modification of the drug target (ribosomal binding site) via erm(B) genes that encode 23S rRNA methylases, and lead to cross-resistance to the ML[S.sub.B] group of agents (ML[S.sub.B] phenotype). (26-29) Importantly, however, the ketolide telithromycin remained highly active against pneumococci in the PROTEKT US study, irrespective of penicillin and/or erythromycin resistance. These findings are supported by the work of Johnson et al. who collected 180 erythromycin-resistant isolates of S. pneumoniae from respiratory tract specimens from pediatric patients between 1994 and 1999 in the states of Alabama. Tennessee and South Carolina (72 erm(B) isolates, 100 mef(A) isolates and 8 containing both erm(B) and mef(A) and demonstrated that telithromycin was uniformly active, inhibiting all at concentrations [less than or equal to]1 mg/L. (30)

The PROTEKT US data also indicate that reduced susceptibility to fluoroquinolones among pneumococci remains low at 0.5% overall. S. pneumoniae isolates that were resistant to levofloxacin also had high MICs for the other fluoroquinolone tested, gatifloxacin (MI[C.sub.50] 4 mg/L, MI[C.sub.90] >4 mg/L). Many of the fluoroquinolone resistant isolates were also resistant to penicillin (MI[C.sub.50] 0.25 mg/L, MI[C.sub.90] 4 mg/L) and the macrolides (erythromycin MI[C.sub.50]4 mg/L, MI[C.sub.90] [greater than or equal to]512 mg/L). As different mechanisms are involved, the apparent association may reflect the early emergence of multiresistant clones. The 18 fluoroquinolone-resistant isolates were susceptible to telithromycin.

Turning to other RTI pathogens investigated during the PROTEKT US study, all isolates of S. pyogenes were susceptible to penicillin, in line with other reports. However, a number of previous reports have indicated that up to 30% of S. pyogenes isolates are resistant to macrolides. (31-33) The PROTEKT US results suggest that macrolide resistance among S. pyogenes in the southern United States is relatively low overall. The majority of S. pyogenes isolates were fully susceptible to the other antimicrobials tested, with the exception of tetracycline. However, high levels of cross-resistance were observed between erythromycin-resistant strains and azithromycin and clarithromycin. All macrolide susceptible and 64 of 66 macrolide-resistant isolates were susceptible to telithromycin.

Among the H. influenzae isolates 26.2% were found to be [beta]-lactamase positive in the southern regions of the United States. Considerable variability in [beta]-lactamase production was observed within the individual regions participating in the study; the largest variation in [beta]-lactamase-positive H. influenzae isolates was seen in the South-central region, ranging from 13.0% in Arkansas to 44.4% in Louisiana. Overall, the [beta]-lactamase prevalence rates in H. influenzae from the United States are comparable to those reported in the SENTRY Program (33% during 1999) and US surveillance studies conducted in 1996 to 1997, 1997, 1997 to 1998 and 1998 (33.4%, 41.6%, 33% and 33.3%, respectively). (3,8,10,11,21) Taken together, these findings suggest that [beta]-lactamase production among H. influenzae remains relatively constant in the United States. However, as with S. pneumoniae, physicians need to be aware of the wide variability in [beta]-lactamase producing H. influenzae both within and across states.

With the exception of ampicillin, resistance of H. influenzae to commonly used antimicrobial agents was rare, regardless of [beta]-lactamase status. One levofloxacin nonsusceptible isolate was identified. Most isolates of H. influenzae were susceptible to the macrolides, in accordance with previous surveillance studies. (4,8) As reported previously [beta]-lactamase negative ampicillin resistant (BLNAR) isolates of H. influenzae were uncommon. (34) Although 10 of the 11 reported in this study were susceptible to a number of tested antimicrobials (cefotaxime, azithromycin, telithromycin, levofloxacin, moxifloxacin, gatifloxacin, tetracycline) their occurrence highlights the need for continued vigilance.

Large-scale surveillance programs, including the current PROTEKT US study, have an increasingly important role to play in guiding clinicians in the choice of the most appropriate antimicrobial agent for the treatment of community-acquired RTIs in specific geographical locations. Recent evidence suggests that pneumococcal resistance may be associated with poor outcome, particularly for patients with severe infections. (15,16,35) Genotype monitoring is being used to determine resistance mechanisms for isolates collected during the PROTEKT US study and the findings will be presented elsewhere in the future. Susceptibility data supports that mef(A) is the predominate macrolide resistance mechanism in the United States given the number of clindamycin resistant isolates (24.9%) among the macrolide resistant S. pneumoniae. Determination of macrolide resistance mechanisms is particularly useful since low-level macrolide resistance mediated by mef(A), may be overcome by drug concentrations that are clinically achievable in tissues. (36) Conversely, strains demonstrating high MICs to erythromycin may lead to microbiologic and clinical failure with macrolides in patients with community acquired pneumonia although recently the clinical relevance of low level mef(A) resistant isolates has been reported. (35-37) It is, however, important to note that despite reports of treatment failure they are few in number and given the millions of macrolide prescriptions written the overall clinical significance of this in the United States is uncertain.

The development of new antimicrobial agents that retain activity against drug-resistant S. pneumoniae, and other common bacterial pathogens, while having a low potential to select for or induce resistance, are vitally important to safeguard future antimicrobial efficacy. The current PROTEKT US results suggest that telithromycin retains high activity among common RTI pathogens including those that have already developed resistance to the [beta]-lactams and macrolides in the southern United States.

Table 1. Activity of antimicroblals against clinical isolates of S.
pneumoniae from the southern United States[a]

                             All
                         (n = 3,867)
                         MIC (mg/L)
                         50
Penicillin               [less than or equal to]0.06
Amoxicillin-clavulanate  [less than or equal to]0.12
Cefuroxime               [less than or equal to]0.12
Clindamycin              [less than or equal to]0.25
Azithromycin                                    0.12
Clarithromycin                                  0.06
Erythromycin                                    0.12
Telithromycin            [less than or equal to]0.015
Levofloxacin                                    1
Gatifloxaein                                    0.25
Tetracyline                                     0.25
Linezolid (b)                                   1
Cotrimoxazole                                   0.5

                               All
                           (n = 3,867)
                              MIC (mg/L)           MIC (mg/L)
                                               90        %I     %R

Penicillin                                      4     14.4  31.7
Amoxicillin-clavulanate                         4      5.5   5.8
Cefuroxime                                      8      2.9  34.6
Clindamycin              [less than or equal to]0.25   0.2   9.1
Azithromycin                                   64      0.3  35.7
Clarithromycin                                 16      0.3  35.5
Erythromycin                                   32      0.1  35.8
Telithromycin                                   0.5    0.3   0.03
Levofloxacin                                    1      0.1   0.5
Gatifloxaein                                    0.5    0.1   0.4
Tetracyline                                    >4      0.3  17.5
Linezolid (b)                                   2       -     -
Cotrimoxazole                                  >4      7.9  40.0

                         South-central

                           (n = 1,455)

                          MIC (mg/L)

                                   50

Penicillin               [less than or equal to]0.06
Amoxicillin-clavulanate  [less than or equal to]0.12
Cefuroxime               [less than or equal to]0.12
Clindamycin              [less than or equal to]0.25
Azithromycin                                    0.25
Clarithromycin                                  0.06
Erythromycin                                    0.12
Telithromycin                                   0.03
Levofloxacin                                       1
Gatifloxaein                                    0.25
Tetracyline                                     0.25
Linezolid (b)                                      2
Cotrimoxazole                                      1

                       South-central
                        (n = 1,455)
                      MIC (mg/L)                   MIC (mg/L)

                                                90      %I   %R

Penicillin                                         4  13.8  32.5
Amoxicillin-clavulanate                            4   8.6   6.3
Cefuroxime                                         8   3.0  35.9
Clindamycin              [less than or equal to]0.25   0.1   6.7
Azithromycin                                      32   0.1  38.7
Clarithromycin                                    16   0.3  38.4
Erythromycin                                      16   0.3  38.6
Telithromycin                                    0.5   0.4   0.0
Levofloxacin                                       1   0.1   0.5
Gatifloxaein                                     0.5   0.1   0.4
Tetracyline                                       >4   0.3  14.2
Linezolid (b)                                      2     -     -
Cotrimoxazole                                     >4   8.0  42.3

                         Southeast (n = 1,063)

                                   50                90    %I    %R

Penicillin                                    0.12  4     14.0  36.4
Amoxicillin-clavulanate[less than or equal to]0.12  4      4.5   9.1
Cefuroxime                                    0.25  8      2.8  39.2
Clindamycin            [less than or equal to]0.25  64     0.2  10.6
Azithromycin                                  0.12  >256   0.5  40.0
Clarithromycin                                0.06  256    0.6  39.8
Erythromycin                                  0.12  >256   0.2  40.2
Telithromycin         [less than or equal to]0.015  0.5    0.3   0.0
Levofloxacin                                     1  1      0.0   0.3
Gatifloxaein                                  0.25  0.5    0.0   0.3
Tetracyline                                   0.25  >4     0.6  18.3
Linezolid (b)                                    1  2        -     -
Cotrimoxazole                                    1  >4     5.9  45.2

                         Southwest (n = 1,349)

                                   50               90     %I   %R

Penicillin             [less than or equal to]0.06  2     15.4  27.0
Amoxicillin-clavulanate[less than or equal to]0.12  2      3.0   2.7
Cefuroxime             [less than or equal to]0.12  8      3.0  29.4
Clindamycin            [less than or equal to]0.25  1      0.2  10.4
Azithromycin                                  0.12  >256   0.2  29.2
Clarithromycin                                0.06  128    0.2  29.0
Erythromycin                                  0.12  >256   0.0  29.3
Telithromycin         [less than or equal to]0.015  0.5    0.2   0.1
Levofloxacin                                     1  1      0.1   0.6
Gatifloxaein                                  0.25  0.5    0.2   0.4
Tetracyline                                   0.25  >4     0.1  20.5
Linezolid (b)                                    1  2        -     -
Cotrimoxazole                                 0.25  >4     9.3  33.4

(a) MIC. minimum inhibitor concentration: %1, % of isolates with
intermediate resistance: %R. % of isolates resistant.
(b) National Committee for Clinical Laboratory Standards. Currently
defines susceptibility to linezolid as a, MIC of [less than or equal
to]2 mg/L, at which 99.8% of isolates were susceptible; no intermediate
or resistant breakpoints have been defined.

Table 2. Penicillin, macrolide, and fluoroquinolone susceptibility among
clinical isolates of S. pneumoniae in the southern United States (a)

                        Penicillin          Macrolide
                 susceptibility (%) (b)  susceptibility (%) (c)

                         No. of    S     I     R     S     I    R
                        isolates

Alabama              150      63.4   9.3  27.3  63.3  0.7  36.0

Arkansas              58      43.1  25.9  31.0  53.4  0.0  46.6

Louisiana             60      36.6  26.7  36.7  58.3  1.7  40.0

Oklahoma              32      40.6   9.4  50.0  43.8  0.0  56.2

Tennessee            636      52.0  12.3  35.7  61.3  0.2  38.5

Texas                519      56.8  14.5  28.7  62.6  0.2  37.2

  South-central    1,455      53.7  13.8  32.5  61.1  0.3  38.6

Florida              405      45.7  13.6  40.7  57.3  0.0  42.7

Georgia              193      53.9  12.9  33.2  63.7  0.0  36.3

Kentucky              60      68.4  13.3  18.3  80.0  0.0  20.0

North Carolina       187      45.4  16.6  38.0  57.8  0.5  41.7

South Carolina        48      50.0   8.3  41.7  56.2  0.0  43.8

Virginia              52      59.6  13.5  26.9  63.5  1.9  34.6

West Virginia        112      48.2  17.0  34.8  53.6  0.0  46.4

  Southeast        1,063 (e)  49.6  14.0  36.4  59.6  0.2  40.2

Arizona               50      62.0  14.0  24.0  72.0  0.0  28.0

California           675      67.4  13.8  18.8  77.0  0.0  23.0

Colorado              65      66.1  13.9  20.0  69.2  0.0  30.8

Nevada                61      62.3  13.1  24.6  75.4  0.0  24.6

New Mexico           109      66.1  11.9  22.0  74.3  0.0  25.7

Utah                 389      35.5  20.0  44.5  58.1  0.0  41.9

  Southwest        1,349      57.6  15.4  27.0  70.7  0.0  29.3

  Southern United  3,867      53.9  14.4  31.7  64.1  0.1  35.8
  States

                        Fluoroquinolone         Penicillin/
                        susceptibility (%) (d)  macrolide (%)

                    S     I    R                  R

Alabama            98.0  0.7  1.3                23.3

Arkansas          100.0  0.0  0.0                24.1

Louisiana         100.0  0.0  0.0                25.0

Oklahoma          100.0  0.0  0.0                43.8

Tennessee          99.5  0.0  0.5                27.5

Texas              99.6  0.0  0.4                24.7

  South-central    99.4  0.1  0.5                26.2

Florida            99.8  0.0  0.2                31.4

Georgia           100.0  0.0  0.0                27.5

Kentucky          100.0  0.0  0.0                11.7

North Carolina     98.9  0.0  1.1                30.0

South Carolina    100.0  0.0  0.0                35.4

Virginia          100.0  0.0  0.0                23.1

West Virginia     100.0  0.0  0.0                31.3

  Southeast        99.7  0.0  0.3                29.2

Arizona            98.0  0.0  2.0                16.0

California         99.4  0.2  0.4                13.9

Colorado           95.4  0.0  4.6                16.9

Nevada             75.4  0.0 24.6               100.0

New Mexico        100.0  0.0  0.0                15.6

Utah               99.7  0.0  0.3                31.9

  Southwest        99.3  0.1  0.6                19.6

  Southern United  99.4  0.1  0.5                24.7
States

(a) S. susceptible: I. intermediate: R. resistant: MIC. minimum
inhibitory concentration.
(b) Penicillin breakpoints: susceptible, MIC [less than or equal
 to]0.06 mg/L: intermediate. MIC 0.12-1 mg/L: resistant, MIC
[greater than or equal to]2 mg/L.
(c) Erythromycin breakpoints: susceptible, MIC [less than or equal
to]0.25 mg/L: intermediate, MIC 0.5 mg/L: resistant, MIC [greater than
or equal to]1 mg/L.
(d) Leyofloxacin breakpoints: susceptible, MIC [less than or equal to]2
mg/L: intermediate, MIC 4 mg/L: resistant, MIC [greater than or equal
to]8 mg/L.
(e) Six isolates from Puerto Rico also submitted: data not shown.

Table 3.  Activity of antimicrobials against clinical isolates of
S. pyogenes from the southern United States (a)

                               All (n = 1,455)
                                 MIC (mg/L)
                                    50

Penicillin               [less than or equal to]0.06
Amoxicillin-clavulanate  [less than or equal to]0.12
Cefuroxime               [less than or equal to]0.12
Clindamycin              [less than or equal to]0.25
Azithromycin                                    0.25
Clarithromycin                                  0.06
Erythromycin             [less than or equal to]0.06
Telithromycin (b)                               0.03
Levofloxacin                                    0.5
Gatifloxacin                                    0.25
Tetracycline                                    0.25
Linezolid (c)                                   1
Cotrimoxazole (b)        [less than or equal to]0.25

                               All (n = 1,455)
                                 MIC (mg/L)
                                     90                  %I         %R

Penicillin               [less than or equal to]0.06    0.0         0.0
Amoxicillin-clavulanate  [less than or equal to]0.12  predicted by
                                                        penicillin
Cefuroxime               [less than or equal to]0.12  predicted by
                                                        penicillin
Clindamycin              [less than or equal to]0.25    0.2         0.3
Azithromycin                                    0.25    0.1         4.6
Clarithromycin                                  0.06    0.1         4.5
Erythromycin                                    0.12    0.1         4.5
Telithromycin (b)                               0.03     N/A         N/A
Levofloxacin                                    1       0.0         0.2
Gatifloxacin                                    0.5     0.0         0.2
Tetracycline                                    0.25    0.4         7.4
Linezolid (c)                                   2        N/A         N/A
Cotrimoxazole (b)                               0.5      N/A         N/A

                           South-central (n = 521)
                                 MIC (mg/L)
                                    50

Penicillin               [less than or equal to]0.06
Amoxicillin-clavulanate  [less than or equal to]0.12
Cefuroxime               [less than or equal to]0.12
Clindamycin              [less than or equal to]0.25
Azithromycin                                    0.25
Clarithromycin                                  0.06
Erythromycin             [less than or equal to]0.06
Telithromycin (b)                               0.03
Levofloxacin                                    0.5
Gatifloxacin                                    0.25
Tetracycline                                    0.25
Linezolid (c)                                   1
Cotrimoxazole (b)        [less than or equal to]0.25

                           South-central (n = 521)
                                 MIC (mg/L)
                                     90                    %I       %R

Penicillin               [less than or equal to]0.06    0.0         0.0
Amoxicillin-clavulanate  [less than or equal to]0.12  predicted by
                                                        penicillin
Cefuroxime               [less than or equal to]0.12  predicted by
                                                        penicillin
Clindamycin              [less than or equal to]0.25    0.2         0.0
Azithromycin                                    0.25    0.0         5.6
Clarithromycin                                  0.06    0.2         5.4
Erythromycin                                    0.12    0.2         5.4
Telithromycin (b)                               0.03     N/A         N/A
Levofloxacin                                    1       0.0         0.6
Gatifloxacin                                    0.25    0.0         0.6
Tetracycline                                    0.25    0.4         6.0
Linezolid (c)                                   2        N/A         N/A
Cotrimoxazole (b)                               0.5      N/A         N/A

                             Southeast (n = 433)
                                 MIC (mg/L)
                                    50

Penicillin               [less than or equal to]0.06
Amoxicillin-clavulanate  [less than or equal to]0.12
Cefuroxime               [less than or equal to]0.12
Clindamycin              [less than or equal to]0.25
Azithromycin                                    0.25
Clarithromycin                                  0.06
Erythromycin             [less than or equal to]0.06
Telithromycin (b)                               0.03
Levofloxacin                                    0.5
Gatifloxacin                                    0.25
Tetracycline                                    0.25
Linezolid (c)                                   1
Cotrimoxazole (b)        [less than or equal to]0.25

                             Southeast (n = 433)
                                 MIC (mg/L)
                                     90                    %I       %R

Penicillin               [less than or equal to]0.06    0.0         0.0
Amoxicillin-clavulanate  [less than or equal to]0.12  predicted by
                                                        penicillin
Cefuroxime               [less than or equal to]0.12  predicted by
                                                        penicillin
Clindamycin              [less than or equal to]0.25    0.2         0.5
Azithromycin                                    0.25    0.0         4.4
Clarithromycin                                  0.06    0.0         4.4
Erythromycin                                    0.12    0.0         4.4
Telithromycin (b)                               0.03     N/A         N/A
Levofloxacin                                    1       0.0         0.0
Gatifloxacin                                    0.25    0.0         0.0
Tetracycline                                    0.5     0.5         9.0
Linezolid (c)                                    2       N/A         N/A
Cotrimoxazole (b)                                1       N/A         N/A

                             Southwest (n = 501)
                                 MIC (mg/L)
                                    50

Penicillin               [less than or equal to]0.06
Amoxicillin-clavulanate  [less than or equal to]0.12
Cefuroxime               [less than or equal to]0.12
Clindamycin              [less than or equal to]0.25
Azithromycin                                    0.25
Clarithromycin                                  0.06
Erythromycin             [less than or equal to]0.06
Telithromycin (b)                               0.03
Levofloxacin                                    0.5
Gatifloxacin                                    0.25
Tetracycline                                    0.25
Linezolid (c)                                   1
Cotrimoxazole (b)        [less than or equal to]0.25

                             Southwest (n = 501)
                                 MIC (mg/L)
                                     90                    %I       %R

Penicillin               [less than or equal to]0.06    0.0         0.0
Amoxicillin-clavulanate  [less than or equal to]0.12  predicted by
                                                        penicillin
Cefuroxime               [less than or equal to]0.12  predicted by
                                                        penicillin
Clindamycin              [less than or equal to]0.25    0.2         0.4
Azithromycin                                    0.25    0.2         3.8
Clarithromycin                                  0.06    0.0         3.8
Erythromycin                                    0.12    0.0         3.8
Telithromycin (b)                               0.03     N/A         N/A
Levofloxacin                                    1       0.0         0.0
Gatifloxacin                                    0.5     0.0         0.0
Tetracycline                                    0.25    0.2         7.6
Linezolid (c)                                   2        N/A         N/A
Cotrimoxazole (b)                               0.5      N/A         N/A
(a) %1. % of isolates with intermediate resistant: MIC, minimum
inhibitory concentration: NCCLS, National Committee for Clinical
Laboratory Standards.
(b) There are currently no NCCLS breakpoints for telithromycin
or cotrimoxazole
(c) NCCLS currently defines susceptibility to linezolid as an MIC of
[less than or equal to]2 mg/L: no intermediate or resistant breakpoints
have been defined.

Table 4.  Macrolide-resistant isolates of S. pyogenes from the southern
United States (a)

                                     Macrolide
                                    susceptibility (b)
                                       (%)
                          No. of     S     I    R
                          isolates

Alabama                        45   91.1  0.0   8.9
Arkansas                       39  100.0  0.0   0.0
Louisiana                      38   94.8  2.6   2.6
Oklahoma                       59   98.3  0.0   1.7
Tennessee                     170   92.4  0.0   7.6
Texas                         170   94.7  0.0   5.3
  South-central               521   94.4  0.2   5.4
Florida                       164   93.3  0.0   6.7
Georgia                        86   98.8  0.0   1.2
Kentucky                       20   95.0  0.0   5.0
North Carolina                 80   95.0  0.0   5.0
South Carolina                  1  100.0  0.0   0.0
Virginia                       23  100.0  0.0   0.0
West Virginia                  39   97.4  0.0   2.6
 Southeast                433 (c)   95.6  0.0   4.4
Arizona                        19   89.5  0.0  10.5
California                    280   97.1  0.0   2.9
Colorado                       29  100.0  0.0   0.0
Nevada                         14  100.0  0.0   0.0
New Mexico                     80   90.0  0.0  10.0
Utah                           79   98.7  0.0   1.3
  Southwest                    501  96.2  0.0   3.8
  Southern United States     1,455  95.4  0.1   4.5
(a) S, susceptible: 1. intermediate: R, resistant: MIC, minimum
inhibitory concentration.
(b) Erythromycin breakpoints: susceptible, MIC
[less than or equal to]0.25 mg/L: intermediate, MIC 0.5 mg/L: resistant,
MIC [greater than or equal to]1 mg/L..
(c) Twenty isolates also collected from Puerto Rico; data not shown.

Table 5. [beta]-lactamase status of South-central, Southeast, and
Southwest U.S. clinical isolates of H. influenzae (a)

                 No. of    [beta]-lactamase-  BLNAR    [beta]
                 isolates  negative (%)        (%)     lactamase-
                                                        positive (%)

Alabama             61       75.4               1 (1.6)  24.6

Arkansas            23       87.0               1 (4.3)  13.0

Louisiana           18       55.6                  0     44.4

Oklahoma            25       60.0               1 (4.0)  40.0

Tennessee          131       64.9               2 (1.5)  35.1

Texas              132       77.3                  0     22.7

  South-central    390       71.3               5 (1.3)  28.7

Florida            140       79.3               1 (0.7)  20.7

Georgia             34       64.7                  0     35.3

Kentucky            18       72.2                  0     27.8

North Carolina      48       79.2                  0     20.8

South Carolina      13       84.6                  0     15.4

Virginia            26       73.1                  0     26.9

West Virginia       27       63.0               2 (7.4)  37.0

  Southeast        306       75.5               3 (1.0)  24.5

Arizona             15       66.7               1 (6.7)  33.3

California         193       76.7               1 (0.5)  23.3

Colorado            18       72.2                    0   27.8

Nevada              15       93.3                    0    6.7

New Mexico          58       70.7               1 (1.7)  29.3

Utah                47       72.3                    0   27.7

  Southwest        346       75.1               3 (0.9)  24.9

  Southern        1,042      73.8              11 (1.1)  26.2
United States

(a) BLNAR, [beta]-lactamase-negative, ampicillin-resistant.

Table 6. Activity of tested antimicrobials against clinical isolates of
H. influenzae from the Southern United States, according to [beta]-
lactamase status (a,b)

MIC (mg/L)
Antimicrobial and                   50
[beta]-lactamase status

Ampicillin
  All isolates           [less than or equal to]0.5
  [beta]-lactamase       [less than or equal to]0.5
  [beta]-lactamase+                            >128
Amoxicillin-clavulanate
  All isolates           [less than or equal to]0.5
  [beta]-lactamase-      [less than or equal to]0.5
  [beta]-lactamase+      [less than or equal to]0.5
Cefprozil (d)
  All isolates                                    4
  [beta]-lactamase-                               2
  [beta]-lactamase+                               8
Cefuroxime
  All isolates                                    1
  [beta]-lactamase                                1
  [beta]-lactamase+                             0.5
Cefotaxime
  All isolates          [less than or equal to]0.12
  [beta]-lactamase-     [less than or equal to]0.12
  [beta]-lactamase+     [less than or equal to]0.12
Clarithromycin
  All isolates                                    8
  [beta]-lactamase-                               8
  [beta]-lactamase+                               8
Azithromycin
  All isolates                                    2
  [beta]-lactamase-                               2
  [beta]-lactamase+                               2
Telithromycin
  All isolates                                    2
  [beta]-lactamase-                               2
  [beta]-lactamase+                               2
Levofloxacin
  All isolates          [less than or equal to]0.06
  [beta]-lactamase-     [less than or equal to]0.06
  [beta]-lactamase+     [less than or equal to]0.06
Gatifloxacin
  All isolates          [less than or equal to]0.03
  [beta]-lactamase-     [less than or equal to]0.03
  [beta]-lactamase+     [less than or equal to]0.03
Moxifloxacin
  All isolates          [less than or equal to]0.03
  [beta]-lactamase-     [less than or equal to]0.03
  [beta]-lactamase+     [less than or equal to]0.03
Tetracycline
  All isolates                                  0.5
  [beta]-lactamase-                             0.5
  [beta]-lactamase+                             0.5
Linezolid (f)
  All isolates                                   16
  [beta]-lactamase-                              16
  [beta]-lactamase+                              16

                                All (n = 1042)
                               ([beta]-lactamase-, n = 769;
                                [beta]-lactamase+, n = 273)
MIC (mg/L)                                MIC (mg/L)

Antimicrobial and                                  90   %I    %R
[beta]-lactamase status

Ampicillin
  All isolates                                   >128   0.6  27.1
  [beta]-lactamase                                  1   0.5   1.4
  [beta]-lactamase+                              >128   0.7  99.3
Amoxicillin-clavulanate
  All isolates                                      1     -   0.2
  [beta]-lactamase-                                 1     -   0.3
  [beta]-lactamase+                                 1     -   0.0
Cefprozil (d)
  All isolates                                     >8  19.4     -
  [beta]-lactamase-                                >8  12.6     -
  [beta]-lactamase+                                >8  38.5     -
Cefuroxime
  All isolates                                      4   2.8   0.8
  [beta]-lactamase                                  4   3.0   0.9
  [beta]-lactamase+                                 2   2.2   0.4
Cefotaxime
  All isolates            [less than or equal to]0.12     0     0
  [beta]-lactamase-       [less than or equal to]0.12   0.0   0.0
  [beta]-lactamase+       [less than or equal to]0.12   0.0   0.0
Clarithromycin
  All isolates                                     16  28.0   6.6
  [beta]-lactamase-                                16  26.8   6.5
  [beta]-lactamase+                                16  31.5   7.0
Azithromycin
  All isolates                                      4     -     -
  [beta]-lactamase-                                 4     -     -
  [beta]-lactamase+                                 4     -     -
Telithromycin
  All isolates                                      4   3.5   0.8
  [beta]-lactamase-                                 4   3.8   0.7
  [beta]-lactamase+                                 4   2.6   1.1
Levofloxacin
  All isolates            [less than or equal to]0.06     -     -
  [beta]-lactamase-       [less than or equal to]0.06     -     -
  [beta]-lactamase+       [less than or equal to]0.06     -     -
Gatifloxacin
  All isolates            [less than or equal to]0.03     -     -
  [beta]-lactamase-       [less than or equal to]0.03     -     -
  [beta]-lactamase+       [less than or equal to]0.03     -     -
Moxifloxacin
  All isolates            [less than or equal to]0.03     -     -
  [beta]-lactamase-       [less than or equal to]0.03     -     -
  [beta]-lactamase+       [less than or equal to]0.03     -     -
Tetracycline
  All isolates                                    0.5   0.0   1.0
  [beta]-lactamase-                               0.5   0.0   0.7
  [beta]-lactamase+                               0.5   0.0   1.8
Linezolid (f)
  All isolates                                     32     -     -
  [beta]-lactamase-                                32     -     -
  [beta]-lactamase+                                32     -     -

                           South-central (n = 390)
                           ([beta]-lactamase-, n = 278;
                           [beta]-lactamase+, n = 112)

                           MIC (mg/L)
Antimicrobial and
[beta]-lactamase status  50

Ampicillin
  All isolates           [less than or equal to]0.5
  [beta]-lactamase       [less than or equal to]0.5
  [beta]-lactamase+                            >128
Amoxicillin-clavulanate
  All isolates           [less than or equal to]0.5
  [beta]-lactamase-      [less than or equal to]0.5
  [beta]-lactamase+      [less than or equal to]0.5
Cefprozil (d)
  All isolates                                    4
  [beta]-lactamase-                               2
  [beta]-lactamase+                               8
Cefuroxime
  All isolates                                    1
  [beta]-lactamase                                1
  [beta]-lactamase+                             0.5
Cefotaxime
  All isolates           [less than or equal to]0.12
  [beta]-lactamase-      [less than or equal to]0.12
  [beta]-lactamase+      [less than or equal to]0.12
Clarithromycin
  All isolates                                     8
  [beta]-lactamase-                                8
  [beta]-lactamase+                                8
Azithromycin
  All isolates                                     2
  [beta]-lactamase-                                2
  [beta]-lactamase+                                2
Telithromycin
  All isolates                                     2
  [beta]-lactamase-                                2
  [beta]-lactamase+                                2
Levofloxacin
  All isolates           [less than or equal to]0.06
  [beta]-lactamase-      [less than or equal to]0.06
  [beta]-lactamase+      [less than or equal to]0.06
Gatifloxacin
  All isolates           [less than or equal to]0.03
  [beta]-lactamase-      [less than or equal to]0.03
  [beta]-lactamase+      [less than or equal to]0.03
Moxifloxacin
  All isolates           [less than or equal to]0.03
  [beta]-lactamase-      [less than or equal to]0.03
  [beta]-lactamase+      [less than or equal to]0.03
Tetracycline
  All isolates                                   0.5
  [beta]-lactamase-                              0.5
  [beta]-lactamase+                              0.5
Linezolid (f)
  All isolates                                    16
  [beta]-lactamase-                               16
  [beta]-lactamase+                               16

                           South-central (n = 390)
                           ([beta]-lactamase-, n = 278;
                           [beta]-lactamase+, n = 112)

                          MIC (mg/L)
Antimicrobial and         90     %I    %R
[beta]-lactamase status

Ampicillin
  All isolates                                   >128   0.5  30.0
  [beta]-lactamase                                  1     1   0.7
  [beta]-lactamase+                              >128     0   100
Amoxicillin-clavulanate
  All isolates                                      1     -   0.3
  [beta]-lactamase-                                 1     -   0.4
  [beta]-lactamase+                                 1     -   0.0
Cefprozil (d)
  All isolates                                    >8  22.6     -
  [beta]-lactamase-                               >8  15.5     -
  [beta]-lactamase+                               >8  40.2     -
Cefuroxime
  All isolates                                     4   3.1   0.8
  [beta]-lactamase                                 4   3.2   0.7
  [beta]-lactamase+                                2   2.7   0.9
Cefotaxime
  All isolates           [less than or equal to]0.12     0     0
  [beta]-lactamase-      [less than or equal to]0.12     0     0
  [beta]-lactamase+      [less than or equal to]0.12     0     0
Clarithromycin
  All isolates                                    16  25.9   7.7
  [beta]-lactamase-                               16  23.7   7.6
  [beta]-lactamase+                               16  31.3   8.0
Azithromycin
  All isolates                                     4     -     -
  [beta]-lactamase-                                4     -     -
  [beta]-lactamase+                                4     -     -
Telithromycin
  All isolates                                     4   4.1   0.8
  [beta]-lactamase-                                4   5.0   0.7
  [beta]-lactamase+                                4   1.8   0.9
Levofloxacin
  All isolates           [less than or equal to]0.06     -     -
  [beta]-lactamase-      [less than or equal to]0.06     -     -
  [beta]-lactamase+      [less than or equal to]0.06     -     -
Gatifloxacin
  All isolates           [less than or equal to]0.03     -     -
  [beta]-lactamase-      [less than or equal to]0.03     -     -
  [beta]-lactamase+      [less than or equal to]0.03     -     -
Moxifloxacin
  All isolates           [less than or equal to]0.03     -     -
  [beta]-lactamase-      [less than or equal to]0.03     -     -
  [beta]-lactamase+      [less than or equal to]0.06     -     -
Tetracycline
  All isolates                                   0.5     0   1.5
  [beta]-lactamase-                              0.5     0   0.7
  [beta]-lactamase+                              0.5   0.0   3.6
Linezolid (f)
  All isolates                                    32     -     -
  [beta]-lactamase-                               32     -     -
  [beta]-lactamase+                               32     -     -

                             Southeast (n = 306)
                             ([beta]-lactamase-, n = 231;
                             [beta]-lactamase+, n = 75)
                              MIC (mg/L)

Antimicrobial and                     50
[beta]-lactamase status

Ampicillin
  All isolates            [less than or equal to]0.5
  [beta]-lactamase                               1.8
  [beta]-lactamase+                             >128
Amoxicillin-clavulanate
  All isolates            [less than or equal to]0.5
  [beta]-lactamase-       [less than or equal to]0.5
  [beta]-lactamase+       [less than or equal to]0.5
Cefprozil (d)
  All isolates                                     4
  [beta]-lactamase-                                2
  [beta]-lactamase+                                8
Cefuroxime
  All isolates                                   0.5
  [beta]-lactamase                               0.5
  [beta]-lactamase+                              0.5
Cefotaxime
  All isolates           [less than or equal to]0.12
  [beta]-lactamase-      [less than or equal to]0.12
  [beta]-lactamase+      [less than or equal to]0.12
Clarithromycin
  All isolates                                     8
  [beta]-lactamase-                                8
  [beta]-lactamase+                                8
Azithromycin
  All isolates                                     2
  [beta]-lactamase-                                2
  [beta]-lactamase+                                2
Telithromycin
  All isolates                                     2
  [beta]-lactamase-                                2
  [beta]-lactamase+                                2
Levofloxacin
  All isolates           [less than or equal to]0.06
  [beta]-lactamase-      [less than or equal to]0.06
  [beta]-lactamase+      [less than or equal to]0.06
Gatifloxacin
  All isolates           [less than or equal to]0.03
  [beta]-lactamase-      [less than or equal to]0.03
  [beta]-lactamase+      [less than or equal to]0.03
Moxifloxacin
  All isolates           [less than or equal to]0.03
  [beta]-lactamase-      [less than or equal to]0.03
  [beta]-lactamase+      [less than or equal to]0.03
Tetracycline
  All isolates                                   0.5
  [beta]-lactamase-                              0.5
  [beta]-lactamase+                              0.5
Linezolid (f)
  All isolates                                    16
  [beta]-lactamase-                               16
  [beta]-lactamase+                               16

                             Southeast (n = 306)
                             ([beta]-lactamase-,n = 231;
                             [beta]-lactamase+, n = 75)
                              MIC (mg/L)

Antimicrobial and                    90                %I    %R
[beta]-lactamase status

Ampicillin
  All isolates                                  >128   0.7  25.2
  [beta]-lactamase        [less than or equal to]0.5     1   0.4
  [beta]-lactamase+                             >128   1.3  98.7
Amoxicillin-clavulanate
  All isolates                                      1    -   0.0
  [beta]-lactamase-                                1     -   0.0
  [beta]-lactamase+                                1     -   0.0
Cefprozil (d)
  All isolates                                    >8  15.0     -
  [beta]-lactamase-                                8   8.7     -
  [beta]-lactamase+                               >8  34.7     -
Cefuroxime
  All isolates                                     4   2.0   0.7
  [beta]-lactamase                                 4   2.2   0.9
  [beta]-lactamase+                                2   1.3   0.0
Cefotaxime
  All isolates           [less than or equal to]0.12   0.0   0.0
  [beta]-lactamase-      [less than or equal to]0.12   0.0   0.0
  [beta]-lactamase+      [less than or equal to]0.12   0.0   0.0
Clarithromycin
  All isolates                                    16  31.0   5.2
  [beta]-lactamase-                               16  31.6   4.3
  [beta]-lactamase+                               16  29.3   8.0
Azithromycin
  All isolates                                     4     -     -
  [beta]-lactamase-                                4     -     -
  [beta]-lactamase+                                4     -     -
Telithromycin
  All isolates                                     4   2.3   1.0
  [beta]-lactamase-                                4   2.2   0.4
  [beta]-lactamase+                                4   2.7   2.7
Levofloxacin
  All isolates           [less than or equal to]0.06     -     -
  [beta]-lactamase-      [less than or equal to]0.06     -     -
  [beta]-lactamase+      [less than or equal to]0.06     -     -
Gatifloxacin
  All isolates           [less than or equal to]0.03     -     -
  [beta]-lactamase-      [less than or equal to]0.03     -     -
  [beta]-lactamase+      [less than or equal to]0.03     -     -
Moxifloxacin
  All isolates           [less than or equal to]0.03     -     -
  [beta]-lactamase-      [less than or equal to]0.03     -     -
  [beta]-lactamase+      [less than or equal to]0.03     -     -
Tetracycline
  All isolates                                   0.5   0.0   0.0
  [beta]-lactamase-                              0.5   0.0   0.0
  [beta]-lactamase+                              0.5   0.0   0.0
Linezolid (f)
  All isolates                                    32     -     -
  [beta]-lactamase-                               32     -     -
  [beta]-lactamase+                               32     -     -

                             Southwest (n = 346)
                             ([beta]-lactamase-, n = 260;
                             [beta]-lactamase+, n = 86)
                             MIC (mg/L)
Antimicrobial and                     50
[beta]-lactamase status

Ampicillin
  All isolates           [less than or equal to]0.5
  [beta]-lactamase                              1.3
  [beta]-lactamase+                            >128
Amoxicillin-clavulanate
  All isolates           [less than or equal to]0.5
  [beta]-lactamase-      [less than or equal to]0.5
  [beta]-lactamase+      [less than or equal to]0.5
Cefprozil (d)
  All isolates                                    4
  [beta]-lactamase-                               4
  [beta]-lactamase+                               8
Cefuroxime
  All isolates                                    1
  [beta]-lactamase                                1
  [beta]-lactamase+                               1
Cefotaxime
  All isolates          [less than or equal to]0.12
  [beta]-lactamase-     [less than or equal to]0.12
  [beta]-lactamase+     [less than or equal to]0.12
Clarithromycin
  All isolates                                    8
  [beta]-lactamase-                               8
  [beta]-lactamase+                               8
Azithromycin
  All isolates                                    2
  [beta]-lactamase-                               2
  [beta]-lactamase+                               2
Telithromycin
  All isolates                                    2
  [beta]-lactamase-                               2
  [beta]-lactamase+                               2
Levofloxacin
  All isolates          [less than or equal to]0.06
  [beta]-lactamase-     [less than or equal to]0.06
  [beta]-lactamase+     [less than or equal to]0.06
Gatifloxacin
  All isolates          [less than or equal to]0.03
  [beta]-lactamase-     [less than or equal to]0.03
  [beta]-lactamase+     [less than or equal to]0.03
Moxifloxacin
  All isolates          [less than or equal to]0.03
  [beta]-lactamase-     [less than or equal to]0.03
  [beta]-lactamase+     [less than or equal to]0.03
Tetracycline
  All isolates                                 0.5
  [beta]-lactamase-                            0.5
  [beta]-lactamase+                            0.5
Linezolid (f)
  All isolates                                  16
  [beta]-lactamase-                             16
  [beta]-lactamase+                             16

                         Southwest (n = 346)
                         ([beta]-lactamase-,
                          n = 260; [beta]-lactamase+, n = 86)
                          MIC (mg/L)

Antimicrobial and                     90                %I    %R
[beta]-lactamase status

Ampicillin
  All isolates                                   >128   0.6  25.4
  [beta]-lactamase         [less than or equal to]0.5     1   0.4
  [beta]-lactamase+                              >128   1.2  98.8
Amoxicillin-clavulanate
  All isolates                                      1     -   0.3
  [beta]-lactamase-                                 1     -   0.4
  [beta]-lactamase+                                 1     -   0.0
Cefprozil (d)
  All isolates                                     >8  19.7     -
  [beta]-lactamase-                                >8  13.1     -
  [beta]-lactamase+                                >8  39.5     -
Cefuroxime
  All isolates                                      2   3.2   0.9
  [beta]-lactamase                                  4   3.5   1.2
  [beta]-lactamase+                                 2   2.3   0.0
Cefotaxime
  All isolates            [less than or equal to]0.12   0.0   0.0
  [beta]-lactamase-       [less than or equal to]0.12   0.0   0.0
  [beta]-lactamase+       [less than or equal to]0.12   0.0   0.0
Clarithromycin
  All isolates                                     16  27.7   6.6
  [beta]-lactamase-                                16  25.8   7.3
  [beta]-lactamase+                                16  33.7   4.7
Azithromycin
  All isolates                                      4     -     -
  [beta]-lactamase-                                 4     -     -
  [beta]-lactamase+                                 4     -     -
Telithromycin
  All isolates                                      4   3.8   0.6
  [beta]-lactamase-                                 4   3.9   0.8
  [beta]-lactamase+                                 4   3.5   0.0
Levofloxacin
  All isolates            [less than or equal to]0.06     -     -
  [beta]-lactamase-       [less than or equal to]0.06     -     -
  [beta]-lactamase+       [less than or equal to]0.06     -     -
Gatifloxacin
  All isolates            [less than or equal to]0.03     -     -
  [beta]-lactamase-       [less than or equal to]0.03     -     -
  [beta]-lactamase+       [less than or equal to]0.03     -     -
Moxifloxacin
  All isolates            [less than or equal to]0.03     -     -
  [beta]-lactamase-       [less than or equal to]0.03     -     -
  [beta]-lactamase+       [less than or equal to]0.03     -     -
Tetracycline
  All isolates                                    0.5   0.0   1.2
  [beta]-lactamase-                               0.5   0.0   1.2
  [beta]-lactamase+                               0.5   0.0   1.2
Linezolid (f)
  All isolates                                     32     -     -
  [beta]-lactamase-                                32     -     -
  [beta]-lactamase+                                16     -     -

(a) MIC, minimum inhibitory concentration: %1, % of isolates with
intermediate resistance. %R, % of isolates resistant: NCCLS. National
Committee for Clinical Laboratory Standards.
(b) [beta]-lactamase negative: South-central, n = 278; Southeast, n
=229; Southwest, n = 260; [beta]-lactamase positive: South-central, n =
112; Southeast, n = 77, Southwest, n = 86.
(c) No NCCLS intermediate breakpoint.
(d) Cefprozil was tested up to 16 mg/L: the number of resistant isolates
(MIC [greater than or equal to] 32 mg/L) cannot be determined.
(e) No NCCLS intermediate or resistant breakpoints.
(f) No NCCLS breakpoints are currently available.

Acknowledgments

We thank the investigators across the southern states who provided clinical isolates for the PROTEKT US study. We also thank the researchers of CMI (Portland, OR) for their analysis of the isolates, and Micron Research (Upwell, Cambridgeshire, UK) for data analysis and assistance with manuscript preparation.

From the Department of Pathology, University of Alabama at Birmingham, Birmingham, AL., and the Clinical Microbiology Institute, Portland. OR.

The PROTEKT US study is funded by Aventis, 300 Somerset Corporate Boulevard, Bridgewater. NJ. The authors have no proprietary interest in any drug, device, or equipment mentioned in this article.

Reprint requests to Ken Waites, MD, Director of Clinical Microbiology, Department of Pathology WP230, University of Alabama at Birmingham, 619 S. 19th Street, Birmingham, AL 35233-7331. Email: [e-mail]

Accepted July 9, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9610-0974

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RELATED ARTICLE: Key Points

* The 75 centers from the southern United States enrolled in the first year of PROTEKT US (2000-2001) submitted a total of 6364 isolates of S. pneumoniae, H. influenzae and S. pyogenes.

* Among S. pneumoniae penicillin non-susceptibility and erythromycin resistance was variable, ranging from 31.6-64.5% and 20-56.2% respectively between the southern states.

* The incidence of [beta]-lactamase production in H. influenzae among southern states ranged from 6.7% to 44.4% of isolates.

* A total of 99.7% of S. pneumoniae were susceptible to telithromycin and 99.9% of S. pyogenes isolates were inhibited at a MIC of [less than or equal to] 1 mg/L.

* Telithromycin was potent against H. influenzae (95.8% of all isolates susceptible to telithromycin at MIC[less than or equal to] 4 mg/L) irrespective of [beta]-lactamase production.

Ken Waites, MD, and Steve Brown, PHD