Penicillin-resistant Pneumococcal Strains Research Articles

Austrian syndrome and multiple myeloma: A fatal combination

Austrian syndrome and multiple myeloma: A fatal combination

The Impact of the Heptavalent Pneumococcal Conjugate Vaccine on the Epidemiology of Acute Otitis Media Complicated by Otorrhea

The heptavalent pneumococcal conjugate vaccine (PCV7) has a considerable effect on the epidemiology of pneumococcal disease. The aim of this observational hospital-based study was to examine the effect of the PCV7 (introduced in our settings in 2004) on the epidemiology of spontaneously draining acute otitis media. Results of all middle ear fluid cultures (n = 3446) obtained from children with acute otitis media complicated with otorrhea before the introduction of immunization (between 2000 and 2003) were compared with those (n = 2134) obtained during a similar post-PCV7 period (between 2005 and 2008). Results of cultures obtained between 2006 and 2008 were examined prospectively, whereas those obtained in previous years were retrospectively reviewed. Following PCV7 immunization, the rates of otorrhea visits per 10,000 emergency department visits decreased by 38% from 133 to 83 (95% confidence interval of the difference, 42-53; P < 0.001), mainly as a result of the decrease in the incidence of pneumococcal disease (48% decrease-25 vs. 13 per 10,000 emergency department visits; P < 0.001). Otorrhea due to Haemophilus influenzae decreased by 20% (20-16 per 10,000 visits; P < 0.001). Serotype 19A accounted for 1 of 47 (2%) pneumococcal strains in 2006, for 5 of 34 (15%) in 2007, and for 13 of 53 (25%) in 2008 (P for trend: 0.001). In the postvaccine years, penicillin-resistant pneumococcal strains (minimum inhibitory concentration ≥ 2 μg/mL) increased from 4% to 13% (P < 0.001). However, the proportion of pneumococci resistant to macrolides decreased (44% vs. 35%; P = 0.01). After the introduction of immunization, otorrhea incidents decreased considerably, mainly because of the decrease in pneumococcal disease. H. influenzae is now the predominant organism. Serotype 19A has increased significantly and is the most common nonvaccine pneumococcal serotype. Penicillin resistance has increased in recent years.

Emergence of a multidrug-resistant clone (ST320) among invasive serotype 19A pneumococci in Spain

Multidrug-resistant Streptococcus pneumoniae isolates of serotype 19A have emerged all over the world in recent years. The aim of this study was to characterize highly penicillin-resistant pneumococcal strains of the 19A serotype, collected in Spain from 1997 to 2007 from patients with invasive disease. Antibiotic susceptibility was studied by microdilution. All penicillin-resistant pneumococci were typed by PFGE and selected strains were studied by multilocus sequence typing (MLST). The presence of genes related to the Tn916 family of transposons was investigated by PCR. From a total of 1197 invasive pneumococcal isolates of serotype 19A received at the Spanish Reference Laboratory between 1997 and 2007, 51 (4.3%) strains showed high-level resistance to penicillin (MICs of 2-4 mg/L). These 51 isolates belonged to three multiresistant clones related to sequence type (ST)81 (n = 21), ST320 (n = 19) and ST276 (n = 11). All 51 serotype 19A pneumococci were tetracycline-resistant and had the tet(M) gene, and 41 strains were macrolide-resistant, harbouring the erm(B) gene. The presence of int and xis genes was detected in all strains associated with other genes of the Tn916 family. The rise in penicillin-resistant serotype 19A invasive pneumococci in Spain was associated with the emergence and clonal spread of two worldwide-disseminated multiresistant clones (ST276 and ST320). The Spain(23F)-1-19A (ST81) clone remained stable throughout the study period. Multidrug resistance was associated with transposons of the Tn916 family.

In Vitro and In Vivo Activity of Miltefosine Against Penicillin-Sensitive and -Resistant Streptococcus pneumoniae Strains

The in vitro and in vivo activity of miltefosine against penicillin-sensitive and penicillin-resistant pneumococcal strains was studied. The minimum inhibitory concentrations (MICs) of miltefosine were determined in cation-adjusted Mueller Hinton plus 2% lysed horse blood (CAMHB) and in Todd-Hewitt (TH) broth. The respective MICs were higher using CAMHB (128 and 64 mg/L) than using TH broth (4 and 8 mg/L). The In Vivo activity was studied in a murine peritonitis-sepsis model. Miltefosine was orally administered at doses of 15 and 30 mg/kg/day after, at the time of, and before bacterial challenge for 3-5 days. All control and 16 out of the 17 (94.1%) miltefosine-treated animals that were inoculated with the penicillin-sensitive strain died. No survival was observed among control and miltefosine-treated animals inoculated with the penicillin-resistant pneumococcal strain. The In Vivo unresponsiveness of miltefosine in this sepsis model could be attributed to some inhibitory effect of blood, inadequate pharmacokinetics and/or the extracellular localization of the pneumococcus.

β-Lactam Activity against Penicillin-Resistant Streptococcus pneumoniae Strains Exhibiting Higher Amoxicillin versus Penicillin Minimum Inhibitory Concentration Values: An in vitro Pharmacodynamic Simulation

Background: Activity of simulated serum concentrations after oral therapy with 400 mg cefditoren pivoxil b.i.d., 500 mg cefuroxime axetil b.i.d. and 875/125 mg amoxicillin/clavulanic acid b.i.d. and t.i.d. regimens was explored over 24 h against Streptococcus pneumoniae.Methods: Computerized pharmacodynamic simulations were performed against strains with penicillin/amoxicillin/cefuroxime/cefditoren minimum inhibitory concentrations (MICs, µg/ml) and serotypes: strain 1 (0.25/0.12/1/0.12; serotype 6A), strain 2 (2/4/ 2/0.25; serotype 6B), strain 3 (4/16/4/0.5; serotype 14), and strain 4 (4/16/8/1; serotype 14). Results: Bactericidal activity (≧3 log₁₀ reduction) at 12 and 24 h was obtained against all strains with cefditoren, against strains 1 and 2 with cefuroxime and amoxicillin/clavulanic acid t.i.d., but only against strain 1 with amoxicillin/clavulanic acid b.i.d.. Bactericidal activity at 24 h was related to T > MIC of >30% dosing interval, 1.7–2.0 log₁₀ reductions with T > MIC of 20–30%, and <1 log₁₀ reduction or regrowth with T > MIC of 0%. Conclusions: It is difficult to achieve pharmacodynamic coverage and bactericidal activity by physiological concentrations of oral β-lactams against penicillin-resistant pneumococcal strains exhibiting higher amoxicillin versus penicillin MICs. Cefditoren may offer alternatives.

Incremental Increase in Fitness Cost with Increased β‐Lactam Resistance in Pneumococci Evaluated by Competition in an Infant Rat Nasal Colonization Model

We evaluated the impact of resistant penicillin-binding protein (PBP) allele acquisition on the ability of penicillin-resistant (PEN-R) pneumococcal strains to compete with penicillin-susceptible (PEN-S) ancestors for upper-respiratory-tract (URT) colonization. PEN-S serotype 2, 6B, and 9V strains were transformed into derivatives expressing an increasing number of PEN-R PBP forms (2X, 2X-1A, and 2X-1A-2B for serotype 2 and 2X, 2X-2B, and 2X-2B-1A for 6B and 9V). Infant rats were inoculated intranasally with a mix of a PEN-R and PEN-S strains. For consecutive days, samples were collected for assessment of the ratio of PEN-S to PEN-R cells colonizing the URT. The selective index (SI), defined as the change in the natural logarithm of the ratio of PEN-S to PEN-R strains from the inoculum to the nasal-wash samples, quantified differences in fitness. SIs significantly > 0 (indicating a cost of resistant allele acquisition) were observed 4-5 days after colonization in all but serotype 6B pbp2x transfomants. Additional replacements with low-affinity forms of pbp2b and pbp1a genes reduced further ability to compete in all strains. The cost of penicillin-resistance acquisition for the Streptococcus pneumoniae strain competing with its susceptible ancestor to colonize the URT increases with the number of resistant pbp alleles acquired.

Efficacy of Telavancin against Penicillin-Resistant Pneumococci and Staphylococcus aureus in a Rabbit Meningitis Model and Determination of Kinetic Parameters

The penetration of telavancin was 2% into inflamed meninges and ca. 1 per thousand into noninflamed meninges after two intravenous injections (30 mg/kg of body weight). In experimental meningitis, telavancin was significantly superior to vancomycin combined with ceftriaxone against a penicillin-resistant pneumococcal strain. Against a methicillin-sensitive staphylococcal strain, telavancin was slightly but not significantly superior to vancomycin.

Preincubation of Pneumococci with β-Lactams Alone or Combined with Levofloxacin Prevents Quinolone-Induced Resistance without Increasing Intracellular Levels of Levofloxacin

Preincubation of pneumococci with sub-MIC concentrations of ceftriaxone (1/16x MIC), cefotaxime (1/8x MIC), and meropenem (1/4x MIC) alone or combined with levofloxacin (1/8x MIC) over 6 h prevents the emergence of levofloxacin-resistant mutants after 96 h of incubation but does not affect the intracellular accumulation of levofloxacin in two penicillin-resistant pneumococcal strains, suggesting a link between the mechanism of action of beta-lactams and the emergence of quinolone-induced resistance in pneumococci.

Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci.

Ceftriaxone acted synergistically with levofloxacin in time-killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L). Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25. In the experimental rabbit meningitis model, ceftriaxone (1x 125 mg/kg) was slightly less bactericidal (-0.30 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) cfu/mL(.)h) to either monotherapy. In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4. After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC). In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively. The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains.

A technique permitting selection of penicillin-susceptible pneumococcal strains following transformation of a penicillin-resistant strain with a penicillin-susceptibility gene

We report a technique useful for transformation experiments involving bacteria naturally competent for DNA transformation. It allows the selection of antibiotic-susceptible transformants following the transformation of a resistant strain with an antibiotic susceptibility gene. We show the effectiveness of this technique through the selection of penicillin-susceptible (MIC, 0.03 μg/ml) transformants following the transformation of a penicillin-resistant (MIC, 16 μg/ml) pneumococcal strain with a penicillin-susceptibility gene.

Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro.

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (-0.47 Deltalog(10) CFU/ml. h) which was comparable to that of levofloxacin (-0.49 Deltalog(10) CFU/ml. h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (-1.04 Deltalog(10) CFU/ml. h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (parC and parE) and gyrase (gyrA and gyrB) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.

Gemifloxacin is efficacious against penicillin-resistant and quinolone-resistant pneumococci in experimental meningitis.

In experimental rabbit meningitis, gemifloxacin penetrated inflamed meninges well (22 to 33%) and produced excellent bactericidal activity (change in log(10) [Deltalog(10)] CFU/ml/h, -0.68 +/- 0.30 [mean and standard deviation]), even superior to that of the standard regimen of ceftriaxone plus vancomycin (-0.49 +/- 0.09 deltalog(10) CFU/ml/h), in the treatment of meningitis due to a penicillin-resistant pneumococcal strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, gemifloxacin showed good bactericidal activity (-0.48 +/- 0.16 deltalog(10) CFU/ml/h). The excellent antibacterial activity of gemifloxacin was also confirmed by time-kill assays over 8 h in vitro.

Efficacy of gatifloxacin alone and in combination with cefepime against penicillin-resistant Streptococcus pneumoniae in a rabbit meningitis model and in vitro.

Gatifloxacin penetrated well into cerebrospinal fluid (CSF) (49 +/- 11%), measured by comparison of AUC(CSF)/AUC(serum), and showed good bactericidal activity (leading to a decrease of 0.75 +/- 0.17 log10 cfu/mL/h) in the treatment of experimental meningitis in rabbits caused by a penicillin-resistant pneumococcal strain (MIC 4 mg/L). It was significantly more effective than the standard regimen, ceftriaxone with vancomycin, which led to a decrease of 0.53 +/- 0.17 log10 cfu/mL/h. The addition of cefepime to gatifloxacin slightly improved the killing rates (giving a decrease of 0.84 +/- 0.14 log10 cfu/mL/h). In vitro, synergy was demonstrated between cefepime and gatifloxacin by the chequerboard method (fractional inhibitory concentration index = 0.5) and by viable counts over 8 h.

Synergy between Trovafloxacin and Ceftriaxone against Penicillin-Resistant Pneumococci in the Rabbit Meningitis Model and In Vitro

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Meropenem Alone and in Combination with Vancomycin in Experimental Meningitis Caused by a Penicillin-Resistant Pneumococcal Strain

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Increase in penicillin resistance rates in Belgium due to clonal spread of a penicillin-resistant 23F Streptococcus pneumoniae strain.

In 1994 a sudden increase in penicillin resistance was observed in Belgium among invasive pneumococci. To determine whether this increase was due to clonal spread of a resistant strain or to de novo acquisition of penicillin resistance, pneumococci of capsular types 23F, 19, 14, 9, and 6 isolated in 1993 and 1994, were analyzed by capsular serotyping and DNA macrorestriction analysis, resolved by pulsed-field gel electrophoresis. Furthermore, pneumococcal isolates from northern France, a region with a high prevalence of penicillin resistance, and from southern Belgium, a region with a low but increasing prevalence of penicillin resistance, were analyzed. The rate of resistance of invasive pneumococci to penicillin increased from 2.3% in 1993 to 7.6% in 1994. Pneumococcal serotype 23F represented 26.7% of the penicillin-resistant isolates in 1993 and 40.4% in 1994, while the prevalence of serotype 23F decreased from 10.9% in 1993 to 8.8% in 1994. In 1994 up to 35.8% of serotype 23F isolates were penicillin resistant. The Belgian penicillin-resistant 23F isolates from 1994 were genetically closely related to the French 23F penicillin-resistant isolates and, as clones were clearly distinct from the other serotypes as well as from the penicillin-susceptible 23F isolates. These data demonstrate the important contribution of the clonal spread of a penicillin-resistant pneumococcal strain in the overall increase of penicillin resistance in our country.

Pneumococcal Vaccination in the Elderly

Pneumococcal infections, especially pneumococcal pneumonia and pneumococcal bacteraemia are leading causes of morbidity and mortality among the elderly. The emergence of penicillin-resistant pneumococcal strains together with the growing number of old people have emphasised the need for prevention of pneumococcal infections. Prospective cohort studies with pneumonia as the endpoint have so far left open the question of the rationale of vaccinating the risk groups with pneumococcal vaccine. Pneumococcal vaccine has been proven effective against pneumococcal bacteraemia, but the incidence of that disease and thus its importance to the individuals themselves and to the healthcare system is small. Adverse events associated with pneumococcal vaccine are quite frequent but, especially in the elderly, mild and do not limit its use. Clinicians should keep the pneumococcal vaccine in mind and discuss its use with their patients at increased risk for pneumococcal infection. However, before pneumococcal vaccine can be included in national vaccination programmes, its cost-effectiveness in preventing invasive infections must be assured or definitive evidence obtained of its effectiveness against non-invasive pneumococcal infection.

Is Streptococcus pneumoniae a nosocomially acquired pathogen?

Streptococcus pneumoniae is most prominently a major cause of community-acquired infections of the respiratory tract, central nervous system, and bloodstream, but there is an increasing interest in its role in the epidemiology of hospital-acquired infections. Penicillin-resistant pneumococcal strains appeared 3 decades ago and now are present worldwide, often displaying multiple resistance due to antibiotic selective pressure. Horizontal spread can cause either sporadic cases or hospital outbreaks, primarily in younger children and elderly patients. Pneumococcal transmission from one patient to another can be documented by polymerase chain reaction or pulsed-field gel electrophoresis typing. Nosocomial acquisition of infection, along with pediatric age, previous hospitalization, and previous beta-lactam therapy, are the main risk factors significantly associated with penicillin-resistant pneumococcal infections. Nosocomial acquisition also is associated with higher mortality from pneumococcal disease. The importance of penicillin resistance as a risk factor significantly associated with higher mortality from pneumococcal infection is found in some studies, but not in others. Mortality from pneumococcal pneumonia is approximately the same for human immunodeficiency virus (HIV)-infected patients without acquired immunodeficiency syndrome (AIDS) as for HIV-negative subjects, but it is significantly higher in AIDS patients. Penicillin-resistant strains are involved in the vast majority of hospital outbreaks, whether presenting as clinically manifest infection or a simple colonization. Pneumococcal vaccination is recommended universally in order to lower the incidence of invasive infection, although a number of problems can limit its effectiveness.

In Vitro Evaluation of Sparfloxacin Activity and Spectrum Against 24,940 Pathogens Isolated in the United States and Canada, the Final Analysis

Sparfloxacin, a recently marketed oral fluoroquinolone, was tested against 24,940 recent clinical strains isolated from blood stream and respiratory tract cultures at 187 hospitals in the USA and Canada. Sparfloxacin activity was compared with 5 to 13 antimicrobial agents using either Etest (AB BIODISK, Solna, Sweden) and a reference broth microdilution or a standardized disk diffusion method. When applying recommended MIC breakpoint criteria of sparfloxacin susceptibility (≤0.5 μg/mL) for Streptococcus pneumoniae (4,410 strains) and other Streptococcus spp. (554 isolates), 93% and 88% were inhibited, respectively. Furthermore, at ≤1 μg/mL sparfloxacin susceptibility rates for streptococci increased to 98% overall and 99.3% for S. pneumoniae. In contrast, only 46% and 68% of pneumococci were susceptible to ciprofloxacin (MIC 90, 3 μg/mL; susceptible at ≤1 μg/mL) and penicillin (MIC 90, 1.5 μg/mL; susceptible at ≤0.06 μg/mL), respectively. Differences between regions in the USA for rates of penicillin-resistant pneumococcal strains were observed (greatest resistances in southeast and midwest), but results indicate that the sparfloxacin potency was not adversely influenced (MIC 90, 0.5 μg/mL). Also pneumococcal isolates from the lower respiratory tract were more resistant to penicillin and other β-lactams. Nearly all Haemophilus species and Moraxella catarrhalis strains, including those harboring β-lactamases, were susceptible to tested fluoroquinolones (sparfloxacin, ciprofloxacin), amoxicillin/clavulanic acid, and newer oral cephalosporins. Sparfloxacin was very active against oxacillin-susceptible Staphylococcus aureus (MIC 90, 0.12 μg/mL; 96–97% susceptible), Klebsiella spp. (MIC 90 0.12 μg/mL), and other tested enteric bacilli (92–95% susceptible). Comparisons between the broth microdilution MIC and disk diffusion interpretive results demonstrated excellent intermethod susceptibility category agreement (>95%) using current sparfloxacin breakpoints, but some compounds (cefpodoxime disk diffusion tests for S. aureus) may require modifications. These results demonstrate that new Gram-positive focused fluoroquinolones (sparfloxacin) possess an excellent in vitro activity and spectrum against pathogens that cause respiratory tract infections. This spectrum of activity includes strains resistant to other antimicrobial classes, including the oral cephalosporins, macrolides, amoxicillin/clavulanic acid, and earlier fluoroquinolones (ciprofloxacin, ofloxacin). Overall, sparfloxacin inhibited 89% to nearly 100% of the isolates (species variable) tested against those species against which it has Food and Drug Administration indications for clinical use.

Comparative in vitro assessment of sparfloxacin activity and spectrum using results from over 14,000 pathogens isolated at 190 medical centers in the USA

Sparfloxacin, a new orally administered fluoroquinolone, was tested against 14,182 clinical strains isolated (generally blood stream and respiratory tract cultures) at nearly 200 hospitals in the United States (USA) and Canada. Sparfloxacin activity was compared with 13 other compounds by Etest (AB BIODISK, Solna, Sweden), broth microdilution, or a standardized disk diffusion method. Using the Food and Drug Administration/product package insert MIC breakpoint for sparfloxacin susceptibility (≤0.5 μg/ml), 94% of Streptococcus pneumoniae (2666 isolates) and 89% of the other streptococci (554 isolates) were susceptible. However, at ≤1 μg/ml (the breakpoint for all nonstreptococcal species) sparfloxacin susceptibility rates increased to 100% and 98%, respectively, for the two groups of streptococci. Only 50% and 65% of pneumococci were susceptible to ciprofloxacin (MIC 90, 3 μg/ml) and penicillin (MIC 90, 1.5 μg/ml), respectively. Although there were significant differences between regions in the USA in the frequency of penicillin-resistant pneumococcal strains, results indicate that the overall sparfloxacin MIC 90 was uniformly at 0.5 μg/ml. Nearly all (≥99%) Haemophilus species and Moraxella catarrhalis, including those harboring β-lactamases, were susceptible to sparfloxacin, ciprofloxacin, and amoxicillin/clavulanic acid. Only cefprozil and macrolides demonstrated lower potency and spectrum against these two species. Sparfloxacin was active against oxacillin-susceptible Staphylococcus aureus (96 to 97%), Klebsiella spp. (95%), and other tested enteric bacilli (93%). Comparison between broth microdilution MIC and disk diffusion interpretive results for M. catarrhalis, Staphylococcus aureus, and the Enterobacteriaceae showed an absolute intermethod categorical agreement of >95% using current sparfloxacin breakpoints, in contrast to those of cefpodoxime for S. aureus where a conspicuous discord (98% versus 59%) between methods was discovered. These results demonstrate that sparfloxacin possesses sufficient in vitro activity and spectrum versus pathogens that cause respiratory tract infections (indications), especially strains resistant to other drug classes such as the earlier fluoroquinolones, oral cephalosporins, macrolides, and amoxicillin/clavulanic acid. The sparfloxacin susceptibility breakpoint for streptococci may require modification (≤1 μg/ml) based on the MIC population analysis presented here. A modal MIC (0.38 to 0.5 μg/ml) was observed at the current breakpoint. Regardless, sparfloxacin inhibited 89% (nonpneumococcal Streptococcus spp.) to 100% ( Haemophilus spp., M. catarrhalis) of the isolates tested with a median activity of 97% against indicated species.