Antimicrobial susceptibilities of Clostridium difficile isolated in Japan

Clostridium difficile is a common causative organism of antimicrobial-associated diarrhea and is often responsible for nosocomial infection. C. difficile infection has traditionally been treated with metronidazole (MNZ) or vancomycin (VCM); however, MNZ-resistant strains have reported in some countries. In this study the broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of 15 drugs against 157 clinical isolates of C. difficile in Japan. All C. difficile isolates tested were susceptible to MNZ; MIC₅₀ was 0.25 μg/ml, MIC₉₀ was 0.5 μg/ml, and MIC range was 0.06–1 μg/ml. C. difficile isolates were also susceptible to VCM; MIC₅₀ was 0.5 μg/ml, MIC₉₀ was 1 μg/ml, and MIC range was 0.12–2 μg/ml. Susceptibility to teicoplanin was also similar: MIC₅₀ was 0.12 μg/ml, MIC₉₀ was 0.12 μg/ml, and MIC range was 0.03–0.25 μg/ml. The susceptibility of C. difficile isolates must be monitored continuously because a strain with reduced susceptibility to MNZ or VCM might emerge in the future.     

Comparative In Vitro Activities of SMT19969, a New Antimicrobial Agent,against Clostridium difficile and 350 Gram-Positive and Gram-Negative Aerobic and Anaerobic Intestinal Flora Isolates

The comparative in vitro activity of SMT19969, a novel, narrow-spectrum, nonabsorbable agent, was studied against 50 ribotype-defined Clostridium difficile strains, 174 Gram-positive and 136 Gram-negative intestinal anaerobes, and 40 Gram-positive aerobes. SMT19969 was one dilution more active against C. difficile isolates (MIC range, 0.125 to 0.5 μg/ml; MIC₉₀, 0.25 μg/ml), including ribotype 027 strains, than fidaxomicin (range, 0.06 to 1 μg/ml; MIC₉₀, 0.5 μg/ml) and two to six dilutions lower than either vancomycin or metronidazole. SMT19969 and fidaxomicin were generally less active against Gram-negative anaerobes, especially the Bacteroides fragilis group species, than vancomycin and metronidazole, suggesting that SMT19969 has a lesser impact on the normal intestinal microbiota that maintain colonization resistance. SMT19969 showed limited activity against other Gram-positive anaerobes, including Bifidobacteria species, Eggerthella lenta, Finegoldia magna, and Peptostreptococcus anaerobius, with MIC₉₀s of >512, >512, 64, and 64 μg/ml, respectively. Clostridium species showed various levels of susceptibility, with C. innocuum being susceptible (MIC₉₀, 1 μg/ml) and C. ramosum and C. perfringens being nonsusceptible (MIC₉₀, >512 μg/ml). Activity against Lactobacillus spp. (range, 0.06 to >512 μg/ml; MIC₉₀, >512 μg/ml) was comparable to that of fidaxomicin and varied by species and strain. Gram-positive aerobic cocci (Staphylococcus aureus, Enterococcus faecalis, E. faecium, and streptococci) showed high SMT19969 MIC₉₀ values (128 to >512 μg/ml).     

U.S.-Based National Sentinel Surveillance Study for the Epidemiology of Clostridium difficile-Associated Diarrheal Isolates and Their Susceptibility to Fidaxomicin

In 2011 a surveillance study for the susceptibility to fidaxomicin and epidemiology of Clostridium difficile isolates in the United States was undertaken in seven geographically dispersed medical centers. This report encompasses baseline surveillance in 2011 and 2012 on 925 isolates. A convenience sample of C. difficile isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution (CLSI M11-A8). Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration, or European Union of Clinical Antimicrobial Susceptibility Testing (EUCAST) breakpoints were applied where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of 322 strains, stratified by institution, underwent restriction endonuclease analysis (REA). The fidaxomicin MIC₉₀ was 0.5 μg/ml for all isolates regardless of REA type or toxin gene profile, and all isolates were inhibited at ≤1.0 μg/ml. By REA typing, BI strains represented 25.5% of the isolates. The toxin gene profile of tcdA, tcdB, and cdtA/B positive with a tcdC 18-bp deletion correlated with BI REA group. Moxifloxacin and clindamycin resistance was increased among either BI or binary toxin-positive isolates. Metronidazole and vancomycin showed reduced susceptibility (EUCAST criteria) in these isolates. Geographic variations in susceptibility, REA group and binary toxin gene presence were observed. Fidaxomicin activity against C. difficile isolated in a national surveillance study did not change more than 1 year after licensure. This analysis provides baseline results for future comparisons.     

Dalbavancin is active in vitro against biofilms formed by dalbavancin-susceptible enterococci

We tested the in vitro activity of dalbavancin, vancomycin and daptomycin against 83 enterococcal isolates in planktonic and biofilm states. The MIC₉₀ for vancomycin-susceptible Enterococcus faecalis was 0.125 and 4 μg/mL for dalbavancin and daptomycin, respectively. For vancomycin-resistant Enterococcus faecium, the MIC₉₀ was >16 and 2 μg/mL for dalbavancin and daptomycin, respectively. Dalbavancin minimum biofilm inhibitory concentrations (MBICs) for vancomycin-susceptible and -resistant isolates were ≤0.25 and >16 μg/mL, respectively. The daptomycin MBIC₉₀ for all isolates was 4 μg/mL. For E. faecalis and E. faecium, dalbavancin minimum biofilm bactericidal concentrations (MBBCs) for vancomycin-susceptible and -resistant isolates were ≤4 and >16 μg/mL, respectively, whereas vancomycin MBBCs were >128 μg/mL for all isolates, and daptomycin MBBC₉₀ values for both species were 128 μg/mL. In summary, dalbavancin exhibited in vitro activity against all tested isolates of vancomycin-susceptible, but not against vancomycin-resistant enterococci; activity was observed in both the planktonic and biofilm states.     

A global evaluation of voriconazole activity tested against recent clinical isolates of Candida spp.

Voriconazole susceptibility testing was performed on 7191 Candida spp. from 78 centers worldwide between 2004 and 2007. Voriconazole was very active in vitro (MIC₅₀/MIC₉₀, 0.008/0.25 μg/mL; 98% susceptible). In comparison to 5866 Candida spp. isolates collected during global surveillance from 1997 to 2001, there were no changes in voriconazole mean MIC or MIC distribution.     

In vitro susceptibilities of Aspergillus species to voriconazole,itraconazole, and amphotericin B

We studied the in vitro activity of voriconazole (VCZ) itraconazole (ITZ) and amphotericin B (AMB) against 216 clinical isolates of Aspergillus spp. (142 Aspergillus fumigatus and 74 nonfumigatus Aspergillus spp. isolates) using a broth macrodilution method. The MICs (μg/mL) (mean, range) for A. fumigatus were: VCZ 0.88, 0.25–4; ITZ 0.54, 0.25–4; AMB 2.16, 0.5–8. MIC₉₀s were: VCZ 2, ITZ 1, AMB 4. MICs for nonfumigatus Aspergillus spp. were: VCZ 1.57, 0.25–4; ITZ 1.74, 0.25–4; AMB 2.88, 0.5–8. MIC₉₀s for this group were: VCZ 4, ITZ 4, AMB 4. We also studied the susceptibility to VCZ of 18 AMB-resistant (mean, MIC 6.0 μg/mL) and 28 ITZ-resistant (mean, MIC 13.28 μg/mL) A. fumigatus isolates selected in the laboratory. The mean MICs of VCZ were 0.59 μg/mL for AMB-resistant and 1.32 μg/mL for ITZ-resistant isolates. Our study showed that VCZ and ITZ had comparable in vitro activity against the isolates studied, except against A. fumigatus, where the MIC of ITZ was lower. The azoles had better in vitro activity than AMB against A. fumigatus and non-fumigatus spp. The non-fumigatus Aspergillus spp. were less susceptible to all three antifungals evaluated. When tested against ITZ- or AMB-resistant A. fumigatus strains, VCZ retained good activity, showing only a modest rise in the MIC against ITZ-resistant strains.     

Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014)

The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC_50/90 for S. pneumoniae (2014) was 0.06/0.06 μg/mL, similar to 2010 (MIC_50/90, 0.06/0.12 μg/mL). The omadacycline MIC₉₀ (0.06–0.12 μg/mL) was similar for the penicillin-susceptible, -intermediate, -resistant, multidrug-resistance (MDR; ≥3 classes), and ceftriaxone nonsusceptible subgroups. Omadacycline MIC₉₀ values were 0.06–0.12 μg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern.     

Fidaxomicin Inhibits Clostridium difficile Toxin A-Mediated Enteritis in the Mouse Ileum

Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 μM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1β (IL-1β) protein and mRNA expression. Treatment with fidaxomicin (20 μM) or its primary metabolite, OP-1118 (120 μM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1β protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 μM) and metronidazole (20 μM) did not alter toxin A-induced histologic damage and IL-1β protein expression. In addition to its well known antibacterial effects against C. difficile, fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins.     

In vitro activity of tedizolid against the Mycobacterium abscessus complex

Infections due to Mycobacterium abscessus carry a poor prognosis since this rapidly growing mycobacterium is intrinsically resistant to most antibiotics. Here, we evaluate the in vitro activity of the new oxazolidinone tedizolid against a collection of 44 M. abscessus clinical isolates. The MIC₅₀s and MIC₉₀s of tedizolid (2 and 8 μg/mL, respectively) were 2- to 16-fold lower than those of linezolid. There was no difference between the 3M. abscessus subspecies. Time-kill assays did not show any bactericidal activity at 4- and 8-fold the MIC. Combination of tedizolid with clarithromycin was synergistic against 1 out of 6 isolates, while indifferent interactions were observed for tedizolid combined with tigecycline, ciprofloxacin, and amikacin.     

A correlation between reduced susceptibilities to vancomycin and daptomycin among the MRSA isolates selected in mutant selection window of both vancomycin and daptomycin

Guidelines for the treatment of MRSA infection, recently published by the IDSA and JSC, recommend daptomycin for sepsis and skin and soft tissue infections comparably to or more strongly than vancomycin. Meanwhile MIC creeping with an increased isolation frequency of MRSA isolates with vancomycin MIC of 2 μg/mL has become a problem. In the present study, the MIC creeping rate of MRSA strains in the Tohoku district, Japan in 2012 was 13%, a significantly higher value than 3.3% in 2008 (P < 0.01). Of these isolates, the MIC and mutant prevention concentration (MPC) values of daptomycin and vancomycin were determined for 30 clinical isolates of MRSA in 2012. The MIC₅₀/MIC₈₀ values of daptomycin and vancomycin were 0.125/0.5 μg/mL and 0.125/1 μg/mL, respectively. The MPC₅₀/MPC₈₀ values of daptomycin and vancomycin were both 32/64 μg/mL. In the present study, the mutant selection window (MSW) of daptomycin and vancomycin was ≥64 MIC. Of strains that selected in the MSW, daptomycin non-susceptible isolates accounted for 70.0%, while MRSA with vancomycin MIC of 2 μg/mL accounted for 26.7%. On the other hand, 50% of the strains that selected in the vancomycin MSW were daptomycin non-susceptible strain. The detection rate of MRSA with vancomycin MIC of 2 μg/mL that selected in the daptomycin MSW was 36.7%. These results showed that MRSA with vancomycin MIC of 2 μg/mL and daptomycin non-susceptible isolates were selected by exposure to both antibiotics. Therefore, though vancomycin is frequently used for treatment of MRSA infection, both antibiotics should be selected as a first-line drug appropriately.     

Worldwide summary of telavancin spectrum and potency against Gram-positive pathogens: 2007 to 2008 surveillance results

Telavancin was approved in the United States and Canada for the treatment of adult patients with complicated skin and skin-structure infections (cSSSI) caused by susceptible Gram-positive isolates. In this study, telavancin and comparator antimicrobial activities were determined against a total of 24?017 clinical isolates, including Staphylococcus aureus, coagulase-negative Staphylococcus spp. (CoNS), Enterococcus spp., and various Streptococcus spp. Overall, telavancin was highly active across all geographic regions for S. aureus (MIC_50/90, 0.12/0.25 μg/mL; 100.0% susceptible), CoNS (MIC_50/90, 0.12/0.25 μg/mL), vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.25/0.5 μg/mL; 100.0% susceptible), Enterococcus faecium (MIC_50/90, 0.06/0.12 μg/mL), Streptococcus pneumoniae (MIC_50/90, ≤0.015/0.03 μg/mL), viridans group Streptococcus spp. (MIC_50/90, 0.03/0.06 μg/mL; 100.0% susceptible), and β-hemolytic Streptococcus spp. (MIC_50/90, 0.03/0.12 μg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC_50/90, 0.25/0.5 μg/mL) and E. faecium (MIC_50/90, 0.06/0.25 μg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI.     

Activity of MK-0991 (l-743,872), a new echinocandin,compared with those of LY303366 and four other antifungal agents tested against blood stream isolates of Candida spp.

MK-0991 (formerly L-743,872) is a water soluble semisynthetic echinocandin that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of MK-0991 and an echinocandin derivative LY303366, compared with that of itraconazole, fluconazole, amphotericin B and 5-flucytosine against 400 blood stream isolates of Candida spp. (nine species) obtained from more than 30 different medical centers. MICs for all antifungal drugs were determined by the NCCLS method using RPMI 1640 test medium. Both MK-0991 and LY303366 were very active against all Candida spp. isolates (MIC₉₀, 0.25 and 1 μg/mL, respectively). MK-0991 was twofold to 256-fold more active than amphotericin B, fluconazole, itraconazole (except against C. parapsilosis), and 5-flucytosine (except against C. glabrata and C. parapsilosis). LY303366 was comparable to MK-0991, but was fourfold less active against C. tropicalis (MIC₉₀, 0.5 versus 0.12 μg/mL) and C. parapsilosis (MIC₉₀, >2 versus 1 μg/mL). All of the isolates for which fluconazole and itraconazole had elevated MICs (≥64 μg/mL and ≥1 μg/mL, respectively) were inhibited by ≤0.5 μg/mL of MK-0991 and LY303366. These results suggest both MK-0991 and LY303366 possess promising antifungal activity and further in vitro and in vivo investigations are warranted.     

Susceptibility of Clostridium difficile Isolates of Varying Antimicrobial Resistance Phenotypes to SMT19969 and 11 Comparators

We determined the in vitro activity of SMT19969 and 11 comparators, including metronidazole, vancomycin, and fidaxomicin, against 107 C. difficile isolates of different antimicrobial resistance phenotypes. Fidaxomicin and SMT19969 were the most active. The fidaxomicin and SMT19969 geometric mean MICs were highest in ribotypes known to show multiple resistance. Coresistance to linezolid and moxifloxacin was evident in ribotypes 001, 017, 027, and 356. The high-level ceftriaxone resistance in ribotypes 356 and 018 was location linked.     

Mutant selection window of four quinolone antibiotics against clinical isolates of Streptococcus pneumoniae,Haemophilus influenzae and Moraxella catarrhalis

Community-acquired pneumonia and otitis media are caused by several bacterial species, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. For the treatment of these diseases, various quinolones are frequently used. We determined the mutant prevention concentration (MPC) of four quinolones, levofloxacin, sitafloxacin, tosufloxacin, and garenoxacin, using 92 clinical isolates and evaluated each mutant selection window (MSW). Furthermore, the DNA sequence of the quinolone resistance-determining region (QRDR) for the resistant mutant selected based on the MSW was determined. The MIC₉₀ and MPC₉₀ of levofloxacin were 0.781 μg/mL and 6.250 μg/mL for S. pneumoniae and 0.049 μg/mL and 1.563 μg/mL for M. catarrhalis and were higher than those for the other three quinolones. In addition, 5 strains of 30 S. pneumoniae (16.7%) selected based on the MSW of levofloxacin acquired resistance to only levofloxacin. In these 5 strains, a mutation of gyrA and/or parC was detected.In this study, no resistant mutant was selected in the MSW of any of the other three quinolones. On the other hand, clinical isolates of H. influenzae showed no resistance by all quinolone exposure.Finally, The MIC value and the mutation status in the QRDR did not change after 14 passages in antibiotic-free medium. In conclusion, our findings suggest that the increased use of levofloxacin may contribute to the increased quinolone-resistance of S. pneumoniae and M. catarrhalis.     

Antifungal effect of ophthalmic preservatives phenylmercuric nitrate and benzalkonium chloride on ocular pathogenic filamentous fungi

In the present study, the antifungal effects of phenylmercuric nitrate and benzalkonium chloride versus those of natamycin and ketoconazole were assessed against 216 filamentous fungi isolates from cases of fungal keratitis. They included 112 Fusarium isolates, 94 Aspergillus isolates, and 10 Alternaria alternata isolates. The strains were tested by broth dilution antifungal susceptibility testing of filamentous fungi approved by the Clinical and Laboratory Standards Institute M38-A document. The results showed that the MIC₅₀ values of phenylmercuric nitrate were 0.0156, 0.0156, and 0.0313 μg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The MIC₉₀ values of phenylmercuric nitrate were 0.0313, 0.0313, and 0.0313 μg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The MIC₅₀ values of benzalkonium chloride were 16, 32, and 8 μg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The MIC₉₀ values of benzalkonium chloride were 32, 32, and 16 μg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The study indicates that phenylmercuric nitrate has considerable antifungal activity and its effect is significantly superior to those of benzalkonium chloride, natamycin, and ketoconazole against ocular pathogenic filamentous fungi in vitro, deserving further investigation for treating fungal keratitis as a main drug.     

In vitro activity of various antibiotics against clinical strains of Legionella species isolated in Japan

The activities of various antibiotics against 58 clinical isolates of Legionella species were evaluated using two methods, extracellular activity (minimum inhibitory concentration [MIC]) and intracellular activity. Susceptibility testing was performed using BSYEα agar. The minimum extracellular concentration inhibiting intracellular multiplication (MIEC) was determined using a human monocyte-derived cell line, THP-1. The most potent drugs in terms of MICs against clinical isolates were levofloxacin, garenoxacin, and rifampicin with MIC₉₀ values of 0.015 μg/ml. The activities of ciprofloxacin, pazufloxacin, moxifloxacin, clarithromycin, and azithromycin were slightly higher than those of levofloxacin, garenoxacin, and rifampicin with an MIC₉₀ of 0.03–0.06 μg/ml. Minocycline showed the highest activity, with an MIC₉₀ of 1 μg/ml. No resistance against the antibiotics tested was detected. No difference was detected in the MIC distributions of the antibiotics tested between L. pneumophila serogroup 1 and L. pneumophila non-serogroup 1. The MIECs of ciprofloxacin, pazufloxacin, levofloxacin, moxifloxacin, garenoxacin, clarithromycin, and azithromycin were almost the same as their MICs, with MIEC₉₀ values of 0.015–0.06 μg/ml, although the MIEC of minocycline was relatively lower and that of rifampicin was higher than their respective MICs. No difference was detected in the MIEC distributions of the antibiotics tested between L. pneumophila serogroup 1 and L. pneumophila non-serogroup 1. The ratios of MIEC:MIC for rifampicin (8) and pazufloxacin (2) were higher than those for levofloxacin (1), ciprofloxacin (1), moxifloxacin (1), garenoxacin (1), clarithromycin (1), and azithromycin (1). Our study showed that quinolones and macrolides had potent antimicrobial activity against both extracellular and intracellular Legionella species. The present data suggested the possible efficacy of these drugs in treatment of Legionella infections.     

In Vitro Activity of Voriconazole Against Candida Species

The in vitro activity of voriconazole was compared with that of itraconazole and fluconazole against 181 isolates of Candida albicans, 124 isolates of Candida glabrata, and 20 isolates of Candida krusei obtained from the early 1980s through the mid-1990s. Voriconazole had greater intrinsic activity than fluconazole or itraconazole against all three Candida species. For C. glabrata, C. krusei, and C. albicans, the MIC₅₀ values for voriconazole were 1 μg/mL, 0.5 μg/mL, and 0.01 μg/mL, respectively, compared with fluconazole MIC₅₀ values of 8 μg/mL, 64 μg/mL, and 0.25 μg/mL, respectively. If isolates from AIDS patients were excluded, MIC values for isolates from the 1990s were no higher than those noted for isolates from the 1980s. Voriconazole, a new triazole antifungal agent, appears to have enhanced activity against these three species of Candida; the clinical relevance of these findings should be studied in treatment trials.     

In Vitro and In Vivo Activities of the Novel Ketolide RBx 14255 against Clostridium difficile

The MIC₉₀ of RBx 14255, a novel ketolide, against Clostridium difficile was 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. An in vitro time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile. Furthermore, in the hamster model of C. difficile infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficile treatment.     

Surveillance of iclaprim activity: In vitro susceptibility of gram-positive pathogens collected from 2012 to 2014 from the United States,Asia Pacific,Latin American and Europe

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is highly active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 2814 Gram-positive clinical isolates from the United States, Asia Pacific, Latin American and Europe collected between 2012 and 2014 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC₅₀/MIC₉₀ for all S. aureus, methicillin susceptible S. aureus, methicillin resistant S. aureus, beta-hemolytic streptococci, and Streptococcus pneumoniae were 0.06/0.12, 0.06/0.12, 0.06/0.5, 0.06/0.25, and 0.06/2 μg/mL, respectively. Iclaprim was 8 to 32-fold more potent than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. The MIC₉₀ of iclaprim was also lower than most of the comparators including linezolid and vancomycin against Gram-positive pathogens. Iclaprim demonstrated potent activity against a contemporary collection (2012–2014) of Gram-positive clinical isolates from the United States, Asia Pacific, Latin America and Europe.     

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 (MIC₉₀, 3 μg/mL; susceptible at ≤1 μg/mL) and penicillin (MIC₉₀, 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 (MIC₉₀, 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 (MIC₉₀, 0.12 μg/mL; 96–97% susceptible), Klebsiella spp. (MIC₉₀ 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.