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1.  Antianaerobe Activity of RBX 7644 (Ranbezolid), a New Oxazolidinone, Compared with Those of Eight Other Agents 
The activity of ranbezolid (RBX 7644), a new oxazolidinone, against 306 anaerobes was compared with those of 11 other agents. The MICs at which 50% of the isolates tested are inhibited and those at which 90% of the isolates tested are inhibited (in micrograms per milliliter) were as follows: ranbezolid, 0.03 and 0.5; linezolid, 2 and 4; vancomycin, >16 and >16; teicoplanin, 1 and >16; quinupristin-dalfopristin, 1 and >8; amoxicillin-clavulanate, 0.5 and 2; imipenem, 0.125 and 1; clindamycin, 0.25 and 8; metronidazole, 1 and 4; gatifloxacin, 0.5 and 4; and moxifloxacin, 0.5 and 2, respectively. Ranbezolid had very good in vitro activity against both gram-negative and -positive anaerobes.
doi:10.1128/AAC.47.3.1143-1147.2003
PMCID: PMC149336  PMID: 12604558
2.  Susceptibilities of Haemophilus influenzae and Moraxella catarrhalis to ABT-773 Compared to Their Susceptibilities to 11 Other Agents 
The activity of the ketolide ABT-773 against Haemophilus and Moraxella was compared to those of 11 other agents. Against 210 Haemophilus influenzae strains (39.0% β-lactamase positive), microbroth dilution tests showed that azithromycin and ABT-773 had the lowest MICs (0.5 to 4.0 and 1.0 to 8.0 μg/ml, respectively), followed by clarithromycin and roxithromycin (4.0 to >32.0 μg/ml). Of the β-lactams, ceftriaxone had the lowest MICs (≤0.004 to 0.016 μg/ml), followed by cefixime and cefpodoxime (0.008 to 0.125 and ≤0.125 to 0.25 μg/ml, respectively), amoxicillin-clavulanate (0.125 to 4.0 μg/ml), and cefuroxime (0.25 to 8.0 μg/ml). Amoxicillin was only active against β-lactamase-negative strains, and cefprozil had the highest MICs of all oral cephalosporins tested (0.5 to >32.0 μg/ml). Against 50 Moraxella catarrhalis strains, all of the compounds except amoxicillin and cefprozil were active. Time-kill studies against 10 H. influenzae strains showed that ABT-773, at two times the MIC, was bactericidal against 9 of 10 strains, with 99% killing of all strains at the MIC after 24 h; at 12 h, ABT-773 gave 90% killing of all strains at two times the MIC. At 3 and 6 h, killing by ABT-773 was slower, with 99.9% killing of four strains at two times the MIC after 6 h. Similar results were found for azithromycin, with slightly slower killing by erythromycin, clarithromycin, and roxithromycin, especially at earlier times. β-Lactams were bactericidal against 8 to 10 strains at two times the MIC after 24 h, with slower killing at earlier time periods. Most compounds gave good killing of five M. catarrhalis strains, with β-lactams killing more rapidly than other drugs. ABT-773 and azithromycin gave the longest postantibiotic effects (PAEs) of the ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by clarithromycin, erythromycin, and roxithromycin. β-Lactam PAEs were similar and shorter than those of the ketolide-macrolide-azalide group for all strains tested.
doi:10.1128/AAC.45.1.67-72.2001
PMCID: PMC90241  PMID: 11120946
3.  Comparative Antianaerobic Activity of BMS 284756 
Agar dilution MIC methodology was used to compare the activity of BMS 284756 with those of ciprofloxacin, levofloxacin, moxifloxacin, trovafloxacin, amoxicillin-clavulanate, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 357 anaerobes. Overall, the respective MICs at which 50% of the isolates tested were inhibited (MIC50s) and MIC90s (in micrograms per milliliter) were as follows: BMS 284756, 0.5 and 2.0; ciprofloxacin, 2.0 and 16.0; levofloxacin, 1.0 and 8.0; moxifloxacin, 0.5 and 4.0; trovafloxacin, 0.5 and 2.0; amoxicillin-clavulanate, 0.5 and 2.0; piperacillin-tazobactam, 0.25 and 8.0; imipenem, 0.06 and 1.0; clindamycin, 0.25 and 8.0; and metronidazole, 1.0 and >16.0. BMS 284756 is a promising new quinolone with excellent antianaerobic activity.
doi:10.1128/AAC.45.2.589-592.2001
PMCID: PMC90331  PMID: 11158759
4.  Antipneumococcal Activity of ABT-773 Compared to Those of 10 Other Agents 
MICs, time-kills, and postantibiotic effects (PAEs) of ABT-773 (a new ketolide) and 10 other agents were determined against 226 pneumococci. Against 78 ermB- and 44 mefE-containing strains, ABT-773 MICs at which 50% of the isolates tested were inhibited (MIC50s) and MIC90s were 0.016 to 0.03 and 0.125 μg/ml, respectively. Clindamycin was active only against macrolide-resistant strains containing mefE (MIC50, 0.06 μg/ml; MIC90, 0.125 μg/ml). Activities of pristinamycin (MIC90, 0.5 μg/ml) and vancomycin (MIC90, 0.25 μg/ml) were unaffected by macrolide or penicillin resistance, while β-lactam MICs rose with those of penicillin G. Against 19 strains with L4 ribosomal protein mutations and two strains with mutations in domain V of 23S rRNA, ABT-773 MICs were 0.03 to 0.25 μg/ml, while macrolide and azalide MICs were all ≥16.0 μg/ml. ABT-773 was bactericidal at twice the MIC after 24 h for 8 of 12 strains (including three strains with erythromycin MICs greater than or equal to 64.0 μg/ml). Kill kinetics of erythromycin, azithromycin, clarithromycin, and roxithromycin against macrolide-susceptible strains were slower than those of ABT-773. ABT-773 had longer PAEs than macrolides, azithromycin, clindamycin, or β-lactams, including against ermB-containing strains. ABT-773, therefore, shows promising in vitro activity against macrolide-susceptible as well as -resistant pneumococci.
PMCID: PMC89981  PMID: 10858350
5.  In Vitro Development of Resistance to Telithromycin (HMR 3647), Four Macrolides, Clindamycin, and Pristinamycin in Streptococcus pneumoniae 
The ability of 50 sequential subcultures in subinhibitory concentrations of telithromycin (HMR 3647), azithromycin, clarithromycin, erythromycin A, roxithromycin, clindamycin, and pristinamycin to select for resistance was studied in five macrolide-susceptible and six macrolide-resistant pneumococci containing mefE or ermB. Telithromycin selected for resistance less often than the other drugs.
PMCID: PMC89694  PMID: 10639373
6.  Activity of Retapamulin against Streptococcus pyogenes and Staphylococcus aureus Evaluated by Agar Dilution, Microdilution, E-Test, and Disk Diffusion Methodologies 
The in vitro activity of retapamulin against 106 Staphylococcus aureus isolates and 109 Streptococcus pyogenes isolates was evaluated by the agar dilution, broth microdilution, E-test, and disk diffusion methodologies. Where possible, the tests were performed by using the CLSI methodology. The results of agar dilution, broth microdilution, and E-test (all with incubation in ambient air) for S. aureus yielded similar MICs, in the range of 0.03 to 0.25 μg/ml. These values corresponded to zone diameters between 25 and 33 mm by the use of a 2-μg retapamulin disk. Overall, 99% of the agar dilution results and 95% of E-test results for S. aureus were within ±1 dilution of the microdilution results. For S. pyogenes, the MICs obtained by the agar and broth microdilution methods (both after incubation in ambient air) were in the range of 0.008 to 0.03 μg/ml, and E-test MICs (with incubation in ambient air) were 0.016 to 0.06 μg/ml. For S. pyogenes, 100% of the agar dilution MIC results were within ±1 dilution of the broth microdilution results. E-test MICs (after incubation in ambient air) were within ±1 and ±2 dilutions of the broth microdilution results for 76% and 99% of the isolates, respectively. E-test MICs for S. pyogenes strains in CO2 were up to 4 dilutions higher than those in ambient air. Therefore, it is recommended that when retapamulin MICs are determined by E-test, incubation be done in ambient air and not in CO2, due to the adverse effect of CO2 on the activity of this compound. Diffusion zones (with incubation in CO2) for S. pyogenes were 18 to 24 mm. Retapamulin MICs for all strains by all methods (with incubation in ambient air) were ≤0.25 μg/ml. These results demonstrate that S. pyogenes (including macrolide-resistant strains) and S. aureus (including methicillin-resistant and vancomycin-nonsusceptible strains) are inhibited by very low concentrations of retapamulin and that all four testing methods are satisfactory for use for susceptibility testing.
doi:10.1128/AAC.50.5.1727-1730.2006
PMCID: PMC1472194  PMID: 16641442
7.  Antipneumococcal Activity of Ertapenem (MK-0826) Compared to Those of Other Agents 
The activities of ertapenem (MK-0826) and eight other agents against a range of penicillin-susceptible and -resistant pneumococci were tested by determination of MICs by the microdilution method and by the time-kill methodology. For 125 penicillin-susceptible, 74 penicillin-intermediate, and 86 penicillin-resistant pneumococci, the MICs at which 50% of isolates are inhibited (MIC50s) and MIC90s, as determined by the microdilution method, were as follows: for ertapenem, 0.016 and 0.03, 0.125 and 0.5, and 0.5 and 1.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; for amoxicillin, ≤0.016 and 0.03, 0.25 and 1.0, and 2.0 and 2.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; for cefprozil, 0.125 and 0.25, 1.0 and 8.0, and 16.0 and 16.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; for cefepime, ≤0.016 and 0.06, 0.5 and 1.0, and 1.0 and 2.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; for ceftriaxone, ≤0.016 and 0.06, 0.25 and 1.0, and 1.0 and 2.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; for imipenem, ≤0.008 and ≤0.008, 0.03 and 0.25, and 0.25 and 0.25 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; for meropenem, ≤0.008 and 0.016, 0.125 and 0.5, and 0.5 and 1.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively; and for clarithromycin, 1.0 and >32.0, 1.0 and >32.0, and >32.0 and >32.0 μg/ml for penicillin-susceptible, penicillin-intermediate, and penicillin-resistant pneumococci, respectively. For 64 strains for which quinolone MICs were increased (ciprofloxacin MICs, ≥4.0 μg/ml), the MIC90 of ertapenem was 1.0 μg/ml and the MIC90s of the other β-lactams tested and clarithromycin were >32.0 μg/ml. Against four penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains, testing by the time-kill methodology showed that ertapenem at two times the MIC was bacteriostatic (99% killing) after 12 h and bactericidal (99.9% killing) against all strains by 24 h, with 90% killing of all strains at two times the MIC after 6 h. At the MIC, ertapenem was bacteriostatic against all strains tested after 24 h. Although the bactericidal activity of imipenem at the MIC after 24 h was significantly greater than that of ertapenem, the kinetics of the two drugs at two times the MIC were similar after 24 h. The killing kinetics of clarithromycin were slower than those of ertapenem and other agents, with clarithromycin at two times the MIC having bactericidal activity against seven of eight macrolide-susceptible strains after 24 h.
doi:10.1128/AAC.46.1.42-46.2002
PMCID: PMC126980  PMID: 11751109
8.  Activities of a New Fluoroketolide, HMR 3787, and Its (Des)-Fluor Derivative RU 64399 Compared to Those of Telithromycin, Erythromycin A, Azithromycin, Clarithromycin, and Clindamycin against Macrolide-Susceptible or -Resistant Streptococcus pneumoniae and S. pyogenes 
Antimicrobial Agents and Chemotherapy  2001;45(11):3242-3245.
Activities of HMR 3787 and RU 64399 were compared to those of three macrolides, telithromycin, and clindamycin against 175 Streptococcus pneumoniae isolates and 121 Streptococcus pyogenes isolates. HMR3787 and telithromycin were the most active compounds tested against pneumococci. Telithromycin and RU 64399 were equally active against macrolide-susceptible (MICs, 0.008 to 0.06 μg/ml) and -resistant S. pyogenes isolates, but HMR 3787 had lower MICs for ermB strains.
doi:10.1128/AAC.45.11.3242-3245.2001
PMCID: PMC90817  PMID: 11600391
9.  Bacteriologic Efficacies of Oral Azithromycin and Oral Cefaclor in Treatment of Acute Otitis Media in Infants and Young Children 
A prospective, open-label, randomized study was conducted in order to determine the bacteriologic efficacies of cefaclor and azithromycin in acute otitis media (AOM). Tympanocentesis was performed on entry into the study and 3 to 4 days after initiation of treatment. Bacteriologic failure after 3 to 4 days of treatment with both drugs occurred in a high proportion of culture-positive patients, especially in those in whom AOM was caused by Haemophilus influenzae (16 of 33 [53%] of those treated with azithromycin and 13 of 34 [52%] of those treated with cefaclor). Although a clear correlation of the persistence of the pathogen with increased MICs of the respective drugs could be demonstrated for Streptococcus pneumoniae, no such correlation was found for H. influenzae. It is proposed that susceptibility breakpoints for H. influenzae should be considerably lower than the current ones for both cefaclor and azithromycin for AOM caused by H. influenzae.
PMCID: PMC89626  PMID: 10602721
11.  Population Structure of KPC-Producing Klebsiella pneumoniae Isolates from Midwestern U.S. Hospitals 
Genome sequencing of carbapenem-resistant Klebsiella pneumoniae isolates from regional U.S. hospitals was used to characterize strain diversity and the blaKPC genetic context. A phylogeny based on core single-nucleotide variants (SNVs) supports a division of sequence type 258 (ST258) into two distinct groups. The primary differences between the groups are in the capsular polysaccharide locus (cps) and their plasmid contents. A strict association between clade and KPC variant was found. The blaKPC gene was found on variants of two plasmid backbones. This study indicates that highly similar K. pneumoniae subpopulations coexist within the same hospitals over time.
doi:10.1128/AAC.00125-14
PMCID: PMC4136011  PMID: 24913165
12.  Surveillance of Carbapenem-Resistant Klebsiella pneumoniae: Tracking Molecular Epidemiology and Outcomes through a Regional Network 
Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem-resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either blaKPC-2 (48%) or blaKPC-3 (51%). One isolate tested positive for blaNDM-1, a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with blaKPC-3 (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants.
doi:10.1128/AAC.02636-14
PMCID: PMC4068524  PMID: 24798270
13.  Comparative Genomic Analysis of KPC-Encoding pKpQIL-Like Plasmids and Their Distribution in New Jersey and New York Hospitals 
The global spread of Klebsiella pneumoniae carbapenemase (KPC) is predominately associated with K. pneumoniae strains genotyped as sequence type 258 (ST258). The first ST258-associated plasmid, pKpQIL, was described in Israel in 2006, but its history in the northeastern United States remains unknown. Six pKpQIL-like plasmids from four K. pneumoniae isolates (three ST258 and one ST234), one Escherichia coli isolate, and one Enterobacter aerogenes isolate, collected from 2003 to 2010 in New York (NY) and New Jersey (NJ) hospitals, were completely sequenced. The sequences and overall sizes of the six plasmids are highly similar to those of pKpQIL; the major difference is that five of six NJ/NY strains harbor blaKPC-2, while pKpQIL contains blaKPC-3. Moreover, a 26.7-kb fragment was inverted in pKpQIL-234 (from ST234 K. pneumoniae), while a 14.5-kb region was deleted in pKpQIL-Ec (from ST131 E. coli). PCR screening of 284 other clinical K. pneumoniae isolates identified 101 (35.6%) harboring pKpQIL-like plasmids from 9 of 10 surveyed hospitals, demonstrating the wide dissemination of pKpQIL in this region of endemicity. Among the positive isolates, 87.1% were typed as ST258 and 88.1% carried blaKPC-2. The finding of pKpQIL-like plasmid in this study from strains that predate the initial report of KPC in Israel provides evidence that pKpQIL may have originated in the United States. Our findings demonstrate that pKpQIL plasmids are both spreading clonally in ST258 strains and spreading horizontally to different sequence types and species, further highlighting the clinical and public health concerns associated with carbapenem resistance.
doi:10.1128/AAC.00120-14
PMCID: PMC3993205  PMID: 24614371
14.  Molecular Survey of the Dissemination of Two blaKPC-Harboring IncFIA Plasmids in New Jersey and New York Hospitals 
Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains have spread worldwide and become a major threat in health care facilities. Transmission of blaKPC, the plasmid-borne KPC gene, can be mediated by clonal spread and horizontal transfer. Here, we report the complete nucleotide sequences of two novel blaKPC-3-harboring IncFIA plasmids, pBK30661 and pBK30683. pBK30661 is 74 kb in length, with a mosaic plasmid structure; it exhibits homologies to several other plasmids but lacks the plasmid transfer operon (tra) and the origin of transfer (oriT) that are required for plasmid transfer. pBK30683 is a conjugative plasmid with a cointegrated plasmid structure, comprising a 72-kb element that highly resembles pBK30661 (>99.9% nucleotide identities) and an extra 68-kb element that harbors tra and oriT. A PCR scheme was designed to detect the distribution of blaKPC-harboring IncFIA (pBK30661-like and pBK30683-like) plasmids in a collection of clinical Enterobacteriaceae isolates from 10 hospitals in New Jersey and New York. KPC-harboring IncFIA plasmids were found in 20% of 491 K. pneumoniae isolates, and all carried blaKPC-3. pBK30661-like plasmids were identified mainly in the epidemic sequence type 258 (ST258) K. pneumoniae clone, while pBK30683-like plasmids were widely distributed in ST258 and other K. pneumoniae sequence types and among non-K. pneumoniae Enterobacteriaceae species. This suggests that both clonal spread and horizontal plasmid transfer contributed to the dissemination of blaKPC-harboring IncFIA plasmids in our area. Further studies are needed to understand the distribution of this plasmid group in other health care regions and to decipher the origins of pBK30661-like and pBK30683-like plasmids.
doi:10.1128/AAC.02749-13
PMCID: PMC4023724  PMID: 24492370
15.  Complete Sequence of a KPC-Producing IncN Multidrug-Resistant Plasmid from an Epidemic Escherichia coli Sequence Type 131 Strain in China 
We report here the nucleotide sequence of a novel blaKPC-2-harboring incompatibility group N (IncN) plasmid, pECN580, from a multidrug-resistant Escherichia coli sequence type 131 (ST131) isolate recovered from Beijing, China. pECN580 harbors β-lactam resistance genes blaKPC-2, blaCTX-M-3, and blaTEM-1; aminoglycoside acetyltransferase gene aac(6′)-Ib-cr; quinolone resistance gene qnrS1; rifampin resistance gene arr-3; and trimethoprim resistance gene dfrA14. The emergence of a blaKPC-2-harboring multidrug-resistant plasmid in an epidemic E. coli ST131 clone poses a significant potential threat in community and hospital settings.
doi:10.1128/AAC.02587-13
PMCID: PMC4023777  PMID: 24395232
16.  Complete Nucleotide Sequence of a blaKPC-Harboring IncI2 Plasmid and Its Dissemination in New Jersey and New York Hospitals 
Antimicrobial Agents and Chemotherapy  2013;57(10):5019-5025.
Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains have spread worldwide and become a significant public health threat. blaKPC, the plasmid-borne KPC gene, was frequently identified on numerous transferable plasmids in different incompatibility replicon groups. Here we report the complete nucleotide sequence of a novel blaKPC-3-harboring IncI2 plasmid, pBK15692, isolated from a multidrug-resistant K. pneumoniae ST258 strain isolated from a New Jersey hospital in 2005. pBK15692 is 78 kb in length and carries a backbone that is similar to those of other IncI2 plasmids (pR721, pChi7122-3, pHN1122-1, and pSH146-65), including the genes encoding type IV pili and shufflon regions. Comparative genomics analysis of IncI2 plasmids reveals that they possess a conserved plasmid backbone but are divergent with respect to the integration sites of resistance genes. In pBK15692, the blaKPC-3-harboring Tn4401 was inserted into a Tn1331 element and formed a nested transposon. A PCR scheme was designed to detect the prevalence of IncI2 and pBK15692-like plasmids from a collection of clinical strains from six New Jersey and New York hospitals isolated between 2007 and 2011. IncI2 plasmids were found in 46.2% isolates from 318 clinical K. pneumoniae strains. Notably, 59 pBK15692-like plasmids (23%) have been identified in 256 KPC-bearing K. pneumoniae strains, and all carried KPC-3 and belong to the epidemic ST258 clone. Our study revealed that the prevalence of IncI2 plasmids has been considerably underestimated. Further studies are needed to understand the distribution of this plasmid group in other health care regions and decipher the association between IncI2 plasmids and blaKPC-3-bearing ST258 strains.
doi:10.1128/AAC.01397-13
PMCID: PMC3811408  PMID: 23896467
17.  Complete Sequence of a blaKPC-2-Harboring IncFIIK1 Plasmid from a Klebsiella pneumoniae Sequence Type 258 Strain 
We report the nucleotide sequence of a novel blaKPC-2-harboring IncFIIK1 plasmid, pBK32179, isolated from a carbapenem-resistant Klebsiella pneumoniae ST258 strain from a New York City patient. pBK32179 is 165 kb long, consists of a large backbone of pKPN3-like plasmid, and carries an 18.5-kb blaKPC-2-containing element that is highly similar to plasmid pKpQIL. pBK32179-like plasmids were identified in 8.3% of strains in a collection of 96 K. pneumoniae isolates from hospitals in the New York City area.
doi:10.1128/AAC.02332-12
PMCID: PMC3591897  PMID: 23295924
18.  Complete Nucleotide Sequences of blaKPC-4- and blaKPC-5-Harboring IncN and IncX Plasmids from Klebsiella pneumoniae Strains Isolated in New Jersey 
Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae have emerged as major nosocomial pathogens. blaKPC, commonly located on Tn4401, is found in Gram-negative bacterial strains, with the two most common variants, blaKPC-2 and blaKPC-3, identified in plasmids with diverse genetic backgrounds. In this study, we examined blaKPC-4- and blaKPC-5-bearing plasmids recovered from two K. pneumoniae strains, which were isolated from a single New Jersey hospital in 2005 and 2006, respectively. IncN plasmid pBK31551 is 84 kb in length and harbors blaKPC-4, blaTEM-1, qnrB2, aac(3)-Ib, aph(3′)-I, qacF, qacEΔ1, sul1, and dfrA14, which confer resistance to β-lactams, quinolones, aminoglycosides, quaternary ammonium compounds, and co-trimoxazole. The conserved regions within pBK31551 are similar to those of other IncN plasmids. Surprisingly, analysis of the Tn4401 sequence revealed a large IS110- and Tn6901-carrying element (8.3 kb) inserted into the istA gene, encoding glyoxalase/bleomycin resistance, alcohol dehydrogenase, and S-formylglutathione hydrolase. Plasmid pBK31567 is 47 kb in length and harbors blaKPC-5, dfrA5, qacEΔ1, and sul1. pBK31567 belongs to a novel IncX subgroup (IncX5) and possesses a highly syntenic plasmid backbone like other IncX plasmids; however, sequence similarity at the nucleotide level is divergent. The blaKPC-5 gene is carried on a Tn4401 element and differs from the genetic environment of blaKPC-5 described in Pseudomonas aeruginosa strain P28 from Puerto Rico. This study underscores the genetic diversity of multidrug-resistant plasmids involved in the spread of blaKPC genes and highlights the mobility and plasticity of Tn4401. Comparative genomic analysis provides new insights into the evolution and dissemination of KPC plasmids belonging to different incompatibility groups.
doi:10.1128/AAC.01648-12
PMCID: PMC3535970  PMID: 23114770
19.  Antianaerobic Activity of a Novel Fluoroquinolone, WCK 771, Compared to Those of Nine Other Agents 
Agar dilution MIC methodology was used to compare the activity of WCK 771 with those of ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin, piperacillin, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 350 anaerobes. Overall, the MICs (in micrograms per milliliter) at which 50 and 90%, respectively, of the isolates tested were inhibited were as follows: WCK 771, 0.5 and 2.0; ciprofloxacin, 2.0 and 32.0; levofloxacin, 1.0 and 8.0; gatifloxacin, 0.5 and 4.0; moxifloxacin, 0.5 and 4.0; piperacillin, 2.0 and 64.0; piperacillin-tazobactam, ≤0.125 and 8.0; imipenem, 0.125 and 1.0; clindamycin, 0.125 and 16.0; and metronidazole, 1.0 and >16.0.
doi:10.1128/AAC.48.8.3188-3192.2004
PMCID: PMC478502  PMID: 15273148
20.  Activities of HMR 3787 and RU 64399 Compared with Those of Four Other Agents against Haemophilus influenzae and Haemophilus parainfluenzae 
Activities of HMR 3787, a new 2-fluoroketolide, and its (des)-fluor derivative, RU 64399, were tested against 111 Haemophilus influenzae and 26 H. parainfluenzae strains and compared with those of telithromycin, erythromycin, azithromycin, and clarithromycin. HMR 3787 and RU 64399 MICs were comparable with those of azithromycin but were less affected by incubation in CO2. Time-kill studies of 12 strains showed that HMR 3787, RU 64399, and telithromycin were bactericidal against all strains after 24 h at two times the MIC.
doi:10.1128/AAC.47.1.405-407.2003
PMCID: PMC149015  PMID: 12499225
21.  Antistreptococcal Activity of Telithromycin Compared with Seven Other Drugs in Relation to Macrolide Resistance Mechanisms in Russia 
The susceptibilities of 468 recent Russian clinical Streptococcus pneumoniae isolates and 600 Streptococcus pyogenes isolates, from 14 centers in Russia, to telithromycin, erythromycin, azithromycin, clarithromycin, clindamycin, levofloxacin, quinupristin-dalfopristin, and penicillin G were tested. Penicillin-nonsusceptible S. pneumoniae strains were rare except in Siberia, where their prevalence rate was 13.5%: most were penicillin intermediate, but for three strains (two from Smolensk and one from Novosibirsk) the MICs of penicillin G were 4 or 8 μg/ml. Overall, 2.5% of S. pneumoniae isolates were resistant to erythromycin. Efflux was the prevalent resistance mechanism (five strains; 41.7%), followed by ribosomal methylation encoded by constitutive erm(B), which was found in four isolates. Ribosomal mutation was the mechanism of macrolide resistance in three isolates; one erythromycin-resistant S. pneumoniae isolate had an A2059G mutation in 23S rRNA, and two isolates had substitution of GTG by TPS at positions 69 to 71 in ribosomal protein L4. All S. pyogenes isolates were susceptible to penicillin, and 11% were erythromycin resistant. Ribosomal methylation was the most common resistance mechanism for S. pyogenes (89.4%). These methylases were encoded by erm(A) [subclass erm(TR)] genes, and their expression was inducible in 96.6% of isolates. The rest of the erythromycin-resistant Russian S. pyogenes isolates (7.6%) had an efflux resistance mechanism. Telithromycin was active against 100% of pneumococci and 99.2% of S. pyogenes, and levofloxacin and quinupristin-dalfopristin were active against all isolates of both species.
doi:10.1128/AAC.46.9.2963-2968.2002
PMCID: PMC127395  PMID: 12183254
22.  Susceptibilities to Telithromycin and Six Other Agents and Prevalence of Macrolide Resistance Due to L4 Ribosomal Protein Mutation among 992 Pneumococci from 10 Central and Eastern European Countries 
The macrolide and levofloxacin susceptibilities of 992 isolates of Streptococcus pneumoniae from clinical specimens collected in 1999 and 2000 were determined in 10 centers in Central and Eastern European countries. The prevalences of penicillin G-intermediate (MICs, 0.125 to 1 μg/ml) and penicillin-resistant (MICs, ≤2 μg/ml) Streptococcus pneumoniae isolates were 14.3 and 16.6%, respectively. The MICs at which 50% of isolates are inhibited (MIC50s) and the MIC90s of telithromycin were 0.016 and 0.06 μg/ml, respectively; those of erythromycin were 0.06 and >64 μg/ml, respectively; those of azithromycin were 0.125 and >64 μg/ml, respectively; those of clarithromycin were 0.03 and >64 μg/ml, respectively; and those of clindamycin were 0.06 and >64 μg/ml, respectively. Erythromycin resistance was found in 180 S. pneumoniae isolates (18.1%); the highest prevalence of erythromycin-resistant S. pneumoniae was observed in Hungary (35.5%). Among erythromycin-resistant S. pneumoniae isolates, strains harboring erm(B) genes (125 strains [69.4%]) were found to be predominant over strains with mef(E) genes (25 strains [13.4%]), L4 protein mutations (28 strains [15.6%]), and erm(A) genes (2 strains [1.1%]). Similar pulsed-field gel electrophoresis patterns suggested that some strains containing L4 mutations from the Slovak Republic, Bulgaria, and Latvia were clonally related. Of nine strains highly resistant to levofloxacin (MICs, >8 μg/ml) six were isolated from Zagreb, Croatia. Telithromycin at ≤0.5 μg/ml was active against 99.8% of S. pneumoniae isolates tested and may be useful for the treatment of respiratory tract infections caused by macrolide-resistant S. pneumoniae isolates.
doi:10.1128/AAC.46.2.371-377.2002
PMCID: PMC127073  PMID: 11796344
23.  In Vitro Selection of Resistance to Clinafloxacin, Ciprofloxacin, and Trovafloxacin in Streptococcus pneumoniae 
Antimicrobial Agents and Chemotherapy  2000;44(10):2740-2746.
Ability of daily sequential subcultures in subinhibitory concentrations of clinafloxacin, ciprofloxacin, and trovafloxacin to select resistant mutants was studied in 10 pneumococci (ciprofloxacin MICs, 1 to 4 μg/ml, and clinafloxacin and trovafloxacin MICs, 0.06 to 0.125 μg/ml [n = 9]; ciprofloxacin, clinafloxacin, and trovafloxacin MICs, 32, 0.5, and 2 μg/ml, respectively [n = 1]). Subculturing was done 50 times, or until MICs increased fourfold or more. Mutants for which MICs were fourfold (or more) higher than those for parent strains were selected in five strains by clinafloxacin, in six strains by trovafloxacin, and nine strains by ciprofloxacin. Sequence analysis of type II topoisomerase showed that most mutants had mutations in ParC at Ser79 or Asp83 and in GyrA at Ser81, while a few mutants had mutations in ParE or GyrB. In the presence of reserpine, the MICs of ciprofloxacin and clinafloxacin for most mutants were lower (four to eight times lower), but for none of the mutants were trovafloxacin MICs lower, suggesting an efflux mechanism affecting the first two agents but not trovafloxacin. Single-step mutation rates were also determined for eight strains for which the MICs were as follows: 0.06 μg/ml (clinafloxacin), 0.06 to 0.125 μg/ml (trovafloxacin), and 1 μg/ml (ciprofloxacin). Single-step mutation rates with drugs at the MIC were 2.0×10−9 to <1.1×10−11, 5.0×10−4 to 3.6×10−9, and 4.8×10−4 to 6.7×10−9, respectively. For two strains with clinafloxacin MICs of 0.125 to 0.5 μg/ml trovafloxacin MICs of 0.125 to 2 μg/ml, ciprofloxacin MICs of 4 to 32 μg/ml mutation rates with drugs at the MIC were 1.1×10−8−9.6×10−8, 3.3×10−6−6.7×10−8, and 2.3×10−5−2.4×10−7, respectively. Clinafloxacin was bactericidal at four times the MIC after 24 h against three parent and nine mutant strains by time-kill study. This study showed that single and multistep clinafloxacin exposure selected for resistant mutants less frequently than similar exposures to other drugs studied.
PMCID: PMC90145  PMID: 10991854
24.  Antipneumococcal Activities of GAR-936 (a New Glycylcycline) Compared to Those of Nine Other Agents against Penicillin-Susceptible and -Resistant Pneumococci 
GAR-936, a new glycylcycline, had lower MICs (≤0.016 to 0.125 μg/ml) for 201 penicillin- and tetracycline-susceptible and -resistant pneumococcal strains than tetracycline (≤0.06 to 128 μg/ml), minocycline (≤0.06 to 16.0 μg/ml), or doxycycline (≤0.06 to 32.0 μg/ml). GAR-936 was also bactericidal against 11 of 12 strains tested at the MIC after 24 h, with significant kill rates at earlier time points.
PMCID: PMC89820  PMID: 10722519
25.  Activities and Postantibiotic Effects of Gemifloxacin Compared to Those of 11 Other Agents against Haemophilus influenzae and Moraxella catarrhalis 
The activity of gemifloxacin against Haemophilus influenzae and Moraxella catarrhalis was compared to those of 11 other agents. All quinolones were very active (MICs, ≤0.125 μg/ml) against 248 quinolone-susceptible H. influenzae isolates (40.7% of which were β-lactamase positive); cefixime (MICs, ≤0.125 μg/ml) and amoxicillin-clavulanate (MICs ≤4.0 μg/ml) were active, followed by cefuroxime (MICs, ≤16.0 μg/ml); azithromycin MICs were ≤4.0 μg/ml. For nine H. influenzae isolates with reduced quinolone susceptibilities, the MICs at which 50% of isolates are inhibited (MIC50s) were 0.25 μg/ml for gemifloxacin and 1.0 μg/ml for the other quinolones tested. All strains had mutations in GyrA (Ser84, Asp88); most also had mutations in ParC (Asp83, Ser84, Glu88) and ParE (Asp420, Ser458), and only one had a mutation in GyrB (Gln468). All quinolones tested were equally active (MICs, ≤0.06 μg/ml) against 50 M. catarrhalis strains; amoxicillin-clavulanate, cefixime, cefuroxime, and azithromycin were very active. Against 10 H. influenzae strains gemifloxacin, levofloxacin, sparfloxacin, and trovafloxacin at 2× the MIC and ciprofloxacin at 4× the MIC were uniformly bactericidal after 24 h, and against 9 of 10 strains grepafloxacin at 2× the MIC was bactericidal after 24 h. After 24 h bactericidal activity was seen with amoxicillin-clavulanate at 2× the MIC for all strains, cefixime at 2× the MIC for 9 of 10 strains, cefuroxime at 4× the MIC for all strains, and azithromycin at 2× the MIC for all strains. All quinolones except grepafloxacin (which was bactericidal against four of five strains) and all ß-lactams at 2× to 4× the MIC were bactericidal against five M. catarrhalis strains after 24 h; azithromycin at the MIC was bactericidal against all strains after 24 h. The postantibiotic effects (PAEs) against four quinolone-susceptible H. influenzae strains were as follows: gemifloxacin, 0.3 to 2.3 h; ciprofloxacin, 1.3 to 4.2 h; levofloxacin, 2.8 to 6.2 h; sparfloxacin, 0.6 to 3.0 h; grepafloxacin, 0 to 2.1 h; trovafloxacin, 0.8 to 2.8 h. At 10× the MIC, no quinolone PAEs were found against the strain for which quinolone MICs were increased. Azithromycin PAEs were 3.7 to 7.3 h.
PMCID: PMC89738  PMID: 10681330

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