In vitro activities of RWJ-54428 (MC-02,479) against multiresistant gram-positive bacteria

RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC at which 90% of isolates are inhibited (MIC(90)) of 2 microg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times more active than imipenem, with an MIC(90) of 2 microg/ml. RWJ-54428 was active against S. aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus isolates with reduced susceptibility to glycopeptides (RWJ-54428 MIC range, < or = 0.0625 to 1 microg/ml). RWJ-54428 was eight times more potent than methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC(90), 0.5 microg/ml). For ampicillin-susceptible Enterococcus faecalis (including vancomycin-resistant and high-level aminoglycoside-resistant strains), RWJ-54428 had an MIC(90) of 0.125 microg/ml. RWJ-54428 was also active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs ranged between < or = 0.0625 and 1 microg/ml for ampicillin-susceptible strains and 0.125 and 8 microg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains of Streptococcus pneumoniae (MIC(90)s, 0.25, 0.125, and < or = 0.0625 microg/ml, respectively). RWJ-54428 was only marginally active against most gram-negative bacteria; however, significant activity was observed against Haemophilus influenzae and Moraxella catarrhalis (MIC(90)s, 0.25 and 0.5 microg/ml, respectively). This survey of the susceptibilities of more than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428 indicates that this new cephalosporin has the potential to be useful in the treatment of infections due to gram-positive bacteria, including strains resistant to currently available antimicrobials.     

In vitro activity of a new cephalosporin,RWJ-54428, against streptococci,enterococci and staphylococci,including glycopeptide-intermediate Staphylococcus aureus

The need for new antimicrobial agents with activity against Gram-positive organisms has become increasingly important because of emerging resistance. We compared the activity of a new b-lactam antimicrobial agent, RWJ-54428 (MC-02 479), with representatives of other classes of antimicrobial agents against 76 Staphylococcus aureus (including four glycopeptide- intermediate strains), 50 coagulase-negative staphylococci, 20 Enterococcus faecalis, 20 Enterococcus faecium, 10 Enterococcus gallinarum/Enterococcus casseliflavus, 54 Streptococcus pneumoniae and 22 viridans streptococcal isolates. The MIC(90) of RWJ-54,428 was < or = 2 mg/L for all groups of bacteria tested except E. faecium. The activity against four strains of glycopeptide-intermediate S. aureus was similar to that for other methicillin-resistant S. aureus isolates (range 0.5-2.0 mg/L).     

In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90) of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 microg/ml, respectively, whereas they were 0.5 and 0.5 microg/ml, respectively, for methicillin-susceptible S. aureus. The MIC(50) and MIC(90) were 1 and 4 microg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 microg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 microg/ml, respectively. The MIC(50) and MIC(90) of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 microg/ml, respectively, but they were 4 and 8 microg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC(90)s of RWJ-54428 were 0.03, 0.25, and 0.5 microg/ml, respectively, with the highest MIC for a pneumococcus being 1 microg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 microg/ml. MICs for Lancefield group A, B, C, and G streptococci were < or =0.008 microg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.     

In vivo antibacterial activity of RWJ-54428, a new cephalosporin with activity against gram-positive bacteria

RWJ-54428 (MC-02,479) is a new cephalosporin with activity against resistant gram-positive organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. The in vivo efficacy of RWJ-54428 was evaluated against gram-positive bacteria in four mouse models of infection. RWJ-54428 was effective in vivo against methicillin-susceptible and -resistant S. aureus in a mouse model of sepsis, with 50% effective doses being similar to those of vancomycin. In a single-dose neutropenic mouse thigh model of infection, RWJ-54428 at 30 mg/kg of body weight showed activity similar to that of vancomycin at 30 mg/kg against a strain of methicillin-resistant S. aureus. RWJ-54428 also showed a prolonged in vivo postantibiotic effect in this model. In a mouse model of pneumonia due to a penicillin-susceptible strain of Streptococcus pneumoniae, RWJ-54428 displayed efficacy and potency superior to those of penicillin G and cefotaxime. In a mouse model of pyelonephritis due to Enterococcus faecalis, RWJ-54428 had bactericidal effects similar to those of vancomycin and ampicillin, but at two- to threefold lower total daily doses. These studies show that RWJ-54428 is active in experimental mouse models of infection against gram-positive organisms, including strains resistant to earlier cephalosporins and penicillin G.     

RWJ-54428 (MC-02,479), a new cephalosporin with high affinity for penicillin-binding proteins,including PBP 2a,and stability to staphylococcal beta-lactamases

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 micro g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC(50)) of 0.7 micro g/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC(50) of 0.8 micro g/ml and a MIC of 0.5 micro g/ml. The affinity of RWJ-54428 for PBPs of beta-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A beta-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal beta-lactamases, including beta-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to beta-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against beta-lactam-resistant gram-positive bacteria.     

In vivo pharmacodynamics of a new oxazolidinone (linezolid)

Linezolid is a new oxazolidinone with activity against gram-positive cocci. We determined the in vivo activity of linezolid against four strains of Staphylococcus aureus (two methicillin-susceptible S. aureus [MSSA] strains and two methicillin-resistant S. aureus strains) and one penicillin-susceptible Streptococcus pneumoniae (PSSP) strain, two penicillin-intermediate S. pneumoniae strains, and five penicillin-resistant S. pneumoniae strains. The mice had 10(6.3) to 10(7.7) CFU/thigh before therapy and were then treated for 24 h with 5 to 1,280 mg of linezolid/kg divided into 1, 2, 4, 8, or 16 doses. The killing activities after 4 h of therapy ranged from 2.4 to 5.0 log(10) CFU/thigh against S. pneumoniae and 1.35 to 2.2 log(10) CFU/thigh against S. aureus. Increasing doses produced minimal concentration-dependent killing; doses of 20 and 80 mg/kg produced no in vivo postantibiotic effects (PAEs) with PSSP and modest PAEs (3.4 and 3.2 h) with MSSA. Pharmacokinetic studies at doses of 20 and 80 mg/kg by high-pressure liquid chromatography analysis exhibited peak dose values of 0.68 and 0.71 and elimination half-lives of 1.02 and 1.00 h. Linezolid MICs ranged from 0.5 to 1.0 micro g/ml for S. pneumoniae and from 1.0 to 4.0 micro g/ml for S. aureus. A sigmoid dose-response model was used to estimate the dose required to achieve a net bacteriostatic effect over 24 h. Static doses against S. pneumoniae ranged from 22.2 to 97.1 mg/kg/24 h and from 133 to 167 mg/kg/24 h for S. aureus. The 24-h area under the concentration-time curve (AUC)/MIC ratio was the major parameter determining the efficacy of linezolid against PSSP (R(2) = 82% for AUC/MIC versus 57% for T>MIC and 59% for the peak level in serum/MIC [peak/MIC]). It was difficult to determine the most relevant pharmacokinetic/pharmacodynamic parameter with S. aureus, although the outcomes correlated slightly better with the 24-h AUC/MIC ratio (R(2) = 75%) than with the other parameters (T>MIC R(2) = 75% and peak/MIC R(2) = 65%). The 24-h AUC/MIC ratio required for a bacteriostatic effect with linezolid varied from 22 to 97 (mean = 48) for pneumococci and from 39 to 167 (mean = 83) for staphylococci. Based upon a pharmacokinetic goal of a 24-h AUC/MIC of 50 to 100, a dosage regimen of 600 mg given either intravenously or orally twice daily would achieve success against organisms with MICs as high as 2 to 4 micro g/ml.     

Pharmacodynamics of a new streptogramin, XRP 2868, in murine thigh and lung infection models

XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10(6.8) to 10(8.4) CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and -1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 10(6.1) to 10(7.8) CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 microg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs +/- standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 +/- 10 and 31 +/- 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.     

Bactericidal activities of meropenem and ertapenem against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a neutropenic mouse thigh model

The purpose of this study was to examine the in vivo efficacies of meropenem and ertapenem against extended-spectrum-beta-lactamase (ESBL)-producing isolates with a wide range of MICs. Human-simulated dosing regimens in mice were designed to approximate the free drug percent time above the MIC (fT>MIC) observed for humans following meropenem at 1 g every 8 h and ertapenem at 1 g every 24 h. An in vivo neutropenic mouse thigh infection model was used to examine the bactericidal effects against 31 clinical ESBL Escherichia coli and Klebsiella pneumoniae isolates and 2 non-ESBL isolates included for comparison at a standard 10(5) inoculum. Three isolates were examined at a high 10(7) inoculum as well. Meropenem displayed greater in vitro potency, with a median MIC (range) (microg/ml) of 0.125 (0.03 to 32), than did ertapenem, with 0.5 (0.012 to 128). Seven of the 31 ESBL isolates were removed from the efficacy analysis due to their inability to establish infection in the mouse model. When MICs wereMIC>or=23%) and meropenem (fT>MIC>or=75%). Ertapenem showed bacterial regrowth for seven of eight isolates, with MICs of>or=2 microg/ml (fT>MICMIC=30 to 65%). At a 10(7) inoculum, both agents eradicated bacteria due to adequate exposures (fT>MIC=20 to 45%). Due to low MICs, no difference in bacterial kill was noted for the majority of ESBL isolates tested. However, for isolates with raised ertapenem MICs of>or=2 microg/ml, meropenem displayed sustained efficacy due to its greater in vitro potency and higher resultant fT>MIC.     

Pharmacodynamic assessment of ertapenem (MK-0826) against Streptococcus pneumoniae in a murine neutropenic thigh infection model

The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against Streptococcus pneumoniae strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen S. pneumoniae isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 10(5) to 10(6) CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from -0.22 to -4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the S. pneumoniae isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were 相似文献   

Pharmacodynamics of a new cephalosporin, PPI-0903 (TAK-599), active against methicillin-resistant Staphylococcus aureus in murine thigh and lung infection models: identification of an in vivo pharmacokinetic-pharmacodynamic target

PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant Streptococcus pneumoniae and Staphylococcus aureus. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with S. pneumoniae ATCC 10813, S. aureus ATCC 29213, or Escherichia coli ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours. Nonlinear regression analysis was used to determine which pharmacokinetic-pharmacodynamic (PK-PD) index (total and free 65% drug) best correlated with CFU/thigh at 24 h. Similar to other beta-lactam antibiotics, PPI-0903 produced short to modest in vivo PAEs with either S. pneumoniae or E. coli. The percent time that serum concentrations were above the MIC (%T>MIC) was the PK-PD index that best correlated with efficacy (R2=84 to 88% for the three organisms, compared with 9 to 41% for peak/MIC and 30 to 82% for the area under the concentration-time curve/MIC). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the free-drug %T>MIC needed for efficacy of PPI-0903 varied among pathogens (including resistant strains). Mice infected with one of five isolates of S. pneumoniae, four isolates of S. aureus, or four gram-negative bacilli were treated for 24 h with 0.10 to 400 mg/kg of PPI-0903 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h and to produce a reduction in the burden of organisms from the start of therapy by 1 and 2 log10 CFU/thigh. MICs ranged from 0.008 to 1 microg/ml. Mean free-drug %T>MICs+/-the standard deviation associated with the static effect endpoint for S. pneumoniae, S. aureus, and gram-negative isolates were 39+/-9, 26+/-8, and 32+/-6, respectively. Methicillin and penicillin resistance did not alter the magnitude of free-drug %T>MIC required for efficacy. The free-drug %T>MIC necessary for efficacy was slightly reduced in animals with normal neutrophil counts. Treatment effect was similar in both the thigh and lung infection models. The pharmacodynamic characteristics of PPI-0903 are similar to those of other compounds within the cephalosporin class.     

Efficacy of human simulated exposures of ceftaroline administered at 600 milligrams every 12 hours against phenotypically diverse Staphylococcus aureus isolates

Ceftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline against S. aureus in both the neutropenic and immunocompetent mouse thigh infection models. Twenty-six S. aureus isolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 μg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log(10) CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log(10) CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log(10) CFU/ml reduction (log(10) CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 μg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all tested S. aureus isolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline against S. aureus, including MRSA, with MICs of ≤4 μg/ml.     

Pharmacodynamics of the new fluoroquinolone gatifloxacin in murine thigh and lung infection models

Gatifloxacin is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of gatifloxacin and determine which pharmacokinetic (PK)-pharmacodynamic (PD) parameter best correlated with efficacy. The thighs of mice were infected with 10(6.5) to 10(7.4) CFU of strains of Staphylococcus aureus, Streptococcus pneumoniae, or Escherichia coli, and the mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg of body weight per day, with the dose fractionated for dosing every 3, 6, 12, and 24 h. Levels in serum were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were calculated from serial values of the log(10) numbers of CFU per thigh 2 to 4 h after the administration of doses of 8 and 32 mg/kg. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the numbers of CFU per thigh at 24 h. Pharmacokinetic studies revealed peak/dose values of 0.23 to 0.32, area under the concentration-time curve (AUC)/dose values of 0.47 to 0.62, and half-lives of 0.6 to 1.1 h. Gatifloxacin produced in vivo PAEs of 0.2 to 3.1 h for S. pneumoniae and 0.4 to 2.3 h for S. aureus. The 24-h AUC/MIC was the PK-PD parameter that best correlated with efficacy (R(2) = 90 to 94% for the three organisms, whereas R(2) = 70 to 81% for peak level/MIC and R(2) = 48 to 73% for the time that the concentration in serum was greater than the MIC). There was some reduced activity when dosing every 24 h was used due to the short half-life of gatifloxacin in mice. In subsequent studies we used the neutropenic and nonneutropenic murine thigh and lung infection models to determine if the magnitude of the AUC/MIC needed for the efficacy of gatifloxacin varied among pathogens (including resistant strains) and infection sites. The mice were infected with 10(6.5) to 10(7.4) CFU of four isolates of S. aureus (one methicillin resistant) per thigh, nine isolates of S. pneumoniae (two penicillin intermediate, four penicillin resistant, and two ciprofloxacin resistant) per thigh, four isolates of the family Enterobacteriaceae per thigh, a single isolate of Pseudomonas aeruginosa per thigh, and 10(8.3) CFU of Klebsiella pneumoniae per lung. The mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg every 6 or 12 h. A sigmoid dose-response model was used to estimate the dose (in milligrams per kilogram per 24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.015 to 8 microg/ml. The 24-h AUC/MICs for each static dose (1.7 to 592) varied from 16 to 72. Mean +/- standard deviation 24-h AUC/MICs for isolates of the family Enterobacteriaceae, S. pneumoniae, and S. aureus were 41 +/- 21, 52 +/- 20, and 36 +/- 9, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC required for efficacy. The 24-h AUC/MICs required to achieve bacteriostatic effects against K. pneumoniae were quite similar in the thigh and lung (70 versus 56 in neutropenic mice and 32 versus 43 in nonneutropenic mice, respectively). The magnitude of the 24-h AUC/MIC of gatifloxacin required for efficacy against multiple pathogens varied only fourfold and was not significantly altered by drug resistance or site of infection.     

In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci, and enterococci.

The in vitro activity of RP 59500, a semisynthetic pristinamycin, was compared with the activities of vancomycin, oxacillin, ampicillin, gentamicin, ciprofloxacin, and rifampin against five Staphylococcus species, five Streptococcus species, and four Enterococcus species. For staphylococci, MICs were 0.13 to 1 microgram/ml and the MICs for 90% of the strains tested (MIC90s) were 0.13 to 0.5 microgram/ml; there were no differences between oxacillin-susceptible and -resistant strains. For streptococci, MICs were 0.03 to 4 micrograms/ml and MIC90s were 0.25 to 2 micrograms/ml; viridans group streptococci were the least susceptible streptococci. For enterococci, MICs were 0.25 to 32 micrograms/ml and MIC90s were 2 to 4 micrograms/ml; Enterococcus faecalis was the least susceptible. Vancomycin was the only comparative drug with consistent activity against all species of gram-positive cocci. With RP 59500, raising the inoculum 100-fold, lowering the pH of cation-adjusted Mueller-Hinton broth to 5.5, or omitting cation supplementation had little effect on MICs, but 50% serum increased MICs 2 to 4 dilution steps. The differences between MBCs and MICs were greater for staphylococci and enterococci than for streptococci. Time-kill studies with 24 strains indicated that RP 59500 concentrations 2-, 4-, and 16-fold greater than the MICs usually killed bacteria of each species at similar rates; reductions in CFU per milliliter were less than those observed with oxacillin or vancomycin against staphylococci and less than those observed with ampicillin against enterococci. RP 59500 antagonized the bactericidal activities of oxacillin and gentamicin against Staphylococcus aureus ATCC 29213 and that of ampicillin against E. faecalis ATCC 29212. Against the latter, combination with gentamicin was indifferent. RP 59500 has a broad spectrum of in vitro activity against gram-positive cocci; combining it with other drugs is not advantageous.     

Pharmacodynamics of the new des-f(6)-quinolone garenoxacin in a murine thigh infection model

Garenoxacin is a new des-F(6)-quinolone with broad-spectrum activity against both gram-positive cocci and gram-negative bacilli. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of garenoxacin and determine which pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with efficacy. Serum drug levels following three fourfold-escalating single-dose levels of garenoxacin were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 16 and 64 mg/kg of body weight. Mice had 10(6.5) to 10(6.7) CFU of Streptococcus pneumoniae strain ATCC 10813 or Staphylococcus aureus strain ATCC 33591 per thigh when they were treated for 24 h with garenoxacin at a dose of 4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing regimens. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the measurement of CFU/thigh at 24 h. Pharmacokinetic studies yielded peak/dose values of 0.2 to 0.3, area under the concentration-time curve (AUC)/dose values of 0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin produced in vivo PAEs of 1.4 to 8.2 h with S. pneumoniae ATCC 10813, 7.6 to >12.4 h with S. aureus ATCC 25923, and 0 to 1.5 h with Klebsiella pneumoniae ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD parameter that best correlated with efficacy (R2=71 to 90% for the two organisms compared with 43 to 56% for the peak/MIC ratio and 47 to 75% for percent time above the MIC [% T>MIC]). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC ratio needed for efficacy of garenoxacin varied among pathogens (including resistant strains). Mice had 10(5.9) to 10(7.2) CFU of 6 strains of S. aureus (2 methicillin resistant), 11 strains of S. pneumoniae (5 penicillin susceptible, 1 penicillin intermediate, and 5 penicillin resistant, and of the resistant strains, 3 were also ciprofloxacin resistant), and 4 gram-negative strains per thigh when treated for 24 h with 1 to 64 mg of garenoxacin per kg every 12 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4 microg/ml. The free drug 24-h AUC/MIC ratios for each static dose (2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC ratios +/- standard deviations for S. pneumoniae, S. aureus, and gram-negative strains were 33 +/- 18, 81 +/- 37, and 33 +/- 30, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy.     

In vivo pharmacodynamic profiling of doripenem against Pseudomonas aeruginosa by simulating human exposures

Doripenem is a new broad-spectrum carbapenem with activity against a range of gram-negative pathogens, including nonfermenting bacteria such as Pseudomonas aeruginosa. The objective of this study was to evaluate simulated human exposures to doripenem using a neutropenic murine thigh infection model against 24 clinical P. aeruginosa isolates with a wide range of MICs. Dosing regimens in mice were designed to approximate the free time above MIC (fT>MIC) observed with 500 mg doripenem every 8 h given as either a 1-h or 4-h intravenous infusion in humans. Maximal antibacterial killing was associated with doripenem exposures of > or =40% fT>MIC; bacteriostatic effects were noted at approximately 20% fT>MIC. The simulated 1-h infusion provided bactericidal effects for isolates with MICs of < or =2 microg/ml, while variable killing was noted for isolates with MICs of 4 to 8 microg/ml and regrowth for isolates with an MIC of 16 microg/ml. The 4-h infusion regimen displayed similar killing for isolates with MICs of < or =2 microg/ml and enhanced activity for two of the four isolates with an MIC of 4 microg/ml. Given that the 4-h regimen yields negligible fT>MIC for MICs of > or =8 microg/ml, regrowth was generally observed. Simulated doses of 500 mg doripenem every 8 h infused over 1 h demonstrated antibacterial killing for P. aeruginosa isolates with MICs of 0.125 to 8 microg/ml. Exposures of > or =40% fT>MIC resulted in the most pronounced bactericidal effects, while killing was variable for 20 to 30% fT>MIC. Infusing doses over 4 h enhanced efficacy against selected pseudomonal isolates with an MIC of 4 microg/ml.     

N,N-dimethylglycyl-amido derivative of minocycline and 6-demethyl-6-desoxytetracycline, two new glycylcyclines highly effective against tetracycline-resistant gram-positive cocci.

The in vitro activities of the N,N-dimethylglycyl-amino derivative of minocycline (DMG-MINO) and 6-dimethyl-6-dexoxytetracycline (DMG-DMDOT), members of a new generation of tetracyclines, were evaluated by an agar dilution method and were compared with those of tetracycline and minocycline against 224 tetracycline-resistant and 73 tetracycline-susceptible recent clinical isolates of gram-positive cocci, including multiple-antibiotic-resistant methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The MICs of DMG-MINO and DMG-DMDOT were up to 500- to 2,000-fold lower than those of tetracycline against methicillin-resistant S. aureus and Streptococcus pneumoniae (MIC for 50% of strains tested [MIC50], < 0.06 microgram/ml). Against Streptococcus groups A, B, C, and G and Enterococcus faecalis, the MIC50 was 0.5 microgram/ml. MIC50s were greater only for coagulase-negative staphylococci (2 micrograms/ml). These data indicate that DMG-MINO and DMG-DMDOT are very potent drugs, and further in vitro and in vivo studies are warranted.     

Pharmacodynamics of TD-1792, a novel glycopeptide-cephalosporin heterodimer antibiotic used against Gram-positive bacteria, in a neutropenic murine thigh model

TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log(10) CFU kill effective dose (ED(1-log kill)) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log(10) CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log(10) stasis dose (ED(stasis)) and ED(1-logkill) doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r(2) = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r(2) = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r(2) = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log(10) CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.     

In vitro antibacterial activities of DQ-113, a potent quinolone, against clinical isolates

The antibacterial activity of DQ-113, formerly D61-1113, was compared with those of antibacterial agents currently available. MICs at which 90% of the isolates tested are inhibited (MIC90s) of DQ-113 against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and methicillin-susceptible and -resistant coagulase-negative staphylococci were 0.03, 0.008, 0.03, and 0.06 microg/ml, respectively. Moreover, DQ-113 showed the most potent activity against ofloxacin-resistant and methicillin-resistant S. aureus, with a MIC90 of 0.25microg/ml. DQ-113 inhibited the growth of all strains of Streptococcus pneumoniae, including penicillin-resistant strains, and Streptococcus pyogenes at 0.06 microg/ml, and DQ-113 was more active than the other quinolones tested against Enterococcus faecalis and Enterococcus faecium with MIC90s of 0.25 and 2 microg/ml, respectively. Against vancomycin-resistant enterococci, DQ-113 showed the highest activity among the reference compounds, with a MIC range from 0.25 to 2 microg/ml. DQ-113 also showed a potent activity against Haemophilus influenzae, including ampicillin-resistant strains (MIC90, 0.015 microg/ml), and Moraxella catarrhalis (MIC90, 0.03 microg/ml). The activity of DQ-113 was roughly comparable to that of levofloxacin against all species of ENTEROBACTERIACEAE: The MICs of DQ-113 against ofloxacin-susceptible Pseudomonas aeruginosa ranged from 0.25 to 2 microg/ml, which were four times higher than those of ciprofloxacin. From these results, DQ-113 showed the most potent activity against gram-positive pathogens among antibacterial agents tested.     

Efficacy of human simulated exposures of ceftaroline against phenotypically diverse Enterobacteriaceae isolates

Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including Enterobacteriaceae, and Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical Enterobacteriaceae in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five Enterobacteriaceae isolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and five Escherichia coli isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log(10) CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤ 1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤ 2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against Enterobacteriaceae with MICs of ≤ 1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.     

Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations

Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the treatment of respiratory-tract infections in children. While this agent has provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Streptococcus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the neutropenic murine thigh infection model. To simulate the pharmacokinetic profile of cefprozil in children, the renal function of mice was impaired with uranyl nitrate, and a commercially available cefprozil suspension (6 mg/kg of body weight) was administered orally every 12 h. Mice were infected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h postinfection, thighs were harvested to determine bacterial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was observed with MICs of < or =3 microg/ml, while either minimal killing or growth was detected with MICs of > or =4 microg/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were < or =2 microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in substantial mortality. These studies demonstrate the effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are < or =2 microg/ml using a drug exposure typically observed in children. These data support a susceptibility breakpoint of < or =2 microg/ml for cefprozil.