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1.  Inoculum Effect with Cefazolin among Clinical Isolates of Methicillin-Susceptible Staphylococcus aureus: Frequency and Possible Cause of Cefazolin Treatment Failure▿  
Methicillin (meticillin)-susceptible Staphylococcus aureus (MSSA) strains producing large amounts of type A β-lactamase (Bla) have been associated with cefazolin failures, but the frequency and impact of these strains have not been well studied. Here we examined 98 MSSA clinical isolates and found that 26% produced type A Bla, 15% type B, 46% type C, and none type D and that 13% lacked blaZ. The cefazolin MIC90 was 2 μg/ml for a standard inoculum and 32 μg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of ≥16 μg/ml with 107 CFU/ml) (9 type A and 10 type C Bla producers). At the high inoculum, type A producers displayed higher cefazolin MICs than type B or C producers, while type B and C producers displayed higher cefamandole MICs. Among isolates from hemodialysis patients with MSSA bacteremia, three from the six patients who experienced cefazolin failure showed a cefazolin inoculum effect, while none from the six patients successfully treated with cefazolin showed an inoculum effect, suggesting an association between these strains and cefazolin failure (P = 0.09 by Fisher's exact test). In summary, 19% of MSSA clinical isolates showed a pronounced inoculum effect with cefazolin, a phenomenon that could explain the cases of cefazolin failure previously reported for hemodialysis patients with MSSA bacteremia. These results suggest that for serious MSSA infections, the presence of a significant inoculum effect with cefazolin could be associated with clinical failure in patients treated with this cephalosporin, particularly when it is used at low doses.
PMCID: PMC2715590  PMID: 19487449
2.  Prevalence of blaZ Gene Types and the Inoculum Effect with Cefazolin among Bloodstream Isolates of Methicillin-Susceptible Staphylococcus aureus 
We sought to define the prevalence of blaZ gene types and the inoculum effect to cefazolin among methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections. The blaZ gene was present in 142/185 (77%) isolates. A total of 50 (27%) isolates had a ≥4-fold increase in the cefazolin MIC from a standard to a high inoculum, and 8 (4%) demonstrated a nonsusceptible cefazolin MIC, all type A blaZ strains. The efficacy of cefazolin in the presence of the inoculum effect requires further study.
PMCID: PMC3421557  PMID: 22585225
3.  Effect of Inoculum and of Beta-Lactamase on the Anti-Staphylococcal Activity of Thirteen Penicillins and Cephalosporins 
Because there are few persuasive data for selecting one semisynthetic penicillin or cephalosporin over another for treatment of serious staphylococcal infections, 118 recent clinical isolates of Staphylococcus aureus were studied to determine to what extent the presence of β-lactamase affected the relative anti-staphylococcal activity of six penicillins and seven cephalosporins. In addition, the effect of inoculum was studied for its possible effect on the anti-staphylococcal activity of the 13 β-lactam antibiotics. By all criteria, methicillin and nafcillin were clearly more resistant to both the inoculum effect and the production of staphylococcal β-lactamase, whereas benzylpenicillin and cephaloridine (especially benzyl-penicillin) were the most susceptible to these effects. Cephazolin was clearly more susceptible to staphylococcal β-lactamase and heavy inocula than the other cephalosporins (with the exception of cephaloridine), whereas cephalothin was the most resistant cephalosporin to these factors. The minimal inhibitory concentration for benzylpenicillin for tests with undiluted inoculum, compared to results with inoculum diluted 10−4, differed by a factor up to 16,384, whereas with methicillin and nafcillin the differences were rarely more than twofold. Ratios for the other 10 antibiotics fell between these extremes. These results suggest that methicillin or nafcillin is most stable to staphylococcal β-lactamase, and that benzylpenicillin and cephaloridine are the most susceptible.
PMCID: PMC429316  PMID: 1167043
4.  In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin 
Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity.
PMCID: PMC3754321  PMID: 23796934
5.  Comparison of the inoculum effects of members of the family Enterobacteriaceae on cefoxitin and other cephalosporins, beta-lactamase inhibitor combinations, and the penicillin-derived components of these combinations. 
We compared the inoculum effects of 105 recent clinical isolates of the family Enterobacteriaceae on cefoxitin, other cephalosporins, aztreonam, and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Piperacillin and aztreonam showed the largest inoculum effect, and cefoxitin showed the smallest. The other cephalosporins tested (cefotetan, ceftizoxime, and ceftriaxone) showed an intermediate inoculum effect. In general, the inoculum effect was of greater magnitude for the penicillin and beta-lactamase inhibitor combinations than for the cephalosporins tested. Bactericidal activity was assayed and morphologic changes were monitored for selected strains exhibiting a large inoculum effect. MICs correlated with bactericidal activity at an inoculum level of 10(5) CFU/ml, while activity at 10(8) CFU/ml was variable. Cefoxitin demonstrated the least filamentous transformation and the most rapid bactericidal activity. Aztreonam showed the most marked filamentous transformation and was no longer bactericidal at 10(8) CFU/ml. The beta-lactamase inhibitor combinations showed variable bactericidal activity, and regrowth occurred with a number of strains with all three agents tested.
PMCID: PMC245050  PMID: 2039208
6.  Activity of Ten Cephalosporins on Biomass of Methicillin-Susceptible and -Resistant Staphylococcus aureus 
The growth curves automatically recorded and printed during the action of 10 cephalosporins on methicillin-susceptible and methicillin-resistant Staphylococcus aureus showed the following. (i) The biomass of methicillin-susceptible S. aureus exposed to the cephalosporins increased before lysis occurred (inoculum, 106 colony-forming units per ml). Lysis was more rapid with cephalothin and cephaloridine, whose minimal inhibitory concentrations were lowest. (ii) The same biomass increase followed by lysis occurred with methicillin-resistant S. aureus, and the speed of lysis was not different from those of cephalothin (without any regrowth), cefoxitin (with regrowth of a few strains), and cephaloridine (regrowth of all strains), with methicillin-susceptible strains. A 2-log increase of inoculum (108 colony-forming units per ml) did not modify significantly the speed of lysis with cephalothin, cephaloridine, and cefoxitin, but regrowth sometimes occurred. The early transitory lysis caused by cephaloridine, cephalothin, cefamandole, and cefoxitin was not suppressed by preincubation with 32 μg of methicillin per ml, but regrowth occurred more frequently. No lysis could be observed with cefazolin, cefotaxime, cephalexin, cephradine, cefuroxime, and cefaclor unless high concentrations were achieved. (iii) From a practical point of view, the early response of the growth curve (4 h) could not determine in every case whether a strain of S. aureus was resistant or susceptible to cephalosporin. A further study of the growth curve (18 of 24 h) was necessary for this purpose. Results obtained after a few hours with automated systems should be interpreted with great caution.
PMCID: PMC283887  PMID: 6901595
7.  Susceptibility of the "penicillinase-resistant" penicillins and cephalosporins to penicillinase of Staphylococcus aureus. 
Journal of Clinical Pathology  1977;30(1):35-39.
The activities of some semisynthetic penicillins and cephalosporins have been tested against clinical strains of Staphylococcus aureus. The apparent activity in vitro varies with the method of testing used. Determination of MICs using light inocula fails to detect the destructive effect of penicillinase on the antibiotic. This was, however, demonstrated reproducibly by the use of a technique in which a heavy inoculum was pre-incubated for two hours before application of antibiotic to wells. This method of testing probably represents most of the clinical situations in which the drugs are used since both in vitro and in vivo a growing culture is exposed to an antibiotic gradient. Flucloxacillin was inactivated by penicillinase considerably more than either methicillin, cloxacillin, or nafcillin. Cephaloridine was the most vulnerable of the cephalosporins. Cephazolin, cephalothin, and cephalexin were intermediate. Cephradine was the least hydrolysed by staphylococcal penicillinase. It is recommended that the activities of all penicillins and cephalosporins against staphylococci should be tested by diffusion at 37 degrees C with pre-incubation of the culture for two hours at this temperature.
PMCID: PMC476631  PMID: 838869
8.  Time-Kill and Synergism Studies of Ceftobiprole against Enterococcus faecalis, Including β-Lactamase-Producing and Vancomycin-Resistant Isolates▿  
Ceftobiprole (BAL9141) is an investigational cephalosporin with broad in vitro activity against gram-positive cocci, including enterococci. Ceftobiprole MICs were determined for 93 isolates of Enterococcus faecalis (including 16 β-lactamase [Bla] producers and 17 vancomycin-resistant isolates) by an agar dilution method following the Clinical and Laboratory Standards Institute recommendations. Ceftobiprole MICs were also determined with a high inoculum concentration (107 CFU/ml) for a subset of five Bla producers belonging to different previously characterized clones by a broth dilution method. Time-kill and synergism studies (with either streptomycin or gentamicin) were performed with two β-lactamase-producing isolates (TX0630 and TX5070) and two vancomycin-resistant isolates (TX2484 [VanB] and TX2784 [VanA]). The MICs of ceftobiprole for 50 and 90% of the isolates tested were 0.25 and 1 μg/ml, respectively. All Bla producers and vancomycin-resistant isolates were inhibited by concentrations of ≤1 and ≤4 μg/ml, respectively, at the standard inoculum concentration. Ceftobiprole MICs at a high inoculum concentration for a subset of five Bla+ E. faecalis isolates were ≤1 μg/ml. Bactericidal activity was observed against four isolates tested at concentrations as low as 1 μg/ml regardless of the production of β-lactamase or vancomycin resistance. A combination of ceftobiprole (0.5 μg/ml) and streptomycin (25 μg/ml) was synergistic against Bla+ TX0630 and TX5070. Ceftobiprole (0.5 μg/ml) plus gentamicin (10 μg/ml) was synergistic against VanB isolate TX2484 and showed enhanced killing, but not synergism, against TX2784 (VanA), despite the absence of high-level resistance to gentamicin. In conclusion, ceftobiprole exhibited good in vitro activity against E. faecalis, including Bla+ and vancomycin-resistant strains, and exhibited synergism with aminoglycosides against selected isolates.
PMCID: PMC1891360  PMID: 17438057
9.  Use of a Heavy Inoculum in the In Vitro Evaluation of the Anti-Staphylococcal Activity of 19 Cephalosporins 
The in vitro activity of 19 cephalosporins against 105 clinical isolates of Staphylococcus aureus and S. epidermidis was determined by using a heavy inoculum, i.e., 108 to 109 organisms per ml, to maximally challenge the antibiotics. The anti-staphylococcal activities of cephaloridine and 87/312 were consistently decreased by the use of a heavy inoculum when compared with the activity obtained with two less-concentrated inocula. The activity of most of the other compounds was also decreased with the use of a heavy inoculum, but this was observed only with selected isolates. Cephapirin, cephalothin, and cefazaflur were the most active drugs against the methicillin-susceptible isolates. Cephaloridine, cefamandole, cefazaflur, and 87/312 had substantial activity against methicillin-resistant staphylococci even with heavy inocula. With the exception of cefaclor against S. aureus, the orally absorbed cephalosporins were generally one-half to one-sixteenth as active as the parenterally administered cephalosporins. The median minimal inhibitory concentrations of five of the 12 parenteral cephalosporins were lower with the methicillin-susceptible S. aureus than with the methicillin-susceptible S. epidermidis strains.
PMCID: PMC352308  PMID: 352261
10.  Cefotetan, a new cephamycin: comparison of in vitro antimicrobial activity with other cephems, beta-lactamase stability, and preliminary recommendations for disk diffusion testing. 
Cefotetan is a new, potent, 7 alpha-methoxy cephalosporin (cephamycin). The in vitro activity of cefotetan tested in a multiphasic, collaborative study against 12,260 consecutive clinical isolates and 448 selected isolates showed 93% of Enterobacteriaceae, 90% of methicillin-susceptible Staphylococcus aureus (broth dilution), 83% of Bacteroides fragilis, and 72% of non-enterococcal streptococci to be inhibited by less than or equal to 8 micrograms/ml. Beta-Lactamase-producing and -nonproducing Haemophilus influenzae strains were inhibited by less than or equal to 1.0 micrograms/ml. Cefotetan's inhibitory spectrum paralleled those of the newest generation of cephems and exceeded those of cefoxitin and cefamandole. No useful activity was present against Streptococcus faecalis or Pseudomonas aeruginosa. Cefotetan was bactericidal without significant inoculum effect and was highly resistant to hydrolysis by Richmond-Sykes types I, III, and IV beta-lactamases. Hydrolysis of the chromogenic cephalosporin PADAC (pyridine-2-azo-p-dimethylaniline cephalosporin) by type I beta-lactamases was markedly inhibited by concentrations of cefotetan similar to those of the potent inhibitor dicloxacillin. Analysis of agar disk diffusion for several disk potencies and broth dilution susceptibility tests by regression and error rate-bounding methods produced preliminary tentative zone standards (30-micrograms disk, using minimal inhibitory concentration breakpoints of less than or equal to 8 micrograms/ml susceptible and greater than 32 micrograms/ml resistant, or 75-micrograms disk, using minimal inhibitory concentration breakpoints of less than or equal to 16 micrograms/ml susceptible and greater than or equal to 64 micrograms/ml resistant) of greater than or equal to 18 mm susceptible, less than or equal to 14 mm resistant, and 15 to 17 mm indeterminate. Staphylococcus aureus testing with the 30-micrograms disk is not recommended.
PMCID: PMC185673  PMID: 6983862
11.  Antibacterial Activity of Cefuroxime, a New Cephalosporin Antibiotic, Compared with That of Cephaloridine, Cephalothin, and Cefamandole 
The in vitro activity of cefuroxime, a new cephalosporin derivative, was compared with that of cephaloridine, cephalothin, and cefamandole against strains of gram-positive and gram-negative bacteria recently isolated from clinical sources. Cefuroxime showed very similar activity to cefamandole against Staphylococcus aureus, Haemophilus influenzae, and most members of the Enterobacteriaceae. It was more active than cefamandole against gonococci, pneumococci, and most streptococci. Increasing the inoculum size appeared to have less effect on the minimum inhibitory concentrations of cefuroxime for gram-negative bacilli than has been found with the other cephalosporin derivatives, and minimum bactericidal concentrations of cefuroxime were only marginally greater than minimum inhibitory concentrations.
PMCID: PMC429599  PMID: 1267441
12.  In Vitro Activity of Cefaclor, a New Orally Administered Cephalosporin Antibiotic 
The in vitro antibacterial activity of cefaclor, cephalothin, and cephalexin against 261 clinical isolates of Staphylococcus aureus and Enterobacteriaceae was compared. Cefaclor and cephalexin were about equally active against S. aureus. Cefaclor was the most active cephalosporin against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. The effect on the antimicrobial activity using a relatively high and low inoculum was pronounced for cefaclor when compared with that of cephalothin.
PMCID: PMC429936  PMID: 907337
13.  Evidence for a purifying selection acting on the β-lactamase locus in epidemic clones of methicillin-resistant Staphylococcus aureus 
BMC Microbiology  2011;11:76.
The β-lactamase (bla) locus, which confers resistance to penicillins only, may control the transcription of mecA, the central element of methicillin resistance, which is embedded in a polymorphic heterelogous chromosomal cassette (the SCCmec element). In order to assess the eventual correlation between bla allotypes and genetic lineages, SCCmec types and/or β-lactam resistance phenotypes, the allelic variation on the bla locus was evaluated in a representative collection of 54 international epidemic methicillin-resistant Staphylococcus aureus (MRSA) clinical strains and, for comparative purposes, also in 24 diverse methicillin-susceptible S. aureus (MSSA) strains.
Internal fragments of blaZ (the β-lactamase structural gene) were sequenced for all strains. A subset of strains, representative of blaZ allotypes, was further characterized by sequencing of internal fragments of the blaZ transcriptional regulators, blaI and blaR1. Thirteen allotypes for blaZ, nine for blaI and 12 for blaR1 were found. In a total of 121 unique single-nucleotide polymorphisms (SNP) detected, no frameshift mutations were identified and only one nonsense mutation within blaZ was found in a MRSA strain. On average, blaZ alleles were more polymorphic among MSSA than in MRSA (14.7 vs 11.4 SNP/allele). Overall, blaR1 was the most polymorphic gene with an average of 24.8 SNP/allele. No correlation could be established between bla allotypes and genetic lineages, SCCmec types and/or β-lactam resistance phenotypes. In order to estimate the selection pressure acting on the bla locus, the average dN/dS values were computed. In the three genes and in both collections dN/dS ratios were significantly below 1.
The data strongly suggests the existence of a purifying selection to maintain the bla locus fully functional even on MRSA strains. Although, this is in agreement with the notion that in most clinical MRSA strains mecA gene is under the control of the bla regulatory genes, these findings also suggest that the apparently redundant function of blaZ gene for the MRSA resistant phenotype is still important for these strains. In addition, the data shows that the sensor-inducer blaR1 is the primary target for the accumulation of mutations in the bla locus, presumably to modulate the response to the presence of β-lactam antibiotic.
PMCID: PMC3102608  PMID: 21496235
β-lactamase; β-lactam resistance; allelic variation; MSSA; MRSA; mecA stabilization
14.  Identification of Cephalosporin-Resistant Staphylococcus aureus with the Disc Diffusion Method 
Methicillin-resistant strains of Staphylococcus aureus, in total 84, representing 16 laboratories in 8 different countries were all resistant to 32 μg of cephalothin per ml with the same typical heteroresistant pattern. With the disc diffusion method, they were easily detected when cephalexin discs were used. With cephalothin discs, on the other hand, 26 to 49% would have been falsely categorized as Group I or II after 24 hr. It is recommended that susceptibility testing of S. aureus to cephalosporins by using the paper disc method be performed with 30-μg cephalexin discs on Mueller-Hinton agar without blood. With an inoculum of 106 bacteria/ml, an incubation temperature of 30 C, and an incubation time of 24 hr, a zone of less than 10 mm indicates presumptive heteroresistance. This corresponds to the international recommendation with a minimal inhibitory concentration of 32 μg/ml as the upper limit of Group II.
PMCID: PMC444236  PMID: 4670484
15.  Antipneumococcal Activity of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin 
Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC50 and MIC90 values (μg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1× and 2× the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2× the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2× the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.
PMCID: PMC1087675  PMID: 15855516
16.  In Vitro Evaluation of BL-S640 Cephalosporin Antibiotic 
BL-S640, a new oral cephalosporin analogue, was evaluated in vitro against 102 gram-negative and 80 gram-positive bacteria. The antimicrobial spectrum was similar to that of previous cephalosporin analogues. Good antimicrobial activity against strains of Escherichia coli, Klebsiella, staphylococci, and streptococci was demonstrated. Relatively poor activity and/or resistance was noted among most strains of Proteus, Providencia, Pseudomonas, and Serratia. In comparative studies BL-S640 had better activity against strains of Hemophilus influenzae, Staphylococcus aureus, and Enterobacteriaceae than many cephalosporin analogues. Variation of susceptibility results was dependent upon the type of media and inoculum size. Cross-resistance between BL-S640 cephalexin, cephalothin, and cefazolin was demonstrated. Among strains of Klebsiella the more rapid selection of resistance ot other cephalosporins was in contrast to BL-S640. Experience in vitro with BL-S640 has documented its antimicrobial activity,and further studies of pharmacokinetics and therapeutic efficacy are indicated.
PMCID: PMC429311  PMID: 1167042
17.  Evaluation of Ceftobiprole in a Rabbit Model of Aortic Valve Endocarditis Due to Methicillin-Resistant and Vancomycin-Intermediate Staphylococcus aureus 
Ceftobiprole is a novel broad-spectrum cephalosporin that binds with high affinity to PBP 2a, the methicillin-resistance determinant of staphylococci, and is active against methicillin- and vancomycin-resistant Staphylococcus aureus. Ceftobiprole was compared to vancomycin in a rabbit model of methicillin-resistant S. aureus aortic valve endocarditis. Ceftobiprole and vancomycin were equally effective against endocarditis caused by methicillin-resistant S. aureus strain 76, whereas ceftobiprole was more effective than vancomycin against the vancomycin-intermediate S. aureus strain HIP5836. The activity of ceftobiprole against drug-resistant strains of S. aureus warrants its further clinical development.
PMCID: PMC549268  PMID: 15728879
18.  Antibacterial Activity of Cefamandole, a New Cephalosporin Antibiotic, Compared with that of Cephaloridine, Cephalothin, and Cephalexin 
The in vitro antibacterial activity of cefamandole, a new cephalosporin antibiotic, was compared with that of cephaloridine, cephalothin, and cephalexin against 1,213 strains of gram-positive and gram-negative bacteria recently isolated from clinical sources. The decreasing order of activity of the four agents against gram-positive cocci was cephaloridine, cephalothin, cefamandole, and cephalexin. However, cefamandole was the most active of the four against Haemophilus species and gram-negative bacilli susceptible to cephalosporins. It was also active against many strains resistant to the other cephalosporins, such as Enterobacter species and indole-positive Proteus species, but there was a marked inoculum effect with all of these organisms, and minimal bactericidal concentrations were usually considerably higher than minimal inhibitory concentrations. Cefamandole, like other cephalosporins, had no useful activity against Pseudomonas species.
PMCID: PMC444475  PMID: 4790616
19.  Comparison of a new cephalosporin, BMY 28142, with other broad-spectrum beta-lactam antibiotics. 
BMY 28142, a new broad-spectrum semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with ceftazidime, cefotaxime, moxalactam, and cefoperazone. The activity of BMY 28142 compared favorably with the activities of the other compounds against both Pseudomonas aeruginosa and Staphylococcus aureus and was somewhat greater against members of the family Enterobacteriaceae. The influence of inoculum size on MICs of BMY 28142 was small for most of the isolates tested, except Enterobacter species. With Enterobacter strains, a marked inoculum effect was found with all of the compounds, and the effect was more pronounced in broth than agar. Still, MICs of BMY 28142 in broth did not exceed 16 micrograms/ml. Of 37 Enterobacteriaceae strains resistant to one or more of the comparison beta-lactams, none were resistant, at a low inoculum size (10(4) CFU), to BMY 28142, compared with 3 for moxalactam, 18 for ceftazidime, 23 for cefotaxime, and 34 for cefoperazone; at an inoculum size of 10(6) CFU, the number of resistant strains was 12, 17, 25, 34, and 37, respectively. Binding to human serum proteins approximated 19%. Recovery of 73% of the drug in mouse urine indicated good bioavailability. The in vitro profile was sustained in vivo by the results obtained with experimental infections in mice. BMY 28142 was as effective as ceftazidime against systemic infection with P. aeruginosa and as effective as cefotaxime against systemic infection with S. aureus. Overall, infections with 18 of 20 strains representing nine genera were responsive to BMY 28142 at doses equivalent to or lower than those of the most effective of the comparison compounds.
PMCID: PMC176239  PMID: 3885849
20.  Comparison of two beta-lactamase-producing strains of Streptococcus faecalis. 
A second strain of enterococcus (PA) producing beta-lactamase (Bla+ phenotype) was compared with the previously reported Bla+ enterococcus, strain HH22. As with the original strain, there was a marked inoculum effect when PA was tested with penicillin, ampicillin, and piperacillin; no difference was noted with methicillin, cephalothin, imipenem, or vancomycin; the difference with ticarcillin was intermediate. High-level gentamicin resistance (Gmr) transferred from PA to an enterococcal recipient strain at a frequency approximately 100-fold lower than for HH22; all Gmr transconjugants from both strains were Bla+, but only PA showed linkage of Gmr and Bla+ with transfer of resistance to streptomycin, tetracycline, and chloramphenicol. EcoRI digestion of plasmid DNA from Gmr Bla+ transconjugants showed no similarities between the two strains. A 5.1-kilobase EcoRI Bla+-encoding fragment derived from HH22 was cloned into an Escherichia coli cloning vector and shown to hybridize to a 10.2-kilobase EcoRI fragment derived from PA; both fragments hybridized to an 840-base-pair staphylococcal Bla+ gene probe. These data indicate that the penicillinases are similar but encoded on different or differently arranged plasmids. The fact that both are transferable emphasizes the potential for this new streptococcal resistance determinant to disseminate.
PMCID: PMC180608  PMID: 3028251
21.  Cephalexin and Cephaloglycin Activity In Vitro and Absorption and Urinary Excretion of Single Oral Doses in Normal Young Adults 
Applied Microbiology  1968;16(11):1684-1694.
A large number of recently isolated bacterial pathogens were tested for susceptibility to cephalexin and cephaloglycin by the replica inoculating method. Strains of group A hemolytic streptococci, viridans (alpha and gamma) streptococci, pneumococci, gonococci, meningococci, and penicillin G-sensitive Staphylococcus aureus were all moderately to highly susceptible to both of these cephalosporin analogues, nearly all of the strains being two to eight (median four) times more susceptible to cephaloglycin than to cephalexin. The penicillin G-resistant, penicillinase-producing strains of S. aureus varied in their susceptibility; many were moderately resistant to both analogues, particularly to cephalexin. Strains of enterococci, Haemophilus influenzae, and most of the common gram-negative bacilli were moderately to highly resistant. Reducing the size of the inoculum had variable effects on inhibition by these drugs, depending on the species or strain. The activity of cephalexin was very little affected by pH of the medium within the clinical range or by incubation at 37 C in broth for up to 24 hr. In contrast, cephaloglycin in broth deteriorated rapidly at 37 C, and its activity was markedly reduced in alkaline medium. Both cephalexin and cephaloglycin were rapidly absorbed and excreted into the urine after single oral doses of 500 mg. Much higher levels were achieved and sustained with the former. Absorption of both analogues was delayed when taken with food, and the levels in the serum were significantly higher and better sustained when probenecid was also given. Very high concentrations of cephalexin were excreted into the urine during the first 4 hr, and the levels were still high in the 4- to 8-hr collection. The concentrations of cephaloglycin in the urine at these times were much lower. An average of 80 to 93% of the dose of cephalexin and 25 to 30% of the cephaloglycin were accounted for as active drug in the urine collected in 8 hr. Both analogues were well tolerated.
PMCID: PMC547740  PMID: 4387222
22.  beta-Lactamase-mediated inactivation and efficacy of cefazolin and cefmetazole in Staphylococcus aureus abscesses. 
12694668 Clinical reports and animal models have demonstrated that cefazolin may have decreased efficacy against some strains of Staphylococcus aureus because of type A beta-lactamase-mediated hydrolysis. We sought to measure biologically active cefazolin concentrations within abscesses with high concentrations of S. aureus and compare the concentrations with those of cefmetazole, a beta-lactamase-stable cephamycin. A type A beta-lactamase-producing strain of S. aureus with a demonstrated inoculum effect against cefazolin (MIC at an inoculum of 5 x 10(5) CFU/ml, 1.0 micrograms/ml; MIC at an inoculum of 5 x 10(7) CFU/ml, 32.0 micrograms/ml) but not cefmetazole (MICs at inocula of 5 x 10(5) and 5 x 10(7) CFU/ml, 2.0 micrograms/ml) was used. Cefazolin or cefmetazole (100 mg/kg of body weight every 8 h for 8 days) was administered to rabbits with infected tissue cages. No differences in the concentrations of the two drugs in the uninfected tissue cages were observed. Higher concentrations of cefmetazole than cefazolin were found in infected tissue cages at day 3 (5.9 +/- 0.7 versus 2.2 +/- 0.3 micrograms/ml; P < 0.01), day 5 (9.1 +/- 2.6 versus 3.6 +/- 0.7 micrograms/ml; P = 0.02), and day 8 (9.4 +/- 1.4 versus 4.8 +/- 0.9 micrograms/ml; P = 0.01) after infection. Cefazolin and cefmetazole were equally effective in reducing the bacterial concentration in the abscess. In vitro experiments demonstrated greater cefazolin than cefmetazole degradation by S. aureus, but the differences were greater in serum than in abscess fluid supernatants. We conclude that abscess cefazolin concentrations are diminished by type A beta-lactamase-producing S. aureus, but this did not affect drug efficacy in this model.
PMCID: PMC187639  PMID: 8452349
23.  In vitro activity of an orally administered cephalosporin, LY164846, against potentially pathogenic respiratory and dermal bacterial isolates. 
The antibacterial activity of LY164846, a new orally administered semisynthetic cephalosporin, was compared with that of amoxicillin-clavulanic acid against 492 potentially pathogenic respiratory tract and dermal isolates. Against groups A, B, and G streptococci; pneumococci; staphylococci (other than methicillin resistant); Haemophilus influenzae; Branhamella catarrhalis; and meningococci, the MICs for 90% of strains tested of LY164846 and amoxicillin-clavulanic acid were less than or equal to 4 and less than or equal to 1 microgram/ml, respectively. LY164846 was equally active against beta-lactamase-positive and -negative strains of Haemophilus and Staphylococcus. MBC to MIC ratios of LY164846 versus H. influenzae were less than or equal to 2, while those with Staphylococcus aureus were more difficult to determine because of skipped tubes or paradoxic effects. There were minimal inoculum, pH, or serum effects on LY164846 activity against H. influenzae and S. aureus. In time-kill studies, LY164846 and amoxicillin-clavulanic acid at double MICs were 99.9 to 100% bactericidal to H. influenzae in 24 h; two times the MIC of LY164846 and four times the MIC of cephalexin were 99.9 to 100% bactericidal to S. aureus in 24 h. Based on error-rate-bounded analysis, the following interpretative guidelines for 30-micrograms LY164846 disk diffusion test diameters are suggested: greater than or equal to 19 mm, susceptible (MIC, less than or equal to 4 micrograms/ml); 16 to 18 mm, intermediate (MIC, greater than 4 but less than or equal to 8 micrograms/ml); less than or equal to 15 mm, resistant (MIC, greater than 8 micrograms/ml).
PMCID: PMC180441  PMID: 3486628
24.  In vitro activities of LY163892, cefaclor, and cefuroxime. 
The in vitro activity of LY163892, a synthetic oral cephalosporin, was compared with those of cefaclor and cefuroxime against 1,193 clinical isolates. MIC ranges and MICs for 50 and 90% of isolates of the three cephalosporins were comparable. The activities of LY163892 and cefaclor were, however, highly inoculum dependent against beta-lactamase-positive Haemophilus influenzae and Staphylococcus aureus; that of cefuroxime was not. LY163892 and cefuroxime appeared stable in microdilution trays stored at 5 and -20 degrees C for 5 weeks, in contrast to cefaclor which remained stable for more than a week only at -5 degrees C.
PMCID: PMC172113  PMID: 3348605
25.  Laboratory Evaluation of FR10024, a New Cephalosporin Derivative 
FR10024 is a broad-spectrum antibiotic. The in vitro antibacterial activity of FR10024 against clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis is greater than that of any of the cephalosporins developed to date. Indole-positive Proteus, Enterobacter, and Citrobacter are resistant to FR10024, as is true for the other cephalosporins. However, more than half of the strains of Enterobacter and Citrobacter tested were susceptible to FR10024 at an inoculum of 106 cells/ml. A single subcutaneous injection of FR10024 to mice with peritoneal infections due to S. aureus and several species of gram-negative bacilli gave a protective effect inferior to that of cefazolin but appeared to be superior to that of cephalothin. When given in two divided doses, however, the protective effect of FR10024 was enhanced and almost equaled that of cefazolin. The serum levels and rates of urinary recovery of FR10024 varied in different animal species. The mean peak serum level of FR10024 in humans after a single intramuscular injection of 500 mg was two times higher than that of cephalothin. The serum half-life after intramuscular injections of 250 and 500 mg was slightly shorter than that of cephalothin. After receiving 250 mg of FR10024 intramuscularly the urinary recovery rate was 87.7% in healthy volunteers. The biliary excretion rate of FR10024 was particularly high. The 24-h excretion of FR10024 in rats was 63.3%, this being six to seven times higher than that for cefazolin, which has the highest biliary excretion of the other known cephalosporins. When FR10024 was injected intramuscularly (20 mg/kg), it was found that the hepatic levels of FR10024 in rats were the highest of all the cephalosporins, including cefazolin, but the levels of FR10024 in other tissues were not as high as those of cefazolin.
PMCID: PMC351918  PMID: 836014

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