Combination effect of antibiotics against bacteria isolated from keratitis using fractional inhibitory concentration index.

PURPOSE: To study the in vitro interaction of fluoroquinolones such as levofloxacin (LVFX), gatifloxacin (GFLX), or moxifloxacin (MFLX) in combination with tobramycin (TOB) or cefmenoxime (CMX) against clinical isolates of bacteria from keratitis. METHODS: The activity of each drug alone was determined by an agar dilution method. Checkerboard synergy testing was then performed against 47 isolates, including Staphylococcus species, Streptococcus species, and Pseudomonas aeruginosa. Antimicrobial combinations were classified as synergistic, additive, indifferent, or antagonistic, according to their fractional inhibitory concentration. RESULTS: The average fractional inhibitory concentration indexes of combined use of LVFX/CMX or GFLX/CMX in Staphylococcus species and Streptococcus species, and LVFX/CMX, GFLX/CMX, MFLX/CMX in gram-negative rods were low. The additive activity of the following drug combinations were seen in more than 70% of isolates: LVFX/CMX and GFLX/CMX against gram-positive cocci and LVFX/CMX, GFLX/CMX, MFLX/CMX against gram-negative rods. No consistent synergistic or antagonistic effect was observed with the combinations used. CONCLUSION: The combination of LVFX/CMX or GFLX/CMX was predominantly additive for all tested isolates.

[Drug sensitivity of causative agents in ocular infection of external adnexa and anterior segments--multicenter study of causative agents and drug sensitivity of ocular infection by the Japanese Association for Ocular Infection part II].

PURPOSE: To report the drug sensitivity of causative agents produced by ocular infection of external adnexa and anterior segments investigated by the nationwide survey conducted by Japanese Association for Ocular Infection between September, 2007 and August, 2008. SUBJECTS AND METHODS: Among all strains isolated, causative and presumed causative agents were selected according to the criteria described, and drug sensitivity tests were conducted by minimum inhibitory concentrations (MIC) with 10 kinds of antimicrobial agents including 5 fluoroquinolones. RESULTS: Among 281 causative isolates, cefmenoxime (CMX) showed the highest sensitivity, followed by fluoroquinolones. Staphylococci and Streptococci were more sensitive to fluoroquinolones when compared to the others. Haemophilus influenzae was very sensitive to all fluoroquinolones. Corynebacterium spp. and Propionibacterium acnes were most sensitive to CMX and erythromycin respectively. CONCLUSION: CMX and fluoroquinolones showed generally good sensitivity among causative pathogens of ocular infection.

Ceftezole, a cephem antibiotic, is an alpha-glucosidase inhibitor with in vivo anti-diabetic activity.

Using a high throughput-compatible assay to screen for potential alpha-glucosidase inhibitors, we found that the beta-lactam antibiotic ceftezole exhibited potent alpha-glucosidase inhibitory activity. In in vitro alpha-glucosidase assays, ceftezole was shown to be a reversible, non-competitive inhibitor of yeast alpha-glucosidase with a Ki value of 5.78 x 10(-7) M when the enzyme mixture was pretreated with ceftezole. Using an in vivo streptozotocin-induced mouse model, we confirmed that blood glucose levels decreased by 30% 20 min after ceftezole treatment (10 mg/kg/day). Expression levels of glycogen synthase kinase-3, peroxisome proliferator-activated receptor-gamma, and uncoupling protein-3 mRNA were also slightly decreased compared to controls following ceftezole treatment. Taken together, these in vivo and in vitro results suggest that ceftezole may be a clinically useful anti-diabetic compound.

In vitro synergistic effects of double combinations of beta-lactams and azithromycin against clinical isolates of Neisseria gonorrhoeae.

In Japan, Neisseria gonorrhoeae, a sexually transmitted pathogen, has recently shown significant resistance to various antimicrobial agents. In this study, a checkerboard method was utilized to investigate the in vitro activities of cefixime (CFIX), cefteram (CFTM), or amoxicillin (AMPC) in combination with azithromycin (AZM) against 25 clinical isolates of N. gonorrhoeae. Synergy, defined as a fractional inhibitory concentration (FIC) index of less than or equal to 0.50, was observed in 32% of isolates with CFIX+AZM, 12% of isolates with CFTM+AZM, and 4% of isolates with AMPC+AZM. Moreover, partial synergy, defined as an FIC index of greater than 0.50 and less than 1, was observed in 44% of isolates with CFIX+AZM, 68% of isolates with CFTM+AZM, and 52% of isolates with AMPC+AZM. In particular, as a result of the combination of CFIX and AZM, for all isolates, significant reductions were observed in the median CFIX minimum inhibitory concentration (MIC; from 0.25 to 0.008 microg/ml; P < 0.0001) and the median AZM MIC (from 0.12 to 0.03 microg/ml; P < 0.0001). However, antagonism, defined as an FIC index of greater than 1, was observed in only 4% of the isolates with both CFIX+AZM and CFTM+AZM, while it was seen in 12% of the isolates with AMPC+AZM. To our knowledge, this is the first study to demonstrate that the in vitro activity of CFIX against N. gonorrhoeae can be significantly enhanced in combination with AZM.

Enhancement of antimicrobial activities of cefteram or clavulanic acid/amoxicillin against cefixime-resistant Neisseria gonorrhoeae in the presence of clarithromycin or azithromycin.

We investigated the enhancement of the antimicrobial activities of beta-lactams against cefixime (CFIX)-resistant Neisseria gonorrhoeae in the presence of macrolides. Ten strains of CFIX-resistant N. gonorrhoeae, isolated between 2000 and 2003 from male patients with urethritis at Jikei University Affiliated Hospital and its related clinics in the Tokyo metropolitan area, were tested. The fractional inhibitory concentrations of clavulanic acid/amoxicillin (CVA/AMPC), CFIX, or cefteram (CFTM), in the presence of clarithromycin (CAM) or azithromycin (AZM), against these strains were determined. Synergism, partial synergism, or additivity was recognized between CVA/AMPC or CFTM and macrolides against nine strains. Additivity and partial synergism between CFTM and macrolides against nine and ten strains, respectively, were also recognized. On the other hand, antagonism between CFIX and macrolides was recognized. These results indicate that combination antimicrobial chemotherapy, using CFTM or CVA/AMPC with macrolides, is a possible alternative treatment for CFIX-resistant N. gonorrhoeae infections.

[Antimicrobial susceptibility surveillance of Streptococcus pneumoniae and Haemophilus influenzae isolates to cefteram and other antimicrobial drugs during January 2003 to July 2004].

The antimicrobial susceptibility of Streptococcus pneumoniae and Haemophilus influenzae isolates during January 2003 to July 2004 was determined to seven various antimicrobial drugs including cefteram (CFTM). The in vitro activities of these drugs against the fresh isolates were compared. The oral cephalosporins including CFTM were potently active against penicillin susceptible S. pneumoniae. The activity of CFTM and cefditoren was the most active among four oral cephalosporins. The susceptibilities of penicillin intermediate S. pneumoniae and penicillin resistant S. pneumoniae to antimicrobial agents were decreased. The MIC of CFTM was not beyond 4 microg/mL for any isolate of S. pneumoniae. The activity of CFTM was very high to beta-lactamase-negative and ampicillin-susceptible H. influenzae isolates. These MIC against all isolates were 0.03 microg/mL or less. The MIC of CFTM was not beyond 1 microg/mL for any isolate of beta-lactamase-positive H. influenzae or beta-lactamase-negative-ampicillin resistant H. influenzae. In conclusion, CFTM exhibits a potent activity against fresh isolates of S. pneumoniae and H. influenzae, and has a potential of effectiveness in the infections.

[The frequency of Streptococcus pneumoniae strains and sensitivity surveillance for several antibiotics in Gifu Prefecture].

The frequency and the antibacterial sensitivity of Streptococcus pneumoniae strains isolated from 6 key hospitals (in 5 areas) and 1 otorhinolaryngology clinic in Gifu Prefecture from February to March, 1999, were investigated with several antibiotics. A total of 128 strains of Streptococcus pneumoniae were isolated throughout the study: 47 strains (36.7%) of penicillin-susceptible S. pneumoniae (PSSP), 51 strains (39.8%) of penicillin-intermediate S. pneumoniae (PISP), and 30 strains (23.4%) of penicillin-resistant S. pneumoniae (PRSP); the resistant bacteria being relatively prominent. In these hospitals, PSSP was isolated by 38.8% in all the key hospitals and by 30% in the otolaryngology clinic with almost no discernible difference. PISP was isolated by 63.3%, higher in the otolaryngology clinic and PRSP by 28.6%, higher in the key hospitals conversely. The MIC90s in PISP and PRSP were determined with the antibiotics. In result, only cefditoren (CDTR) showed favorable antibacterial activities with the MIC90 of 0.78 microgram/ml among penicillins or oral cephems. The MIC90s of carbapenems such as imipenem (IPM), meropenem (MEPM), and panipenem (PAPM) were less than 0.39 microgram/ml; particularly, PAPM showed the highest antibacterial activities. Among new quinolones such as tosufloxacin (TFLX), levofloxacin (LVFX), sparfloxacin (SPFX), and ciprofloxacin (CPFX), TFLX showed the highest antibacterial activities with the MIC90 of 0.39 microgram/ml. Other agents showed very low antibacterial activities as the MIC90s were 25 micrograms/ml in minocycline (MINO) and more than 100 micrograms/ml in clarithromycin (CAM) and clindamycin (CLDM).

[In vitro antibacterial activities of cefteram and other beta-lactam agents against recent clinical isolates].

In vitro antibacterial activity of the third-generation oral cephem cefteram (CFTM)--ten years after its first use in the clinical setting--against recent clinical isolates was evaluated and compared with those of other oral cephems. A total of 851 clinical isolates belonging to 13 species used in this study were collected from five medical institutions across Japan during 1996. CFTM showed excellent antibacterial activity against methicillin-susceptible S. aureus and S. pyogenes, equivalent to those of other third-generation oral cephems, except cefixime. Of the S. pneumoniae strains, a high proportion, 34.1%, were penicillin-resistant strains (PRSP), with MIC values of 2.0 micrograms/ml or above, but the MIC50 of CFTM against PRSP was 1.0 microgram/ml. CFTM and the other third-generation oral cephems showed potent antibacterial activity against E. coli, K. pneumoniae, and P. mirabilis. A few strains of E. coli, however, were highly resistant to third-generation oral cephems; that might include extended-spectrum beta-lactamase producing strains. MIC values against P. vulgaris varied significantly, depending on whether they were determined by the broth micro-dilution method or the agar dilution method; growth was observed at high concentrations in the broth micro-dilution method, in which the skip phenomenon was demonstrated, but not in the agar dilution method. The reason for this discrepancy is unknown. Most strains of S. marcescens, C. freundii, and E. cloacae demonstrated resistance to CFTM and the other third-generation oral cephems. CFTM and the other third-generation oral cephems showed excellent antibacterial activities against M. (B.) catarrhalis, N. gonorrhoeae, and H. influenzae, including ampicillin-resistant strains.

In vitro and in vivo antibacterial activities of CS-834, a novel oral carbapenem.

CS-834 is a novel oral carbapenem antibiotic. This compound is an ester-type prodrug of the active metabolite R-95867. The antibacterial activity of R-95867 was tested against 1,323 clinical isolates of 35 species and was compared with those of oral cephems, i.e., cefteram, cefpodoxime, cefdinir, and cefditoren, and that of a parenteral carbapenem, imipenem. R-95867 exhibited a broad spectrum of activity covering both gram-positive and -negative aerobes and anaerobes. Its activity was superior to those of the other compounds tested against most of the bacterial species tested. R-95867 showed potent antibacterial activity against clinically significant pathogens: methicillin-susceptible Staphylococcus aureus including ofloxacin-resistant strains, Streptococcus pneumoniae including penicillin-resistant strains, Clostridium perfringens, Neisseria spp., Moraxella catarrhalis, most members of the family Enterobacteriaceae, and Haemophilus influenzae (MIC at which 90% of strains are inhibited, < or =0.006 to 0.78 microg/ml). R-95867 was quite stable to hydrolysis by most of the beta-lactamases tested except the metallo-beta-lactamases from Stenotrophomonas maltophilia and Bacteroides fragilis. R-95867 showed potent bactericidal activity against S. aureus and Escherichia coli. Penicillin-binding proteins 1 and 4 of S. aureus and 1Bs, 2, 3, and 4 of E. coli had high affinities for R-95867. The in vivo efficacy of CS-834 was evaluated in murine systemic infections caused by 16 strains of gram-positive and -negative pathogens. The efficacy of CS-834 was in many cases superior to those of cefteram pivoxil, cefpodoxime proxetil, cefdinir, and cefditoren pivoxil, especially against infections caused by S. aureus, penicillin-resistant S. pneumoniae, E. coli, Citrobacter freundii, and Proteus vulgaris. Among the drugs tested, CS-834 showed the highest efficacy against experimental pneumonia in mice caused by penicillin-resistant S. pneumoniae.

[Antibacterial activities of cefmenoxime against recent fresh clinical isolates from patients in sinusitis].

In order to evaluate antimicrobial activity of cefmenoxime (CMX), minimum inhibitory concentrations (MICs) of CMX and control drugs were determined against clinical isolates from patients of sinusitis that were obtained in our laboratory from October of 1993 to March of 1994. The results are summarized as follows; 1. CMX showed strong antimicrobial activities against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella subgenus Branhamella catarrhalis that were 3 major aerobic bacteria from sinusitis. Antimicrobial activities of CMX against benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) and PCG-resistant S. pneumoniae (PRSP) were stronger than those of ampicillin (ABPC), and these strong activities suggested that CMX might have strong antimicrobial activities against beta-lactamase producing H. influenzae and M. (B.) catarrhalis. 2. Antimicrobial activities of CMX against microaerophiles, Streptococcus constellatus, Streptococcus intermedius and Gemella morbillorum and against Peptostreptococcus spp., from chronic sinusitis and odontogenic maxillary sinusitis, were stronger than those of most of the control drugs. 3. The MIC90's of CMX against isolates from patients of sinusitis were < or = 0.025-0.39 micrograms/ml. These values were lower than transitional concentrations in mucous membrane of maxillary sinus obtained when "1% CMX nasal solution" was used with nebulizer. It appears likely that sufficient concentrations exceeding MICs against main organisms would be obtained by nebulizer treatment using CMX nasal solution.

Synthesis and biological properties of a series of optically active 2-oxaisocephems.

A novel series of (6S, 7S)-3,7-disubstituted-8-oxo-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2- carboxylic acids 9a-o, parenteral optically active 2-oxaisocephems, was synthesized, and in vitro and in vivo activities were determined against Gram-positive and Gram-negative bacteria. The 7-[2-(2-aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acet arnido derivatives, 9g, 9m and 9o, had enhanced antibacterial activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis while maintaining Gram-negative activity. It is also significant that these compounds showed more potent activity against MRSA and E. faecalis isolates than cefuzonam (10) and flomoxef (12), which are the most popular third-generation antibiotics. The combination of the 7-[2-(aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acetamido group and 2-oxaisocephem nucleus contributes to the increased antibacterial activity against these clinical isolates. The 7-[2-(2-aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acet ami do derivative 9g provided good subcutaneous efficacy and exhibited more potent activity than cefmenoxime (11) against the systemic infection with S. aureus Smith in mice. The compound 9a with a [2-(2-aminothiazol-4-yl)-2-(Z)-methoxyimino]acetamido group at the 7-position showed high in vivo efficacy on the experimental infection caused by Escherichia coli No. 29 in mice.

In vitro antibacterial activity and beta-lactamase stability of SY5555, a new oral penem antibiotic.

The antibacterial activity of SY5555, a new oral penem antibiotic, was compared with those of cefaclor, cefixime, and cefteram. SY5555 was more active than the comparison agents against methicillin-susceptible Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Citrobacter freundii, Enterobacter cloacae, Morganella morganii, Acinetobacter calcoaceticus, Clostridium spp., and Bacteroides fragilis. Against Providencia spp., Proteus spp., and Haemophilus influenzae, SY5555 was less active than cefixime or cefteram. SY5555 was inactive against methicillin-resistant S. aureus. Enterococcus faecium, Serratia marcescens, Pseudomonas aeruginosa, and Xanthomonas maltophilia, as were the comparison agents. The bactericidal activities of SY5555, cefixime, and cefteram were at or slightly greater than the MICs for clinical isolates of Escherichia coli and Klebsiella pneumoniae. SY5555 was not hydrolyzed by various types of beta-lactamases. However, SY5555 and the comparison agents were hydrolyzed by X. maltophilia (L-1) and P. aeruginosa/pMS354 beta-lactamases, two Bush group 3 beta-lactamases, SY5555 showed a high affinity, as did cefixime and cefteram, for cephalosporinases from C. freundii GN7391 and E. cloacae GN7471 strains. These results suggest that SY5555 may be more specific than existing beta-lactam antibiotics.

Mathematical examination of dual individualization principles (II): The rate of bacterial eradication at the same area under the inhibitory curve is more rapid for ciprofloxacin than for cefmenoxime.

OBJECTIVE: To compare two antibiotics at equal ranges of area under the inhibitory curve (AUIC) exposure to determine if the rate of bacterial eradication differed between these antibiotics. DESIGN: Retrospective comparison of two previously collected studies of similar patients with nosocomial pneumonia. SETTING: Hospitalized patients, most intubated in critical care units with nosocomial pneumonia. PARTICIPANTS: Patients treated with either i.v. ciprofloxacin (n = 74) or the i.v. third-generation cephalosporin cefmenoxime (n = 43) were compared for their length of treatment required to eradicate bacterial pathogens from their respective infection sites, using serial cultures from the site of infection. All patients were also assessed for clinical outcomes. Serum samples were obtained to evaluate individual patient antibiotic pharmacokinetics, which were used to model pharmacodynamics of response. The HPLC assay used for each antibiotic had interday coefficients of variation < 10 percent. Serum concentration versus time profiles were fit using the computer program ADAPT II to determine pharmacokinetic parameters for each patient. The primary drug exposure measure that related to response was the AUIC, calculated as steady-state AUC0-24/minimum inhibitory concentration. RESULTS: AUIC values in the patients ranged from 6.0 to more than 7000, yet the AUIC value was highly predictive of time to bacterial eradication (p < 0.001). Although more than 75 percent of patients eventually achieved eradication of pathogens from tracheal aspirate cultures, ciprofloxacin and cefmenoxime differed significantly in the time required to sterilize these cultures. At appropriate AUIC values (> 250) for ciprofloxacin, the median time to eradication was two days, while cefmenoxime (also at AUIC values > 250) required six days to achieve the same result. CONCLUSIONS: We conclude that the more rapid in vitro bacterial killing, which is characteristic of ciprofloxacin at optimal AUIC values, can manifest in vivo as more rapid clearance of bacteria from the respiratory tract of patients, even when both agents are controlled for initial antibacterial exposure (i.e., same AUIC).

[Antimicrobial activities of cefteram against recently clinically detected and isolated strains from patients with dental infections].

To investigate the antibiotic activity of cefteram (CFTM), the minimum inhibitory concentrations (MICs) of CFTM and of the control drugs were determined against clinically isolated strains received from November 1991 to April 1993 from 19 dental facilities throughout the country, as well as against clinically isolated strains from samples obtained at this center from patients with dental infectious diseases, and the following results were obtained. 1. 430 strains were detected in 198 cases but identified strains amounted to 425. They are comprised of 204 strains of oral streptococci (48.0%), 81 strains of Peptostreptococcus spp. (19.1%), 10 strains of Bacteroides spp. (2.4%), 23 strains of Prevotella spp. (5.4%), and 9 strains of Porphyromonas spp. (2.1%). The ratios of Gram-positive bacteria v.s. Gram-negative bacteria were 78.4% and 21.6%, respectively, and the Gram-positive bacteria were isolated at higher frequency than Gram-negative bacteria. 2. The MIC90's of CFTM against oral streptococci and Peptostreptococcus spp. were 0.10 microgram/ml and 0.05 microgram/ml, and year to year increases of incidences of resistance against CFTM were not observed. Some strains, however, appeared to have obtained resistance to CFTM. 3. Among Bacteroides spp., Prevotella spp., Porphyromonas spp. which used to belong to genus Bacteroides, there were some strains resistant to CFTM. As a whole, however, no year to year increases in the incidence of CFTM resistance among these strains also. 4. Two strains of 6 Staphylococcus aureus subsp. aureus were methicillin-resistant. 5. The above observations indicate that CFTM still shows strong antimicrobial activity against clinically isolated strains that may be involved in dental infections.

[Antibacterial activities of cefmenoxime against recent clinical isolates from patients of otitis media and otitis externa].

Bacteria clinically isolated from patients of otitis media and otitis externa were collected from various medical facilities across Japan during years 1988, 1990 and 1992, and minimum inhibitory concentrations (MICs) of cefmenoxime and of reference drugs were determined against these strains. A comparative analyses of the obtained results revealed some trends described below. 1. Methicillin-resistant Staphylococcus aureus (MRSA), multiple drug resistant Coagulase-negative staphylococci (CNS) and multiple drug resistant Proteus spp. showed a year to year trend toward a steady increasing. Relative frequencies of occurrence of MRSA in these years, however, remained comparable to that of early 1980's. 2. A year to year trend toward increasing was also found for resistant or insensitive Streptococcus pneumoniae to penicillins and cephems. 3. Multiple drug-resistant Pseudomonas aeruginosa strains were also detected but they showed no trend toward increasing.

[The antimicrobial activity of cefteram against recently clinically detected and isolated strains].

In order to examine antibiotic activities of cefteram (CFTM), its minimum inhibitory concentrations (MIC's) and those of other cephem drugs were determined against clinically isolated strains received from July 1990 to June 1991 and from July 1992 to February 1993 from medical facilities throughout the country and against clinically isolated strains detected in our laboratory in samples from patients with various infectious diseases. The obtained results are summarized below. 1. No CFTM-resistant strains were found among beta-streptococci, Klebsiella spp., Proteus mirabilis, Haemophilus influenzae, and Neisseria gonorrhoeae or even when found, they were present in extremely low proportions. 2. It appeared that Streptococcus pneumoniae insensitive or resistant to beta-lactams, as well as cephems-resistant strains of Escherichia coli were increasing. The former included benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) of PCG-resistant S. pneumoniae (PRSP), and the presence of the latter suggests the possibility of the existence of "Extended broad-spectrum beta-lactamase" producing strains. The MIC's of beta-lactams against the above PISP or PRSP, and against cephems-resistant E. coli tended to be high, but those of CFTM were relatively low (in most cases). 3. Proportions of strains resistant to cephems, including CFTM among Citrobacter spp., Enterobacter spp., Serratia marcescens, Proteus vulgaris, Morganella morganii, and Providencia rettgeri were high, and in addition, the existence of these cephem resistant species suggests an increase in multiple drug resistant strains that show resistance to new quinolone drugs. 4. As mentioned above, CFTM is by no means a perfect drug or utility drug and its antimicrobial activities do not cover some recent isolates with multiple drug resistance. Except problems encountered with so-called "attenuated" strains of bacteria, increases in resistance can only be observed at a level of MIC90's, and as far as MIC80's are concerned, CFTM still is as active as before and may be used in the treatment of most infections we encounter in normal medical practices.

Studies on condensed-heterocyclic azolium cephalosporins. III. Synthesis and antibacterial activity of 7 beta-[2-(2-amino-5-substituted-thiazol-4-yl)-2 (Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl-3-cephem-4- carboxylates.

As a part of our research on the synthesis of cephalosporins bearing condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus, we describe herein the synthesis of 7 beta-[2-(2-amino-5-halogeno-, methylthio-, methylsulfinyl-, methylsulfonyl- and sulfothiazol-4-yl)-2(Z)-alkoxyiminoacetamido] cephalosporins and their antibacterial activity. Among the compounds prepared, 7 beta-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)- methoxyiminoacetamido]-3-(imidazo[1,5-a]-pyridinium-1-yl)methyl-3-cephem -4-carboxylate (14) showed good antibacterial activity against both Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, whereas the antibacterial activity against other Gram-negative bacteria was a slightly lower than that of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(im ida zo [1,2-a]pyridinium (I-1) and imidazo[1,5-a]pyridinium (I-4)-1-yl)methyl-3-cephem-4-carboxylates.

Mathematical examination of dual individualization principles (I): Relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciprofloxacin, and tobramycin.

Traditional antibiotic dosage adjustments target predetermined serum concentrations, whereas a host of in vitro studies and recent clinical trials establish that bacteria vary in their susceptibility. Dual individualization, which considers the variance in both antibiotic pharmacokinetics and bacterial susceptibility, has been employed to describe different rates of bacterial eradication in relation to varying serum concentrations. In patients with nosocomial pneumonia, one of the model compounds studied was cefmenoxime, where a target six-hour area under the serum concentration-time curve (AUC) of 140 micrograms.h/mL above minimum inhibitory concentration (MIC) was previously associated with bacterial eradication in an average of four days. The target AUC value of 140 micrograms.h/mL above MIC is unique to cefmenoxime. Ideally, there should be a dual individualized target useful to adjust the dose of any antibiotic. Computer simulations performed to evaluate this hypothesis suggested that each antibiotic had a unique value for target AUC above MIC. These simulations indicated that an optimal AUC above MIC was about 80 percent of the total AUC above the MIC. Predictable rates of bacterial eradication would presumably result from maintaining these relationships across the range of bacterial susceptibility and the range of serum concentration profiles. Each antibiotic has a unique and different 24-hour AUC over MIC value associated with bacterial eradication in 4 days. For cefmenoxime, the target was 540 area units over MIC per 24 hours, tobramycin with 34 area units, and ciprofloxacin with 23 area units per 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical study on cefteram pivoxil in asymptomatic bacteriospermia].

In order to understand the clinical efficacy of cefteram pivoxil (CFTM) in the treatment of asymptomatic bacteriospermia, the following studies were performed. 1. Concentrations of CFTM in the semen after oral administration of 200 mg to normal healthy adults (n = 5) reached a maximum level of 0.66 +/- 0.04 microgram/ml in 5 hours after the administration, then decreased rapidly, and averaged 0.15 +/- 0.03 micrograms at 7 hours after administration. 2. Activities of CFTM, cefaclor (CCL) and lomefloxacin (LFLX) against bacteria which were detected in semen (n = 65) (11 aerobic bacterial strains and 48 anaerobic bacterial strains) were retrospectively studied. The study of activities of these 3 agents against anaerobic bacteria showed that CFTM tended to be more active than CCL, LFLX, and similar tendency was noted in LFLX more than CCL against Peptostreptococcus sp. When penetration of antibiotic agents into semen is considered, however, some anaerobic bacteria as well as some aerobic bacteria may not be eradicated or inhibited, hence farther studies are needed to facilitate the selection of proper methods of administration as well as that of effective antibiotics.