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1.  In vitro modulation of hippocampal pyramidal cell response by quinolones: effects of HA 966 and gamma-hydroxybutyric acid. 
Antimicrobial Agents and Chemotherapy  1996;40(11):2573-2576.
The influence of quinolones on electrically evoked pyramidal cell activity in the rat hippocampus in vitro was studied by using the slice technique. We hoped to learn more about the possible mechanisms for the development of side effects of different quinolones and to find a possible treatment. As reported earlier (W. Dimpfel, M. Spüler, A. Dalhoff, W. Hofmann, and G. Schlüter, Antimicrob. Agents Chemother. 35:1142-1146, 1991), the amplitude of the population spike increased in the presence of ciprofloxacin, lomefloxacin, or ofloxacin about twofold in comparison with reference values. This increase could be prevented in a concentration-dependent manner by the concomitant presence of 3-amino-1-hydroxy-2-pyrrolidone (HA 966), a compound acting at the so-called glycine site of the N-methyl-D-aspartate (NMDA) receptor, but not in the presence of aminophosphonovaleric acid (APV), which acts at a different recognition site of the NMDA receptor. Another tool, 6,7-dinitroquinoxaline-2,3-dione, an antagonist of the so-called AMPA receptor (named after the binding of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] to this site), could not antagonize the effect induced by the quinolones. Activation of the glycine site of the NMDA receptor induced by the presence of D-serine in the superfusion medium also resulted in a concentration-dependent increase in the population spike amplitude. This response remained unchanged in the presence of ciprofloxacin, whereas lomefloxacin and ofloxacin led to further increases in the amplitude, especially in the presence of higher concentrations of D-serine. These results also point to an involvement of the glycine site of the central NMDA receptor in the development of side effects by different quinolones. A complete attenuation of the quinolone-induced effects was obtained in the presence of 2.5 microM gamma-hydroxybutyric acid (GHB), a physiological neuromodulator which is marketed in some countries of Europe as a sedative. It is therefore concluded that the excitatory adverse effects of quinolones might be treated by the administration of GHB.
PMCID: PMC163578  PMID: 8913467
2.  Hydrophilicity of quinolones is not an exclusive factor for decreased activity in efflux-mediated resistant mutants of Staphylococcus aureus. 
The elevated expression of the norA gene is responsible for efflux-mediated resistance to quinolones in Staphylococcus aureus (E.Y.W. Ng, M. Trucksis, and D.C. Hooper, Antimicrob. Agents Chemother. 38:1345-1355, 1994). For S. aureus transformed with a plasmid containing the cloned norA gene, SA113(pTUS20) (H. Yoshida, M. Bogaki, S. Nakamura, K. Ubukata, and M. Konno, J. Bacteriol. 172:6942-6949, 1990), and an overexpressed mutant, SA-1199B (G.W. Kaatz, S.M. Seo, and C.A. Ruble, J. Infect. Dis. 163:1080-1086, 1991), the MICs of norfloxacin increased 16 and 64 times compared with its MICs for the recipient and wild-type strains, SA113 and SA-1199, respectively. MICs of CS-940, however, increased only two and eight times, even though these two fluoroquinolones are similarly hydrophilic (apparent logPs of approximately -1). No good correlation was found, among 15 developed and developing quinolones, between the increment ratio in MICs and hydrophobicity (r = 0.61). Analysis of the quantitative structure-activity relationship among 40 fluoroquinolones revealed that the MIC increment ratio was significantly correlated with the bulkiness of the C-7 substituent and bulkiness and hydrophobicity of the C-8 substituent of fluoroquinolones (r = 0.87) and not with its molecular hydrophobicity (r = 0.47). Cellular accumulation of norfloxacin in SA-1199B was significantly lower than that in SA-1199, and it was increased by addition of carbonyl cyanide m-chlorophenyl hydrazone. On the other hand, accumulations of CS-940 in these strains were nearly identical, and they were not affected by addition of the protonophore.
PMCID: PMC163426  PMID: 8843290
3.  Accumulation of trimethoprim, sulfamethoxazole, and N-acetylsulfamethoxazole in fish and shrimp fed medicated Artemia franciscana. 
In a previous paper (H.J. Nelis, P. Léger, P. Sorgeloos, and A. P. De Leenheer, Antimicrob. Agents Chemother. 35:2486-2489, 1991) it was reported that two selected antibacterial agents, i.e., trimethoprim and sulfamethoxazole, can be efficiently bioencapsulated in nauplii of the brine shrimp Artemia franciscana for administration to fish. This follow-up study showed that larvae of the sea bass and the turbot as well as postlarvae of the white shrimp accumulate the therapeutic agents in high quantities when fed medicated A. franciscana. To monitor their levels as a function of time, the liquid chromatographic method originally developed for the analysis of A. franciscana was modified with respect to chromatography, internal standardization, and sample pretreatment. The levels of trimethoprim ranged from 1 to 7 micrograms/g (sea bass), 1 to 13 micrograms/g (turbot), and 4 to 38 micrograms/g (white shrimp). The corresponding values for sulfamethoxazole were 0.3 to 4 micrograms/g (sea bass), 1 to 42 micrograms/g (turbot), and 4 to 35 micrograms/g (white shrimp). Only the two fish species, unlike the shrimp, metabolized the latter to N-acetylsulfamethoxazole (concentration range, 1 to 10 micrograms/g). These data suggest the potential of the bioencapsulation of therapeutic agents in live food as a tool to control infectious diseases in aquaculture. A preliminary challenge test also confirmed the in vivo efficacy of this approach.
PMCID: PMC163389  PMID: 8807056
4.  Characterization of IS1272, an insertion sequence-like element from Staphylococcus haemolyticus. 
We have previously shown (G. L. Archer, D. M. Niemeyer, J. A. Thanassi, and M. J. Pucci, Antimicrob. Agents Chemother. 38:447-454, 1994) that some methicillin-resistant staphylococcal isolates contain a partial deletion of the genes (mecR1 and mecI) that regulate the transcription of the methicillin resistance structural gene (mecA). When a fragment of DNA inserted at the point of the mecR1 deletion was used as a probe, hybridization with multiple bands was detected for Staphylococcus haemolyticus genomic DNA. In the present study, DNA sequencing of four unique clones recovered from a lambda library of S. haemolyticus revealed identical 1,934-bp elements. Each element, designated IS1272, contained 16-bp terminal inverted repeats (sequence identity, 15 of 16 bp) and two open reading frames of 819 and 687 bp; there were no flanking target site duplications. Database searches yielded amino acid homology with proteins predicted to be encoded by open reading frames from a putative insertion sequence element from Enterococcus hirae. DNA probes from each end and the middle of IS1272 were hybridized with restriction endonuclease-digested genomic DNA from clinical S. haemolyticus, Staphylococcus epidermidis, and Staphylococcus aureus isolates. Each of the 20 or more copies of the element found in S. haemolyticus isolates was intact, and copies were found in most chromosomal SmaI fragments. S. aureus and S. epidermidis isolates contained mostly incomplete fragments of the element, and there were many more hybridizing fragments in methicillin-resistant than in methicillin-susceptible isolates. IS1272, which appears to be primarily resident in S. haemolyticus, has disseminated to multiple staphylococcal species and is prevalent in multiresistant isolates.
PMCID: PMC163232  PMID: 8849253
5.  Modification of penicillin-binding protein 5 associated with high-level ampicillin resistance in Enterococcus faecium. 
High-level ampicillin resistance in Enterococcus faecium has been shown to be associated with the synthesis of a modified penicillin-binding protein 5 (PBP 5) which had apparently lost its penicillin-binding capability (R. Fontana, M. Aldegheri, M. Ligozzi, H. Lopez, A. Sucari, and G. Satta. Antimicrob. Agents Chemother. 38:1980-1983, 1994). The pbp5 gene of the highly resistant strain E. faecium 9439 was cloned and sequenced. The deduced amino acid sequence showed 77 and 54% homologies with the PBPs 5 of Enterococcus hirae and Enterococcus faecalis, respectively. A gene fragment coding for the C-terminal part of PBP 5 containing the penicillin-binding domain was also cloned from several E. faecium strains with different levels of ampicillin resistance. Sequence comparison revealed a few point mutations, some of which resulted in amino acid substitutions between SDN and KTG motifs in PBPs 5 of highly resistant strains. One of these converted a polar residue (the T residue at position 562 or 574) of PBP 5 produced by susceptible and moderately resistant strains into a nonpolar one (A or I). This alteration could be responsible for the altered phenotype of PBP 5 in highly resistant strains.
PMCID: PMC163115  PMID: 8834879
6.  Efficacies of cefotaxime and ceftriaxone in a mouse model of pneumonia induced by two penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2829-2834.
We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.
PMCID: PMC163631  PMID: 9124850
7.  Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. 
Antimicrobial Agents and Chemotherapy  1996;40(10):2300-2305.
Some Candida albicans isolates from AIDS patients with oropharyngeal candidiasis are becoming resistant to the azole antifungal agent fluconazole after prolonged treatment with this compound. Most of the C. albicans isolates resistant to fluconazole fail to accumulate this antifungal agent, and this has been considered a cause of resistance. This phenomenon was shown to be linked to an increase in the amounts of mRNA of a C. albicans ABC (ATP-binding cassette) transporter gene called CDR1 and of a gene conferring benomyl resistance (BENr), the product of which belongs to the class of major facilitator multidrug efflux transporters (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378-2386, 1995). To analyze the roles of these multidrug transporters in the efflux of azole antifungal agents, we constructed C. albicans mutants with single and double deletion mutations of the corresponding genes. The mutants were tested for their susceptibilities to these antifungal agents. Our results indicated that the delta cdr1 C. albicans mutant was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine). The same mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomycin Z, flucytosine, or pradimicin. In contrast, the delta ben mutant was rendered more susceptible only to the mutagen 4-nitroquinoline-N-oxide. However, this mutation increased the susceptibilities of the cells to cycloheximide and cerulenin when the mutation was constructed in a delta cdr1 background. The assay used in the present study could be implemented with new antifungal agents and is a powerful tool for assigning these substances as putative substrates of multidrug transporters.
PMCID: PMC163524  PMID: 8891134
8.  Bacterial biofilms and the bioelectric effect. 
Bacterial biofilms are acknowledged to be a major factor in problems of ineffective sterilization often encountered in clinics, hospitals, and industrial processes. There have been indications that the addition of a relatively small direct current electric field with the sterilant used to combat the biofilm greatly increases the efficacy of the sterilization process. The results of the experiments reported in this paper support the concept of the "bioelectric effect" as reported by J.W. Costerton, B. Ellis, K. Lam, F. Johnson, and A.E. Khoury (Antimicrob. Agents Chemother, 38:2803-2809, 1994). With a current of 1 mA flowing through the chamber containing the biofilm, an increase in the killing of the bacteria of about 8 log orders was observed at the end of 24 h (compared with the control with the same amount of antibacterial agent but no current). We also confirmed that the current alone does not affect the biofilm and that there appear to be optimum levels of both the current and the sterilant that are needed to obtain the maximum effect.
PMCID: PMC163464  PMID: 8878572
9.  Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. 
Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.
PMCID: PMC163329  PMID: 8725999
10.  Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors. 
We previously identified a series of compounds which specifically inhibited the transcription of influenza A and B viruses (J. Tomassini, H. Selnick, M.E. Davies, M.E. Armstrong, J. Baldwin, M. Bourgeois, J. Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994). The compounds, 4-substituted 2,4-dioxobutanoic acids, selectively targeted the cap-dependent endonuclease activity of the transcriptase complex. Additionally, several of these compounds effectively inhibited the replication of influenza virus but not other viruses in cell culture assays. Here, we report on the anti-influenza virus activities of other potent derivatives of the series evaluated in both in vitro and in vivo infectivity assays. These compounds inhibited the replication of influenza virus in yield reduction assays, with 50% inhibitory concentrations ranging from 0.18 to 0.71 microM. These 50% inhibitory concentrations were similar to those observed for inhibition of in vitro transcription (0.32 to 0.54 microM). One selected compound also elicited a dose-dependent inhibition of influenza virus replication in mice following an upper respiratory tract challenge. These studies demonstrate the antiviral efficacy of this inhibitor class and thereby establish the utility of influenza virus endonuclease as a chemotherapeutic target.
PMCID: PMC163316  PMID: 8723491
11.  Chromosomal beta-lactamase genes of Klebsiella oxytoca are divided into two main groups, blaOXY-1 and blaOXY-2. 
The chromosomally encoded beta-lactamase gene (blaOXY-2) of the wild-type Klebsiella oxytoca SL911 was cloned and sequenced. Its nucleotide sequence similarity with the previously sequenced K. oxytoca beta-lactamase gene (blaOXY-1) (Y. Arakawa, M. Ohta, N. Kido, M. Mori, H. Ito, T. Komatsu, Y. Fujii, and N. Kato, Antimicrob. Agents Chemother. 33:63-70, 1989) is 87.3%, and its amino acid similarity is 89.7%. This group of K. oxytoca beta-lactamases is related to chromosomal beta-lactamases of Citrobacter diversus, Proteus vulgaris, and Yersinia enterocolitica and to the plasmid-mediated extended-spectrum beta-lactamases MEN-1 and Toho-1. By colony hybridization with 86 strains susceptible and resistant to aztreonam, isolated in six countries, K. oxytoca beta-lactamase genes hybridized with either a specific blaOXY-1 DNA probe (668 bp) or a blaOXY-2 DNA probe (723 bp). Thus, beta-lactamase genes could be divided into two groups: blaOXY-1 (47% of the strains) and blaOXY-2 (53% of the strains). A study of isoelectric points confirmed the great variability reported in the literature. However, the two beta-lactamase groups were each represented by four different pIs: for OXY-2, 5.2, 5.7, 6.4, and 6.8, with the 5.2 form representing 59% of all OXY-2 enzymes, and for OXY-1, 7.1, 7.5, 8.2, and 8.8, with the 7.5 form representing 88% of all OXY-1 enzymes.
PMCID: PMC163133  PMID: 8834897
13.  Efficacy of continuous flucytosine infusion against Candida lusitaniae in experimental hematogenous murine candidiasis. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2907-2908.
Candida lusitaniae may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. Flucytosine (5-FC) is very active against C. lusitaniae isolates in vitro, while the in vivo response of murine infection to 5-FC is not as good. To evaluate the hypothesis that this discrepancy may be primarily due to the short half-life of 5-FC in mice, we compared the same total dosage of 75 mg of 5-FC per kg of body weight per day given by bolus injections or infused continuously via a subcutaneously implanted pump in immunosuppressed CF1 mice infected with C. lusitaniae. The fungal titers in the kidneys of mice treated with the continuous 5-FC infusion were significantly lower (P < or = 0.05) than those in the kidneys of mice that received bolus injections once or thrice daily. The antifungal activity of 5-FC against murine candidiasis is best evaluated when the drug is administered by continuous infusion.
PMCID: PMC163648  PMID: 9124867
14.  Treatment of enteric fever with pefloxacin for 7 days versus 5 days: a randomized clinical trial. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2898-2900.
In this prospective study of enteric fever, 22 patients received 400 mg of pefloxacin twice daily for 5 days (group A) and 24 received 400 mg of pefloxacin twice daily for 7 days (group B). Causative microorganisms were Salmonella typhi (8 in group A, 11 in group B) and Salmonella paratyphi B (14 in group A, 13 in group B). The clinical cure and bacterial eradication rates were 96% (21 of 22) in group A and 100% in group B. In conclusion, 5-day oral administration of pefloxacin was as effective as 7-day treatment of enteric fever caused by Salmonella spp.
PMCID: PMC163645  PMID: 9124864
15.  Identification of the tetracycline resistance gene, tet(O), in Streptococcus pneumoniae. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2891-2893.
Five isolates of Streptococcus pneumoniae resistant to tetracycline but lacking tet(M) were studied. The tetracycline resistance gene, tet(O), was detected for the first time in the pneumococcus. The gene was amplified and sequenced and found to share 99% nucleotide sequence identity and 99, 99, and 98% deduced amino acid sequence identity with the tet(O) resistance genes of Streptococcus mutans, Campylobacter coli, and Campylobacter jejuni, respectively.
PMCID: PMC163643  PMID: 9124862
16.  Prevalence of antimicrobial resistance among 723 outpatient clinical isolates of Moraxella catarrhalis in the United States in 1994 and 1995: results of a 30-center national surveillance study. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2884-2886.
Seven hundred twenty-three isolates of Moraxella catarrhalis obtained from outpatients with a variety of infections in 30 medical centers in the United States between 1 November 1994 and 30 April 1995 were characterized in a central laboratory. The overall rate of beta-lactamase production was 95.3%. When the National Committee for Clinical Laboratory Standards MIC interpretive breakpoints for Haemophilus influenzae were applied, percentages of strains found to be susceptible to selected oral antimicrobial agents were as follows: azithromycin, clarithromycin, and erythromycin, 100%; tetracycline and chloramphenicol, 100%; amoxicillin-clavulanate, 100%; cefixime, 99.3%; cefpodoxime, 99.0%; cefaclor, 99.4%; loracarbef, 99.0%; cefuroxime, 98.5%; cefprozil, 94.3%; and trimethoprim-sulfamethoxazole, 93.5%.
PMCID: PMC163641  PMID: 9124860
17.  Effects of nifedipine and diltiazem on pharmacokinetics of cefpodoxime following its oral administration. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2879-2881.
We compared the effects of nifedipine and diltiazem on the uptake of cefpodoxime proxetil (CP). The study was aimed at establishing the impact of increased mesenteric blood flow due to calcium channel blockers on passive transport. Twelve volunteers were given CP (200 mg) orally in a crossover design. The absorption, disposition, and elimination parameters of cefpodoxime were compared among the following three treatment groups: CP alone, CP following oral administration of diltiazem (60 mg), or CP following oral administration of nifedipine (20 mg). No statistically significant difference in pharmacokinetic parameters was observed between the three treatment groups.
PMCID: PMC163639  PMID: 9124858
18.  Antimicrobial susceptibility patterns of some recently established coryneform bacteria. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2874-2878.
The susceptibility patterns of 480 isolates representing six recently defined species of coryneform bacteria (Corynebacterium amycolatum [n = 101], Corynebacterium auris [n = 48], Corynebacterium glucuronolyticum [n = 86], Brevibacterium casei [n = 50], Dermabacter hominis [n = 49], and Turicella otitidis [n = 146]) to 17 antimicrobial agents were determined by an agar dilution method. Most significantly, for C. amycolatum strains the MICs at which 90% of isolates are inhibited were > or = 32 micrograms/ml for nearly all agents. However, all 480 strains examined were susceptible to glycopeptide antibiotics.
PMCID: PMC163638  PMID: 9124857
19.  Prevalence of outer membrane porin alteration in beta-lactam-antibiotic-resistant Enterobacter aerogenes. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2854-2858.
We evaluated the prevalence of impermeability as a mechanism associated with resistance against beta-lactam antibiotics in members of the family Enterobacteriaceae. During a 1-year period, 80 strains were selected from 3,110 routinely isolated strains according to their noticeable cross-resistance pattern to cephalosporins. They were tested for (i) outer membrane nonspecific porins involved in the entry of small hydrophilic molecules; (ii) the MICs of cefepime, cefotaxime, imipenem, and moxalactam; and (iii) beta-lactamase production. Immunological investigations using specific probes showed that 23 of 80 strains presented an alteration of the porin content, most of them expressing an additional resistance mechanism. The prevalence of this porin-deficient phenotype is especially high in Enterobacter aerogenes and concerns 6.4% of the clinical isolates.
PMCID: PMC163635  PMID: 9124854
20.  Comparative study of pharmacokinetics of two new fluoroquinolones, balofloxacin and grepafloxacin, in elderly subjects. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2824-2828.
Comparative pharmacokinetics and tolerability were studied in healthy elderly volunteers for two new fluoroquinolones, balofloxacin (Q-35) and grepafloxacin (OPC-17116), the main excretion routes being the renal and hepatic routes, respectively. Both agents were well tolerated in elderly subjects. In comparison with previously reported data from healthy younger adults, the absorption of balofloxacin was slightly delayed and urinary excretion was delayed and diminished. As a significant linear correlation was observed between renal clearance of balofloxacin and creatinine clearance, the delayed and diminished urinary recovery was attributed to the reduced renal function of the elderly subjects enrolled in the study. The absorption of grepafloxacin was also delayed, and the maximum plasma drug concentration and area under the plasma drug concentration-time curve were increased in the elderly by 31 and 48%, respectively, over those in younger adults on the basis of dose normalized to body weight. The plasma terminal elimination half-life and urinary recovery remained unchanged. Decreases in distribution volume and total body clearance in the elderly were considered to be the primary factors contributing to these differences.
PMCID: PMC163630  PMID: 9124849
21.  Comparative serum bactericidal activities of ceftizoxime and cefotaxime against intermediately penicillin-resistant Streptococcus pneumoniae. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2805-2808.
In a randomized crossover study involving 12 healthy volunteers, 1 g of ceftizoxime or cefotaxime was administered intravenously every 12 h for a total of three doses on two separate weekends. The duration of serum bactericidal titers (SBTs) greater than 1:2 and the time serum drug concentrations remained above the MIC (T > MIC) were determined against three clinical isolates of Streptococcus pneumoniae with intermediate resistance to penicillin. The duration of SBTs and T > MIC for both antimicrobial agents exceeded 50% of the dosing interval for all isolates. Ceftizoxime's T > MIC was statistically greater than that of cefotaxime, indicating that its longer half-life in serum (1.7 h) compared with that of cefotaxime (approximately 1 h) compensates for its slightly lower microbiologic activity against the penicillin-resistant pneumococci tested in this study.
PMCID: PMC163626  PMID: 9124845
22.  In vitro susceptibility of penicillin-resistant Streptococcus pneumoniae to levofloxacin, selection of resistant mutants, and time-kill synergy studies of levofloxacin combined with vancomycin, teicoplanin, fusidic acid, and rifampin. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2802-2804.
Among 180 clinical isolates of pneumococci, no strains were found to be resistant to levofloxacin (MIC, > or = 4 micrograms/ml) whereas 9% were resistant to ofloxacin and 7% were resistant to ciprofloxacin. Synergism was demonstrated by time-kill studies in nine of nine strains for the combination of levofloxacin and vancomycin and in six of nine strains for levofloxacin plus teicoplanin. The combinations of levofloxacin with rifampin or fusidic acid were indifferent. Resistant mutants could be selected using incremental concentrations of levofloxacin. For two of nine strains that were initially susceptible to levofloxacin, the MICs reached the resistance range (> or = 4 micrograms/ml). In contrast, ciprofloxacin and ofloxacin selected mutants from the susceptible to the resistant range more frequently (four of six and six of seven strains, respectively). These data argue for further study of levofloxacin against penicillin-resistant pneumococci.
PMCID: PMC163625  PMID: 9124844
23.  Inexpensive 4-hour micro-agar dilution susceptibility determination method. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2792-2795.
Using a micro-agar dilution (MAD) method in which microscope slides are covered with a thin film of agar, and MICs are read microscopically after a 4-h incubation, 18 antibiotics were tested against 29 to 32 microorganisms each. Identical MICs were obtained for microscopic MAD MICs performed in duplicate in 87.1% of the antibiotic-microorganism combinations, and 97.9% were identical within one dilution. When read macroscopically after an 18-h incubation, identical duplicate MICs were obtained in 86.8% of the cases, and 98.4% were identical within one dilution. Using agar dilution as the "gold standard," the correlation obtained with MAD slides read microscopically at 4 h was 94.3%, and macroscopic correlation at 18 h was 97.6%. The correlation of MAD slides with agar dilution for the groups of microorganisms most frequently used was as follows (microscopic/macroscopic): Staphylococcus aureus 96%/98%; Streptococcaceae 97%/98%; Enterobacteriaceae 98%/99%; and Pseudomonadaceae 95%/98%. At the present rate of exchange (fl 1.60 = $1.00f1p4he cost of a MAD slide, including labor, is $1.28 (20 microorganisms tested) or $0.06 per microorganism-antibiotic combination tested. This method is easy to perform, rapid, and inexpensive. It is suitable for use in routine and research laboratories.
PMCID: PMC163623  PMID: 9124842
24.  Borderline methicillin-susceptible Staphylococcus aureus strains have more in common than reduced susceptibility to penicillinase-resistant penicillins. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2769-2774.
Ten epidemiologically unrelated Staphylococcus aureus isolates with borderline levels of susceptibility to antistaphylococcal penicillinase-resistant penicillins (PRPs) were investigated together with appropriate S. aureus control strains. By a nitrocefin microplate assay, all borderline PRP-susceptible test strains were found to produce comparable amounts of beta-lactamase. Hydrolytic activity against another chromogenic substrate (PADAC) and against the PRPs was also demonstrated in membrane preparations from induced cells of 9 of the 10 borderline test strains. When bacterial membranes were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, two methicillin-inducible bands of about 32 and 31 kDa were detected, after Coomassie blue staining, in the membrane protein patterns of the same nine borderline test strains. By gel renaturation and zymographic detection of beta-lactamase activity, both methicillin-inducible membrane proteins were detected with nitrocefin as a substrate, whereas only one band (presumably the smaller protein) was detected with PADAC. With the remaining borderline test strain (a40), only the larger band was detected in the renatured gels with nitrocefin as a substrate. Plasmid DNA analysis revealed that the borderline susceptible test strains, again with the exception of a40, shared a 17.2-kb plasmid yielding four HindIII fragments of 7.0, 5.3, 3.5, and 1.4 kb. In Western blot (immunoblot) experiments using rabbit antiserum to penicillin-binding protein (PBP) 2a, test strain a40, which did not share a number of features characteristically associated with the other borderline test strains, was eventually shown to produce PBP 2a. Five other S. aureus strains, belonging to phage group 94/96, were found to display the borderline phenotype, including such distinguishing features as the membrane-associated PRP- and PADAC-hydrolyzing activity, the two methicillin-inducible membrane proteins, and the 17.2-kb plasmid. These results suggest that borderline susceptible S. aureus strains share more common features than reduced susceptibility to PRPs.
PMCID: PMC163619  PMID: 9124838
25.  Prospective open randomized study comparing efficacies and safeties of a 3-day course of azithromycin and a 10-day course of erythromycin in children with community-acquired acute lower respiratory tract infections. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2765-2768.
The efficacies and safeties of a 3-day, 3-dose course of azithromycin (10 mg/kg of body weight per day) and a 10-day, 30-dose course of erythromycin (40 mg/kg/day) for the treatment of acute lower respiratory tract infections in children were compared in an open randomized multicenter study. Sixty-eight of 85 evaluable patients (80%) had radiologically proven pneumonia, and 20% had bronchitis. Treatment success defined as cure or major improvement was achieved in 42 of 45 (93%) azithromycin recipients versus 36 of 40 (90%) erythromycin recipients. Adverse events were reported in 12 of 45 and 6 of 40 of the patients treated with azithromycin and erythromycin, respectively, a difference which was not statistically significant. In conclusion, a 3-day course of azithromycin is as effective as a 10-day course of erythromycin in the treatment of community-acquired lower respiratory tract infections in children, with comparable safety and acceptability profiles. This shorter treatment course might have a beneficial effect on compliance, especially in the pediatric age group.
PMCID: PMC163618  PMID: 9124837

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