In Vivo Efficacies of Amoxicillin and Cefuroxime against Penicillin-Resistant Streptococcus pneumoniae in a Gerbil Model of Acute Otitis Media

The comparative efficacies of amoxicillin and cefuroxime against acute otitis media caused by a penicillin-resistant (MIC, 2 μg/ml) Streptococcus pneumoniae strain were assessed in a gerbil model by challenging each ear with 10⁷ bacteria through transbullar instillation. Each antibiotic was tested at two doses (5 and 20 mg/kg of body weight) administered at 2, 10, and 18 h postinoculation. Samples were obtained from the middle ear (ME) on days 3 and 7 postinoculation for determination of bacterial counts. Only amoxicillin, at both doses, was able to significantly halt the weight loss in animals, reducing both the number of culture-positive animals and the bacterial concentration in ME samples versus the values for untreated animals. Comparison of the efficacies between the antibiotics, determined by their ability to achieve culture-negative ME specimens, showed that amoxicillin at 5 mg/kg was significantly more active than cefuroxime at the same dose. The use of higher doses of either amoxicillin or cefuroxime did not produce significantly better results than those obtained with the lower dose but caused a greater inflammatory response. The more favorable results obtained with amoxicillin compared with those obtained with cefuroxime could be related to the antimicrobial susceptibility of the pneumococcal strain (MICs and minimum bactericidal concentrations of 1 and 1 μg/ml and 4 and 4 μg/ml for amoxicillin and cefuroxime, respectively) as well as to the better pharmacokinetic parameters obtained with amoxicillin.     

Postantibiotic Effects of ABT-773 and Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae

This study determined the postantibiotic effect (PAE) of ABT-773 versus that of amoxicillin-clavulanate against clinical isolates of Streptococcus pneumoniae and Haemophilus influenzae. The PAEs of ABT-773 and amoxicillin-clavulanate ranged from 2.3 to 6.0 h and 0 to 2.2 h against S. pneumoniae and from 2.7 to 9.1 h and 0 to 0.8 h against H. influenzae, respectively.     

Characterizing In Vivo Pharmacodynamics of Carbapenems against Acinetobacter baumannii in a Murine Thigh Infection Model To Support Breakpoint Determinations

Pharmacodynamic profiling data of carbapenems for Acinetobacter spp. are sparse. This study aimed to determine the pharmacodynamic targets of carbapenems for Acinetobacter baumannii based on a range of percentages of the dosing interval in which free drug concentrations remained above the MIC (fT>MIC) in the neutropenic murine thigh infection model. fT>MIC values of 23.7%, 32.8%, and 47.5% resulted in stasis, 1-log reductions, and 2-log reductions in bacterial density after 24 h, respectively. The pharmacodynamic targets of carbapenems for A. baumannii demonstrated in vivo are similar to those of other Gram-negative bacteria.     

Bacteriological Efficacies of Three Macrolides Compared with Those of Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae

Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined against Streptococcus pneumoniae and Haemophilus influenzae, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable S. pneumoniae slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. Against H. influenzae, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against S. pneumoniae, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (P < 0.01). Against H. influenzae, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (P < 0.01). Azithromycin demonstrated significant in vivo activity (P < 0.05) but was significantly less effective than amoxicillin-clavulanate (P < 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against H. influenzae, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections.     

Activities of newer fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae

The incidence of ciprofloxacin resistance in Streptococcus pneumoniae is low but steadily increasing, which raises concerns regarding the clinical impact of potential cross-resistance with newer fluoroquinolones. To investigate this problem, we utilized an in vitro pharmacodynamic model and compared the activities of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin to that of ciprofloxacin against two laboratory-derived, ciprofloxacin-resistant derivatives of S. pneumoniae (strains R919 and R921). Ciprofloxacin resistance in these strains involved the activity of a multidrug efflux pump and possibly, for R919, a mutation resulting in an amino acid substitution in GyrA. Gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin achieved 99.9% killing of both R919 and R921 in < or =28 h. With respect to levofloxacin, significant regrowth of both mutants was observed at 48 h (P < 0.05). For gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin, regrowth was minimal at 48 h, with each maintaining 99.9% killing against both mutants. No killing of either R919 or R921 was observed with exposure to ciprofloxacin. During model experiments, resistance to gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin did not develop but the MICs of ciprofloxacin and levofloxacin increased 1 to 2 dilutions for both R919 and R921. Although specific area under the concentration-time curve from 0 to 24 h (AUC(0--24))/MIC and maximum concentration of drug in serum (C(max))/MIC ratios have not been defined for the fluoroquinolones with respect to gram-positive organisms, our study revealed that significant regrowth and/or resistance was associated with AUC(0-24)/MIC ratios of < or =31.7 and C(max)/MIC ratios of < or =3.1. It is evident that the newer fluoroquinolones tested possess improved activity against S. pneumoniae, including strains for which ciprofloxacin MICs were elevated.     

Efficacy of High-Dose Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of Streptococcus pneumoniae

The purpose of the present investigation was to determine if the efficacy of amoxicillin-clavulanate against penicillin-resistant Streptococcus pneumoniae could be improved by increasing the pediatric amoxicillin unit dose (90 versus 45 mg/kg of body weight/day) while maintaining the clavulanate unit dose at 6.4 mg/kg/day. A rat pneumonia model was used. In that model approximately 6 log₁₀ CFU of one of four strains of S. pneumoniae (amoxicillin MICs, 2 μg/ml [one strain], 4 μg/ml [two strains], and 8 μg/ml [one strain]) were instilled into the bronchi of rats. Amoxicillin-clavulanate was given by computer-controlled intravenous infusion to approximate the concentrations achieved in the plasma of children following the administration of oral doses of 45/6.4 mg/kg/day or 90/6.4 mg/kg/g/day divided every 12 h or saline as a control for a total of 3 days. Infusions continued for 3 days, and 2 h after the cessation of infusion, bacterial numbers in the lungs were significantly reduced by the 90/6.4-mg/kg/day equivalent dosage for strains for which amoxicillin MICs were 2 or 4 μg/ml. The 45/6.4-mg/kg/day equivalent dosage was fully effective only against the strain for which the amoxicillin MIC was 2 μg/ml and had marginal efficacy against one of the two strains for which amoxicillin MICs were 4 μg/ml. The bacterial load for the strain for which the amoxicillin MIC was 8 μg/ml was not reduced with either dosage. These data demonstrate that regimens which achieved concentrations in plasma above the MIC for at least 34% of a 24-h dosing period resulted in significant reductions in the number of viable bacteria, indicating that the efficacy of amoxicillin-clavulanate can be extended to include efficacy against less susceptible strains of S. pneumoniae by increasing the amoxicillin dose.     

Activity of Amoxicillin-Clavulanate against Penicillin-Resistant Streptococcus pneumoniae in an Experimental Respiratory Infection Model in Rats

High doses of amoxicillin, equivalent to those produced by 500- and 750-mg oral doses in humans (area under the plasma concentration-time curve), were effective against a penicillin-resistant strain of Streptococcus pneumoniae in an experimental respiratory tract infection in immunocompromised rats; this superior activity confirms the results of previous studies. An unexpected enhancement of amoxicillin’s antibacterial activity in vivo against penicillin-resistant and -susceptible S. pneumoniae strains was observed when subtherapeutic doses of amoxicillin were coadministered with the β-lactamase inhibitor potassium clavulanate. The reason for this enhancement was unclear since these organisms do not produce β-lactamase. The differential binding of clavulanic acid and amoxicillin to penicillin-binding proteins may have contributed to the observed effects.     

Activity of Imipenem against Klebsiella pneumoniae Biofilms In Vitro and In Vivo

Encapsulated Klebsiella pneumoniae has emerged as one of the most clinically relevant and more frequently encountered opportunistic pathogens in combat wounds as the result of nosocomial infection. In this report, we show that imipenem displayed potent activity against established K. pneumoniae biofilms under both static and flow conditions in vitro. Using a rabbit ear model, we also demonstrated that imipenem was highly effective against preformed K. pneumoniae biofilms in wounds.     

肺炎链球菌对泰利霉素等抗菌药物的体外抗菌活性

目的了解本院分离的肺炎链球菌对泰利霉素等抗菌药物的体外抗菌活性。方法对本院2005--2007年从各种临床标本收集的97株肺炎链球菌，用K—B纸片法进行药敏试验，测定这些菌株对泰利霉素等3种新近上市和其他7种临床常用抗菌药物的耐药性。结果97株肺炎链球菌对泰利霉素和利奈唑胺的敏感率均为100％，对喹奴普丁-达福普汀也未发现耐药菌株，只是有18．8％的菌株表现为中介。其他抗菌药物的耐药情况如下：对红霉素、克林霉素、万古霉素、左氧氟沙星、氯霉素和四环素的耐药率分别为60．8%、58．8％、0％、2．1％、12．8%和64．5％，对青霉素的敏感率为85．6％。结论本院尚未用于临床的3种新近上市的抗菌药物泰利霉素、利奈唑胺和喹奴普丁-达福普汀，对本院分离的肺炎链球菌有良好的体外抗菌活性。而上述细菌对红霉素、林可霉素以及四环素有较高的耐药性。     

In vitro activity of AR-709 against Streptococcus pneumoniae

We investigated the in vitro activity of AR-709, a novel diaminopyrimidine antibiotic currently in development for treatment of community-acquired upper and lower respiratory tract infections, against 151 Streptococcus pneumoniae strains from various European countries. AR-709 showed excellent activity against both drug-susceptible and multidrug-resistant pneumococci.     

In Vitro and In Vivo Activities of Levofloxacin against Biofilm-Producing Pseudomonas aeruginosa

Interactions between biofilm cells of Pseudomonas aeruginosa and levofloxacin were studied. P. aeruginosa incubated for 6 days with Teflon sheets formed a biofilm on its surface. Against the biofilm bacteria, levofloxacin at an MIC determined by the standard method for the strain was highly bactericidal whereas gentamicin, ceftazidime, and ciprofloxacin showed no significant killing activity. Levofloxacin, ciprofloxacin, and gentamicin, but not ceftazidime, exhibited killing activity against nongrowing cells of the strain incubated in phosphate buffer. In addition, levofloxacin, ciprofloxacin, and ceftazidime, but not gentamicin, showed the ability to penetrate an agar containing alginate. These findings may explain the efficacy of levofloxacin and the ineffectiveness of gentamicin and ceftazidime against biofilm bacteria; however, the cause of the ineffectiveness of ciprofloxacin still remains to be determined. In experimental pneumonia in guinea pigs, in which the biofilm mode of growth of the strain was observed in the lung, only levofloxacin exhibited substantial therapeutic efficacy. These findings suggest the significant role of levofloxacin in therapy of biofilm bacterium-associated infectious diseases.     

In Vitro and In Vivo Activities of Tea Catechins against Helicobacter pylori

The catechin epigallocatechin gallate showed the strongest activity of the six tea catechins tested against Helicobacter pylori (MIC for 50% of the strains tested, 8 microg/ml). It had bactericidal activity at pH 7 but not at pH 相似文献   

In Vitro Activities of the New Ketolide Antibiotics HMR 3004 and HMR 3647 against Streptococcus pneumoniae in Germany

The comparative in vitro activity of HMR 3004 and HMR 3647, new ketolide antibiotics, was tested by a standard agar dilution technique against 221 pneumococcal strains, including isolates with intermediate levels of resistance to penicillin and erythromycin-resistant isolates. The ketolides were more active than other macrolides and showed excellent activity against erythromycin-resistant strains. All the strains were inhibited by ≤2 μg of HMR 3004/ml or by ≤0.5 μg of HMR 3647/ml.     

In Vitro and In Vivo Activities of Moxifloxacin and Clinafloxacin against Mycobacterium tuberculosis

On 10% oleic acid–albumin–dextrose–catalase-enriched 7H11 agar medium, the MIC at which 90% of the isolates are inhibited for 20 strains of Mycobacterium tuberculosis was 0.5 μg of sparfloxacin (SPFX) or moxifloxacin (MXFX) per ml and 1.0 μg of clinafloxacin (CNFX) per ml, indicating that the in vitro activities of SPFX and MXFX were virtually identical and were slightly greater than that of CNFX. However, the in vivo activities of these drugs in a murine tuberculosis model differed considerably. Female Swiss mice were infected intravenously with 6.2 × 10⁶ CFU of the H37Rv strain and treated for 4 weeks, beginning the next day after infection, with isoniazid (INH) serving as the positive control. By the criteria of 30-day survival rate, spleen weight, gross lung lesion, and mean number of CFU in the spleen, treatment with CNFX at up to 100 mg/kg of body weight six times weekly displayed no measurable effect against M. tuberculosis, whereas both SPFX and MXFX were effective; administration six times weekly of either of the latter two drugs demonstrated dosage-dependent bactericidal effects, as measured by enumeration of CFU in the spleens, and MXFX appeared more bactericidal than the same dosage of SPFX. Of the three fluoroquinolones, only MXFX at 100 mg/kg six times weekly appeared as bactericidal as INH at 25 mg/kg six times weekly. Thus, MXFX may be an important component of the newer combined regimens for treatment of tuberculosis.     

In Vitro and In Vivo Activities of Tigecycline-Colistin Combination Therapies against Carbapenem-Resistant Enterobacteriaceae

We assessed the activity of tigecycline (TGC) combined with colistin (COL) against carbapenem-resistant enterobacteria. Synergy occurred in vitro against the majority of isolates, with the exception of Serratia marcescens. In a simple animal model (Galleria mellonella), TGC-COL was superior (P < 0.01) in treating Escherichia coli, Klebsiella pneumoniae, and Enterobacter infections, including those with TGC-COL resistance. Clinical studies are needed to determine whether TGC-COL regimens may be a viable option.     

Two Pharmacodynamic Models for Assessing the Efficacy of Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of Streptococcus pneumoniae

Two models of respiratory tract infection were used to investigate the pharmacodynamics of amoxicillin-clavulanate against Streptococcus pneumoniae. Eight strains of S. pneumoniae were used in a mouse model in which the animals were infected intranasally and were then treated with a range of doses and dose intervals. The time that the plasma amoxicillin concentration remained above the MIC (T>MIC) correlated well with bacterial killing, such that if T>MIC was below 20% there was no effect on bacterial numbers in the lungs. As T>MIC increased, the response, in terms of decreased bacterial load, improved and at T>MICs of greater than 35 to 40% of the dosing interval, bacteriological cure was maximal. On the basis of equivalent T>MICs, these data would suggest that in humans a dosage of 500 mg three times daily (t.i.d.) should have efficacy equal to that of a dosage of 875 mg twice daily (b.i.d.). This hypothesis was evaluated in a rat model in which amoxicillin-clavulanate was given by computer-controlled intravenous infusion to achieve concentrations that approximate the concentrations achieved in the plasma of humans following oral administration of 500/125 mg t.i.d. or 875/125 mg b.i.d. Infusions continued for 3 days and bacterial numbers in the lungs 2 h after the cessation of the infusion were significantly reduced (P < 0.01) by both treatments in strains of S. pneumoniae for which amoxicillin MICs were below 2 μg/ml. When tested against a strain of S. pneumoniae for which the amoxicillin MIC was 4 μg/ml, the simulated 500/125-mg dose was ineffective but the 875/125-mg dose demonstrated a small but significant (P < 0.01) reduction in bacterial numbers. These data confirm the findings in the mouse and indicate that amoxicillin-clavulanate administered at 875/125 mg b.i.d. would be as effective clinically as amoxicillin-clavulanate administered at 500/125 mg t.i.d.     

Activities of cethromycin and telithromycin against recent North American isolates of Streptococcus pneumoniae

The in vitro activities of two investigational ketolides, cethromycin (formerly ABT-773) and telithromycin, were determined for a selected group of 312 Streptococcus pneumoniae isolates from a national surveillance program. The MIC of cethromycin at which 50% of the isolates were inhibited was 0.008 micro g/ml, and the MIC at which 90% of the isolates were inhibited was 0.06 micro g/ml; the corresponding values for telithromycin were 相似文献