Daptomycin In Vitro Activity Tested Against Gram-Positive Strains Collected from European and Latin American Medical Centers in 2003

Abstract

Daptomycin, a cyclic lipopeptide, was susceptibility tested against clinical bacterial isolates consecutively collected in hospitals located in Europe (4,731 strains) and Latin America (1,007 strains) in 2003 as part of a continuing surveillance program. The bacterial isolates tested were Gram-positive pathogens that included staphylococci, streptococci and enterococci. The isolates were tested for susceptibility using broth microdilution methods (broth with 50 mg/L Ca⁺⁺ for testing daptomycin). All isolates, except two Enterococcus faecium strains from Europe, were inhibited at daptomycin MIC of ≤4 mg/L. In addition, 99.4 and 97.3% of isolates were inhibited at daptomycin MIC of ≤2 and ≤1 mg/L, respectively. Except for one Staphylococcus aureus and one viridans group streptococci from Europe and one coagulase-negative staphylococci from Latin America, all staphylococcal and streptococcal isolates were inhibited by 1 mg/L of daptomycin. Resistance to other compounds (vancomycin, oxacillin, and penicillin) did not influence daptomycin activity. The activity of daptomycin was very similar in both geographic regions evaluated and demonstrated the same MIC distribution as isolates evaluated in studies in the United States. The results of this study showed that daptomycin continues to be very active against clinical isolates of Gram-positive cocci isolated in Europe and Latin America.     

In Vitro Evaluation of the Antimicrobial Activity of Meropenem in Combination with Polymyxin B and Gatifloxacin Against Pseudomonas aeruginosa and Acinetobacter baumannii

Abstract

The antimicrobial activity of meropenem combined with either polymyxin B or gatifloxacin was evaluated by the checkerboard method against Pseudomonas aeruginosa (10 strains) and Acinetobacter baumannii (10 strains). In addition, the triple combination of polymyxin B, gatifloxacin, and meropenem was also studied as well as the polymyxin B and gatifloxacin combination. A partial synergism interaction between meropenem and polymyxin B was observed for 80% of the A. baumannii strains. In contrast, this combination showed an indifferent effect for 80% of the P. aeruginosa strains tested. The combination of meropenem and gatifloxacin showed synergism only for two strains of A. baumannii, and partial synergism and additive effect for seven strains and indifference for four strains of both species. For the strains of P. aeruginosa, the double combination of polymyxin B and gatifloxacin and the triple combination of meropenem, polymyxin B and gatifloxacin were indifferent for the majority of the strains tested, that is, 90 and 80% respectively.     

In Vitro Activity of Clarithromycin Alone or in Combination with Other Antimicrobial Agents against Mycobacterium avium-intracellulare. Complex Strains Isolated from AIDS Patients

Summary

The activity of clarithromycin and five other antimicrobial agents, namely amikacin, rifampicin, rifabutin, clofazimine and ciprofloxacin, was assessed both by an agar dilution and a radiometric method in broth on 11 Mycobacterium avium-intracellulare complex (MAC) strains, recently isolated from AIDS patients. Minimum inhibitory concentrations (MICs) radiometrically determined were, in general, several times lower than MICs assessed in agar, probably because of a partial degradation of antimicrobials during the long incubation period needed for tests in solid medium. When tested in broth, rifabutin and clofazimine showed very low MICs90 (0.24 and 0.78 μg/ml, respectively). Ciprofloxacin and clarithromycin also had MICs90 in the range of peak serum levels (1.93 and 3.76 μg/ml, respectively). Moreover, all these antimicrobials are known to concentrate several times in macrophages. MICs90 were higher for amikacin (11 μg/ml) and for rifampicin (8 μg/ml). When clarithromycin was tested against three MAC strains in combination with another drug, it showed a synergistic effect only when combined with rifampicin. Some synergistic effect was observed also when combining clarithromycin with rifampicin and amikacin, whereas in combination with rifabutin and clofazimine there was only an additive effect.     

Ofloxacin: In Vitro Activity Against Recently Isolated Gram-Negative Bacterial Strains

Summary

The activity of ofloxacin was determined against 117 Enter obacteriaceae, 13 Acinetobacter var. anitratus, 124 Pseudomonas aeruginosa in comparison with other antibiotics. Its activity was very high: against Enterobacteriaceae the minimum inhibitory concentration (MIC)₅₀ was 0.125 μg/ml, the MIC₉₀ lμg/ml, and the geometric mean (GM) was 0.4 μg/ml; against Acinetobacter var. anitratus the MIC₅₀ 1 μg/ml, MIC₉₀ 4 μg/ml, GM 1.7 μg/ml. Unlike other authors we found that the activity of ofloxacin was influenced by the selection of P. aeruginosa resistant to carbenicillin and gentamicin.     

In Vitro Activity of Meropenem against Ciprofloxacin-Resistant Enterobacteriaceae and Pseudomonas aeruginosa

Abstract

The in-vitro susceptibilities of a total of 174 ciprofloxacin-resistant Enterobacteriaceae and Pseudomonas aeruginosa were determined. According to the BSAC and NCCLS breakpoints, meropenem, aztreonam, ceftibuten, ceftazidime, imipenem and cefotaxime were the most active (>90%) antimicrobial agents tested against Enterobacteriaceae. Susceptibility of these strains to piperacillin/tazobactam, cefpodoxime and cefixime (84.96%) was higher than that to tobramycin, gentamicin and fosfomycin (50-75%). More than 90% of P. aeruginosa were susceptible to meropenem when both interpretative susceptibility breakpoint criteria were used. Piperacillin, piperacillin/tazobactam and ceftazidime were active against 50-75% of the same strains. Meropenem was the most active antimicrobial tested against all ciprofloxacin-resistant clinical isolates assayed.     

In Vitro and In Vivo Activity of Miltefosine Against Penicillin-Sensitive and -Resistant Streptococcus pneumoniae Strains

Abstract

The in vitro and in vivo activity of miltefosine against penicillin-sensitive and penicillin-resistant pneumococcal strains was studied. The minimum inhibitory concentrations (MICs) of miltefosine were determined in cation-adjusted Mueller Hinton plus 2% lysed horse blood (CAMHB) and in Todd-Hewitt (TH) broth. The respective MICs were higher using CAMHB (128 and 64 mg/L) than using TH broth (4 and 8 mg/L). The In Vivo activity was studied in a murine peritonitis-sepsis model. Miltefosine was orally administered at doses of 15 and 30 mg/kg/day after, at the time of, and before bacterial challenge for 3-5 days. All control and 16 out of the 17 (94.1%) miltefosine-treated animals that were inoculated with the penicillin-sensitive strain died. No survival was observed among control and miltefosine-treated animals inoculated with the penicillin-resistant pneumococcal strain. The In Vivo unresponsiveness of miltefosine in this sepsis model could be attributed to some inhibitory effect of blood, inadequate pharmacokinetics and/or the extracellular localization of the pneumococcus.     

The Antistaphylococcal Pharmacodynamics of Linezolid Alone and in Combination with Doxycycline in an In Vitro Dynamic Model

Abstract

To delineate the possible advantages of linezolid/doxycycline combinations over either drug alone, the in vitro pharmacodynamics of linezolid, doxycycline and linezolid plus doxycycline were studied with Staphylococcus aureus.

S. aureus ATCC 43300 and a clinical isolate S. aureus 479 were exposed to twice-daily linezolid and once-daily doxycycline, alone and in combination, for five consecutive days. Three dosing regimens were simulated with each drug alone: linezolid (AUC₂₄/MIC 30, 60 and 200 h – L30, L60 and L200, respectively) and doxycycline (AUC₂₄/MIC 90, 180 and 520 h – D90, D180 and D520, respectively) and in combination: linezolid plus doxycycline (L30+D90; L60+D180 and L200+D520).

With both S. aureus ATCC 43300 and S. aureus 479 exposed to linezolid or doxycycline, the area between the line crossing each time-kill curve at the level of 10⁸ CFU/mL and the respective time-kill curve (? _E) increased with increasing simulated AUC₂₄/MIC ratios. Each of the combined treatments produced greater ? _Es than the sum of linezolid and doxycycline ? _Es observed in the respective single drug treatments.

This study suggests that linezolid combinations with doxycycline may be synergistic in treating staphylococcal infections.     

Evaluation of Moxifloxacin Activity In Vitro Against Mycobacterium tuberculosis,Including Resistant and Multidrug-Resistant Strains

Abstract

The new quinolone moxifloxacin was tested against 86 strains of Mycobacterium tuberculosis including 13 resistant and 4 multiresistant strains. The antimicrobial susceptibility was tested, in parallel, using two different liquid media, the radiometric Bactec 12B and the Mycobacteria Growth Indicator Tube (Becton Dickinson, USA). All strains but two were susceptible at 0.5 μg/ml of moxifloxacin; for the remaining two strains, both multidrugresistant, the minimal inhibitory concentrations (MIC) were =2 and >4 >g/ml respectively. Our data confirm the high antitubercular in vitro activity of moxifloxacin.     

In- Vitro Activity of Meropenem,a New Carbapenem,Against Imipenem-Resistant Pseudomonas aeruginosa and Xanthomonas maltophilia

Summary

The activity of meropenem, a new carbapenem, as well as imipenem, ceftazidime, aztreonam, tobramycin, amikacin and ciprofloxacin against 18 strains of Xanthomonas maltophilia and 23 strains of Pseudotnonas aeruginosa resistant to imipenem was tested. All strains of X. maltophilia were resistant to both penems. Ceftazidime, tobramycin and ciprofloxacin were the most active antimicrobial agents against this specie. 17% of imipenem-resistant strains of P. aeruginosa were sensitive to meropenem. Ciprofloxacin, amikacin and aztreonam were the most effective agents against these strains.     

Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations

IntroductionIn contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting.MethodsWe retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months.ConclusionsICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.     

In Vitro Activity of Clarithromycin Against Penicillin-Susceptible and Penicillin-Resistant Strains of Streptococcus pneumoniae in a Pharmacodynamic Simulation Model

Abstract

Clarithromycin has shown enhanced activity against Streptococcus pneumoniae, but increased resistance to macrolides has been observed in recent years. Our aim was to investigate its activity against strains of S. pneumoniae with variable susceptibility to this antibiotic and to penicillin. We determined killing curves using the Centriprep-10 pharmacodynamic simulation model, which permits using varying antibiotic concentrations to mimic a pharmacoki-netic human profile in serum (corresponding to an oral dose of 500 mg). Four strains of S. pneumoniae were tested. In susceptible strains, clarithromycin showed bactericidal activity (reductions of up to 2.97 log₁₀ cfu/ml of the initial inoculum). In resistant strains, clarithromycin showed a bacteriostatic effect (<1 log₁₀ cfu/ml reduction). Penicillin-susceptible strains showed higher reductions than penicillin-resistant strains. This effect is important owing to the high minimum inhibitory concentration (MIC) of one of the resistant strains (32 μg/ml). More studies are needed to explain this bacteriostatic activity.     

The Role of IMiDs Alone or in Combination in Prostate Cancer

Recent insights into mechanisms by which prostate cancer becomes castration resistant have allowed better and more rational therapeutic design. These novel therapies have complemented the modest success that chemotherapy has shown in recent years changing the landscape of this disease and leading to improved outcomes. Angiogenesis and immune deregulation are 2 pathways that have increasingly been shown to lead into castration resistant prostate cancer (CRPC). Thalidmide and lenalidomide are immunomodulatory agents with antiangiogenesis properties that have shown activity in this setting with acceptable safety profile. In this review, we discuss briefly the different mechanisms that render prostate cancer castration resistant and elaborate on thalidomide and lenalidomide data in CRPC after reviewing their theoretic mechanisms of action. This timely review coincides with the identification of newer therapies against CRPC affirming our steady movement toward better disease control.     

多西他赛单用或与顺铂联合对舌鳞癌增殖的抑制作用

目的通过进行多西他赛单用或与顺铂联合对舌鳞癌增殖抑制作用的体内外实验研究,探讨其在舌鳞癌乃至头颈部鳞癌治疗中的价值。方法体外培养中国人舌鳞癌细胞系Tscca,采用MTT的方法检测多西他赛与顺铂单药或联合对舌鳞癌细胞增殖的抑制作用;建立人舌鳞癌裸鼠动物模型,通过隔日测量肿瘤的大小和实验结束时肿瘤的重量,研究多西他赛单用或与顺铂联合在体内对舌鳞癌荷瘤鼠的肿瘤生长抑制作用。结果体外研究表明多西他赛单药对人舌鳞癌细胞增殖有抑制作用,这种抑制作用呈剂量依赖性,多西他赛抑制Tscca细胞增殖的IC50为0.018μmol/L;与顺铂联合对Tscca的抑制作用得到显著增强;在体内实验中,DDP组、docetaxel组、DDP docetaxel组的抑瘤率分别为72.6%、73.8%、94.6%,两者联用对荷瘤鼠肿瘤生长发挥了协同作用。结论体内外实验证实多西他赛单用或与顺铂联用可显著抑制舌鳞癌的生长,展现了多西他赛在舌鳞癌治疗方面的前景。     

Analgesic Efficacy and Pharmacokinetic Evaluation of Meperidine and Hydroxyzine, Alone and in Combination

As part of a study to evaluate the analgesic efficacy of meperidine and hydroxyzine, alone and in combination, a double-blind complete crossover study of meperidine (50 mg IM), hydroxyzine (100 mg IM), meperidine (50 mg IM) plus hydroxyzine (100 mg IM), and saline placebo was conducted. Thirty patients with chronic moderate to severe pain due to metastatic cancer were evaluated as to pain relief following administration of all four study medications. All of the treatment groups showed statistically significant analgesic activity as compared to placebo. Hydroxyzine provided sustained pain relief to six hours, whereas meperidine produced analgesia up to two hours. The combination produced additive analgesia only during the first 2 hr. The pharmacokinetics of meperidine and hydroxyzine were compared to observed analgesia. Significant correlation between serum drug levels of meperidine and hydroxyzine and pain relief resulted and the serum levels of meperidine and hydroxyzine necessary for analgesia were calculated to be 0.10-0.15 mg/ml and 60-70 ng/ml; respectively. The observed analgesia of the meperidine/hydroxyzine combination was correlated with the analgesia of the individual agents and the limited additive analgesia observed with the addition of meperidine to hydroxyzine does not justify the added toxicity of the narcotic.     

In Vitro Activity of HMR 3647 Against Anaerobic Bacteria

Abstract

The aim of the present investigation was to determine the In Vitro activity of HMR 3647 compared with other antimicrobial agents against anaerobic bacteria. The activity of HMR 3647 was determined against 342 clinical isolates of anaerobic bacteria by the agar dilution method and was compared with azithromycin, clarithromycin, roxithromycin, erythromycin, cefoxitin, imipenem, clindamycin and metronidazole.

Among the macrolides HMR 3647 and among the beta-lactams imipenem were the most active agents tested. Anaerobic cocci (50 strains) had the following minimum inhibitory concentrations (MICs): HMR 3647, range 0.016-0.125 mg/l; imipenem, range 0.016-0.064 mg/l. Propionibacterium acnes (30 strains): HMR 3647, 0.016-1.0 mg/l; imipenem, 0.032-0.064 mg/l. Clostridium perfringens (30 strains): HMR 3647, 0.125 mg/l; imipenem, 0.016-0.5 mg/l. Clostridium difficile (50 strains): HMR 3647, 0.125-256 mg/l; imipenem, 4.0-8.0 mg/l. Bacteroides fragilis (102 strains): HMR 3647, 0.032-16 mg/l; imipenem, 0.064-0.25 mg/l. Bacteroides and Prevotella species (50 strains): HMR 3647, 0.016-4.0 mg/l; imipenem, 0.016-0.25 mg/l. Fusobacterium nucleatum (30 strains): HMR 3647, 0.016-8.0 mg/l; imipenem, 0.008-0.064 mg/l.

HMR 3647 may be useful as treatment and prophylaxis for infections due to anaerobic bacteria.     

Sudden Increase in Pseudomonas aeruginosa Nosocomial Strains with Broad Host Range Transfer of Antibiotic Resistance

Abstract

We investigated transfer of antibiotic resistance from 51 multiply resistant strains of Pseudomonas aeruginosa isolated from seriously ill patients in the Frankfurt University Clinics. Nine isolates directly transferred resistance to three recipient strains used. Ticarcillin and cephalothin resistance determinants were accepted from eight isolates, and in one case a kanamycin resistance determinant was transferred. The total spectrum of resistance transferred demonstrated that several donor strains transferred a different set of resistance determinants to all three recipient strains. Two P. aeruginosa isolates transferred spectrum of seven resistance determinants including ceftazidime, cefepime and aztreonam, three isolates transferred five determinants and four isolates transferred four resistance determinants. The fact that identical spectra of multiple drug resistance were transferred to recipient strains belonging to three different species (Escherichia coli, Proteus mirabilis and P. aeruginosa), indicates a broad host range in all three transferable genetic elements not observed in previous transfers from P. aeruginosa strains.     

Imipenem and Cefotaxime Resistance: Transduction by Wild-Type Phages in Hospital Strains of Pseudomonas aeruginosa

Summary

A wild-type bacteriophage appeared and was isolated from a Pseudomonas aeruginosa strain resistant to imipenem, cefotaxime, kanamycin and streptomycin (susceptible to carbenicillin, aztreonam, amikacin and fluoroquinolones). The best transducing properties were obtained with phage lysates prepared from bacteria growing on cefotaxime or imipenem. Transducing properties were found specific for individual recipient strain(s) susceptible to all drugs. A high-frequency of transduction was recorded for kanamycin and particularly for cefotaxime resistance determinants, followed by an imipenem determinant. This is now the fourth published wild-type bacteriophage, isolated from lysogenic nosocomial P. aeruginosa resistant to imipenem which was found to transduce this resistance determinant to susceptible pseudomonads.     

Transferable Resistance to Specific Antibiotics in Nosocomial Strains of Pseudomonas aeruginosa from Two Teaching Hospitals

Abstract

We describe the transfer of resistance to kanamycin, carbenicillin and cephaloridine to a recipient strain of Escherichia coli K-12 No. 3110 from three strains of Pseudomonas aeruginosa out of 146 strains tested in 1995. The P.aeruginosa No. 201, 203, 208 donor strains were isolated from patients in the University Clinics in Frankfurt, Germany. They were resistant to most β-lac-tam antibiotics including cephalosporins of the 1st, 2nd and 3rd generation, imipenem, meropenem and aztreon-am. They transferred kanamycin, carbenicillin and cephaloridine resistance determinants to recipient strain E.coli K-12 3110. These determinants were accompanied in strain P.aeruginosa No. 203, with a transfer of cef-tazidime resistance determinants and in P.aeruginosa No. 208 with transfer of cefotaxime, ceftazidime and aztreon-am resistance determinants. Transfer of antibiotic resistance was also studied in 13 nosocomial strains of P.aeruginosa collected for their ceftazidime and/or imipenem resistance in a large Teaching Hospital in Ostrava, Czech Republic. Six of these strains transferred carbenicillin and/or cephaloridine resistance to the E.coli K-12 3110 recipient strain. Resistance to kanamycin and cefotaxime was also co-transferred with carbenicillin and cephaloridine determinants. Ceftazidime, imipenem or ofloxacin resistance was not transferred and is thus, most probably, of chromosomal origin.     

The Antiangiogenic Activity of Flaxseed Oil Alone and Combination with Mefenamic Acid in Vivo and in Vitro Assay

Background: Antiangiogenic agents are commonly used for the management of many types of cancers. Flaxseed oil is a wealthy source of omega-3,omega-6, and lignans, and possesses anticancerous and antioxidant activities. Objective: To investigate the antiangiogenic activity of flaxseed oil alone and in combination with mefenamic acid in a dose-response study. Methods: Oil was extracted from flaxseeds. The ex vivo rat aorta ring assay was used to screen the flaxseed oil alone and in combination with mefenamic acid for possible antiangiogenic activity. Also, the assay was used to determine the dose–response effect.An in vivo chick chorioallantoic membrane (CAM) assay was used to quantify the zone of inhibition of blood vessel by flaxseed oil. Results: The 200,100,50,25,12.5, and 6.25µg/ml of the flaxseed oil inhibited blood vessel growth with values of 91±0.42, 84±2.06,36±2.71, 21±2.15,23±1.56, and 5±0.93%, respectively, withan IC50 value of 45.695 µg/ml. These concentrations showed a dose-dependent inhibition of angiogenesis. At 200, 100, and 50 µg/ml of flaxseed oil in combination with 50 µg/ml of mefenamic acid inhibited blood vessel growth with inhibition percentages of 81.48±0.82,79.63±0.75, and 77.78±1.26, respectively, with an IC50 of 2.27 µg/ml. Also, these concentrations indicated a dose-dependent inhibition of angiogenesis.  Flaxseed oil produced a significant inhibition zone of blood vessels in the CAM assay. The LD50 for flaxseed oil was 5.656g/kg. Conclusion: Flaxseed oil alone and in combination with mefenamic acid exhibited antiangiogenic activity both in ex vivo and in vivo assays. At doses of 2.5, 1.25, 0.625, and 0.312 g/kg of flaxseed oil intraperitoneally injected into mice, no symptoms of toxicity or death of mice due to acute toxicity were observed. However, doses of 5 and 10 g/kg of oil resulted in the death of the majority of mice.