Activity of 2-acetylpyridine and 2-acetylquinoline thiosemicarbazones tested in vitro in combination with other antituberculous drugs

Determinations of minimal inhibitory concentrations (MIC) were carried out using three new 2-acetylpyridine and two new 2-acetylquinoline thiosemicarbazones tested against Mycobacterium tuberculosis, M. kansasii, M. simiae, M. avium, and M. intracellulare. Two of the compounds (Compounds L and 3I) exhibited MIC less than or equal to 5 micrograms per ml for all of the test organisms, except for M. simiae, which was resistant to most antituberculous drugs. The other thiosemicarbazones (Compounds 3L, 2N, 3G, and 2H) were relatively inactive against the nontuberculous mycobacteria. Rifampin, amikacin, and clofazimine were active when tested singly or in combination with Compounds L and 3I. Addition of compound 3I to a mixture of rifampin, amikacin, and clofazimine resulted in combination MIC of less than 0.6 microgram/ml against all of the nontuberculous mycobacteria, suggesting that combinations of this type may be suitable for the treatment of infections caused by these highly drug-resistant organisms.     

Differential effects of free and liposome encapsulated amikacin on the survival of Mycobacterium avium complex in mouse peritoneal macrophages

Liposome-encapsulated amikacin shows significantly greater inhibitory activity against the survival of Mycobacterium avium complex inside mouse peritoneal macrophages than the free drug. Similar results were obtained whether the drug was added simultaneously with, 48 h prior to, or 48 h after the addition of mycobacteria to the macrophages. These observations support the hypothesis that the in vivo intravenous delivery of liposome-encapsulated amikacin results in the localization of the antibiotic in phagosomes containing mycobacteria inside resident macrophages of the liver and spleen.     

In vitro activities of antibiotic combinations against clincal isolates of Pseudomonas aeruginosa

Combination therapy has been recommended to treat Pseudomonas aeruginosa infections worldwide. The purpose of the present study was to determine the in vitro activities of piperacillin, cefepime, aztreonam, amikacin, and ciprofloxacin alone and in combination against 100 clinical isolates of P. aeruginosa from one medical center in southern Taiwan. The combination susceptibility assay was performed using the checkerboard technique. The percentage of resistance of P. aeruginosa to single agents in our study was relatively high for the Asia-Pacific area, except to aztreonam. Piperacillin plus amikacin exhibited the highest potential for synergy (59/100) in this study. Moreover, a high percentage of synergism was also noted with amikacin combined with cefepime (7/100) or aztreonam (16/100). The combination of two beta-lactams, such as cefepime with piperacillin, and aztreonam with cefepime or piperacillin, showed synergistic effects against some P. aeruginosa isolates. Although ciprofloxacin is a good anti-pseudomonal agent, a very low potential for synergy with other antibiotics was demonstrated in this study. No antagonism was exhibited by any combination in our study. Among piperacillin-resistant strains, there was synergy with a beta-lactam plus amikacin, including the combination of piperacillin and amikacin. However, the combination of two beta-lactams, such as piperacillin and cefepime or aztreonam, did not have any synergistic activity against these strains. In summary, the combinations of amikacin with the tested beta-lactams (piperacillin, aztreonam, cefepime) had a greater synergistic effect against P. aeruginosa, even piperacillin-resistant strains, than other combinations. Understanding the synergistic effect on clinical strains may help clinicians choose better empirical therapy in an area with high prevalence of multidrug-resistant P. aeruginosa.     

Gentamicin and Amikacin–An in vitro Comparison using 1000 Clinical Isolates

Summary: The in vitro antimicrobial activities of gentamicin and amikacin against WOO bacteria/ isolates from clinical material were compared. The minimum inhibitory concentrations were determined by an agar dilution technique. Both of these aminoglycoside antibiotics had a similar spectrum of activity, being highly active against most species of aerobic Gram negative bacilli. Gentamicin was more active than amikacin against most species of enterobacteria , Haemophilus influenzae and Staphylococcus aureus but amikacin was more active against a proportion of Klebsiella and Providencia isolates. For most isolates, the differences in activity between gentamicin and amikacin were small, however, amikacin achieves higher serum levels. Most resistant isolates in this survey did not influence patient mortality.     

13种抗生素对快生长分枝杆菌的体外抑菌效果评价

目的 评价快生长分枝杆菌(rapidly growing mycobacteria,RGM)临床分离株对13种抗生素的敏感性特征。方法 收集首都医科大学附属北京胸科医院2015年1月至2019年12月从临床样本中分离出的98株RGM,包括25株偶发分枝杆菌、70株脓肿分枝杆菌和3株龟分枝杆菌。使用Sensititre RAPMYCO药敏板测定13种抗生素(阿米卡星、妥布霉素、阿莫西林-克拉维酸、头孢西丁、亚胺培南、环丙沙星、莫西沙星、克拉霉素、利奈唑胺、米诺环素、多西霉素、替加环素、甲氧苄啶-磺胺甲噁唑)对98株RGM临床分离株的体外抑菌活性。结果 在所测定的13种抗生素中,阿米卡星对所检测的3种RGM临床分离株的体外抑菌活性最佳,对偶发分枝杆菌和脓肿分枝杆菌临床分离株的敏感率分别100.0%(25/25)和90.0%(63/70)。与多西环素、米诺环素相比,替加环素对RGM临床分离株的体外抑菌效果更好,对偶发分枝杆菌和脓肿分枝杆菌临床分离株的敏感率分别为100.0%(25/25)和72.9%(51/70)。莫西沙星和环丙沙星对偶发分枝杆菌临床分离株表现出较强的抑菌活性,敏感率分别为100.0%(25/25)和92.0%(23/25),而对脓肿分枝杆菌临床分离株几乎没有体外抑菌活性,耐药率均为95.7%(67/70)。此外,几乎所有检测的RGM临床分离株均对头孢西丁、多西环素、利奈唑胺、亚胺培南和甲氧嘧啶-磺胺甲噁唑耐药。结论 阿米卡星、替加环素和克拉霉素对脓肿分枝杆菌和偶发分枝杆菌临床分离株具有较好的体外抑菌活性,但在不同菌株间依然存在差异,需要对每个菌种或临床分离菌株进行单独的药物敏感性试验。     

Gentamicin and Amikacin–An in vitro Comparison using 1000 Clinical Isolates

Summary: The in vitro antimicrobial activities of gentamicin and amikacin against WOO bacteria/ isolates from clinical material were compared. The minimum inhibitory concentrations were determined by an agar dilution technique. Both of these aminoglycoside antibiotics had a similar spectrum of activity, being highly active against most species of aerobic Gram negative bacilli. Gentamicin was more active than amikacin against most species of enterobacteria, Haemophilus influenzae and Staphylococcus aureus but amikacin was more active against a proportion of Klebsiella and Providencia isolates. For most isolates, the differences in activity between gentamicin and amikacin were small, however, amikacin achieves higher serum levels. Most resistant isolates in this survey did not influence patient mortality.     

常见非发酵菌的耐药性分析

目的 了解常见非发酵菌的临床分布及耐药情况，指导临床合理使用抗菌药物。方法 2003年1月～2004年12月临床分离的铜绿假单胞菌281株、不动杆菌属190株及嗜麦芽窄食单胞菌63株，用Kirby—Bauer法进行药敏试验。结果 591株非发酵菌中以铜绿假单胞菌（47．5％）、不动杆菌属（32．1％）及嗜麦芽窄食单胞菌（10．7％）为主；主要分布于痰液（62．4％）、皮肤软组织创面分泌物（22．7％）中；耐药性分析显示铜绿假单胞菌对亚胺培南的敏感性最高（92．9％），其它依次为头孢他啶（78．3％）、环丙沙星（78．1％）、头孢吡肟（74．4％）、阿米卡星（70．5％）、哌拉西林-他唑巴坦（70．1％）、头孢哌酮-巴坦（67．9％）、哌拉西林（60．3％）、氨曲南（57．5％）、头孢哌酮（57．1％）、替卡西林-克拉维酸（55．7％）；不动杆菌属对亚胺培南的敏感性也最高（95．7％），其它依次为头孢哌酮-舒巴坦（66．7％）、头孢吡肟（59．3％）、替卡西林-克拉维酸（57．4％）、阿米卡星（55．0％）、哌拉西林-他唑巴坦（51．6％）；嗜麦芽窄食单胞菌对头孢哌酮-舒巴坦的敏感性最高（75．6％），其它依次为头孢他啶（75．5％）、复方磺胺甲嗯唑（74．5％）、替卡西林-克拉维酸（73．7％）、环丙沙星（69．8％）、头孢吡肟（63．4％）、哌拉西林-他唑巴坦（56．8％），对包括亚胺培南在内的其它常用抗菌药物均高度耐药。结论 细菌耐药有一定的地区性，定期对本地区细菌耐药性进行监测，对合理使用抗菌药物、减少耐药菌株的产生和流行有重要的临床指导价值。     

大环内酯类抗生素抗分枝杆菌作用的研究

目的研究大环内酯类抗生素抗分枝杆菌的作用。方法分别测定6种大环内酯类抗生素对20种分枝杆菌(包括结核、牛分枝杆菌和18种非结核分枝杆菌)的试管内最低抑菌浓度。结果不同药物显示不同的试管内抗菌作用谱。结论大环内酯类抗生素是临床非结核分枝杆菌病治疗可选择的药物。     

Antimicrobial susceptibility pattern of blood isolates from a teaching hospital in north India

Bloodstream infections are associated with significant patient morbidity and mortality worldwide. In this study, we examined antimicrobial susceptibility patterns by reviewing the data on 5,704 blood samples that were collected from patients with fever/sepsis admitted to Government Medical College and Hospital, Chandigarh, India, over a period of 1 year from August 2003 to July 2004. Among the 567 qualifying samples, Pseudomonas aeruginosa (19.75%), Escherichia coli (15.17%), Klebsiella pneumoniae (14.99%), and Salmonella enterica serovar Typhi (12.87%) were the most frequently isolated Gram-negative bacteria other than Citrobacter, Acinetobacter, Proteus, and Enterobacter spp. collectively accounting for 80.96% of the isolates. Staphylococus aureus (13.86%) and Enterococcus feacalis (2.35%) were most frequently isolated Gram-positive bacteria other than other Streptococcus and Staphylococcus spp. collectively accounting for 18% of the isolates. Among the antibiotics used for susceptibility testing of Gram-negative isolates, amikacin showed higher activity (76.61%) against Enterobacteriaceae and ciprofloxacin (65.17%) against non-fermenters. However, cefoperazone + sulbactum showed the highest activity (82.66%) among all Gram-negative isolates. For Gram-positive isolates, vancomycin (100%), ciprofloxacin (89.74%) showed the highest activity against Staphylococcus spp. Combinations of antibiotics are often prescribed as emperic therapy for bacteremia, especially for Gram-negative pathogens. Hence the antibiotic susceptibility patterns of blood isolates reported here may be a useful guide for physicians initiating emperic therapy with antibiotics.     

Antibacterial activities of dendritic amphiphiles against nontuberculous mycobacteria

The anti-mycobacterial activities of nine series of dicarboxyl and tricarboxyl dendritic amphiphiles with one alkyl, two alkyl, and cholestanyl tails against Mycobacterium abscessus, Mycobacterium avium, Mycobacterium chelonae, Mycobacterium marinum and Mycobacterium smegmatis have been measured. The dendritic amphiphiles overcame the limited aqueous solubility of natural long-chain fatty acids, alcohols, and amines to enable profiling the susceptibilities of the different mycobacterial species to the physicochemical properties of these amphiphiles. Several dendritic amphiphiles showed strong anti-mycobacterial activity with high critical micelle concentrations and low hemolytic activities thereby offering platforms for the development of antibiotics of higher activity against nontuberculous mycobacteria.     

Postantibiotic effect of amikacin and rifapentine against Mycobacterium avium complex.

Postantibiotic effect (PAE) has received little attention in the therapy of chronic intracellular infections, such as those caused by mycobacteria. Amikacin is active therapeutically against Mycobacterium avium complex, even though serum levels exceed the MIC for only a few hours. To determine the PAE of amikacin and rifapentine for M. avium, bacteria were exposed to concentrations of 1x, 4x, and 10x the MIC of each drug for up to 120 min. Regrowth of M. avium was compared with similarly diluted untreated cultures. No PAE was observed on an inoculum of 10(4) bacteria when rifapentine was used at 5x MIC, although a slight inhibition of growth was obtained at 10x MIC for 2 h. For amikacin, PAE was observed up to 48 h at concentrations of 4x and 8x MIC and exposure times of 30-120 min. A PAE of 22 h was seen with 10(7) cfu of M. avium during incubation for 30 min with amikacin at 4x MIC. These results show that amikacin, unlike rifapentine, has a long PAE against M. avium.     

Penetration of antibiotics into the pancreas in rats: an effect of acute necrotizing pancreatitis

BACKGROUND: Penetration of antibiotics into the pancreas is considered to be an important criterion in determining the most appropriate antibiotic treatment during severe acute pancreatitis. Our study investigated pancreatic penetration of five antibiotics in rats with and without acute necrotizing pancreatitis (ANP) (non-pancreatitis rats (NR), pancreatitis rats (AP)). METHODS: ANP was induced by intraductal bile acid injection, and 3 h later the antibiotic was administered. In both NR and AP the antibiotic concentrations were evaluated in blood and pancreatic tissue 90 min after antibiotic administration. RESULTS: The tissue/serum (T/S) ratios for NR were 16% with amikacin, 24% with amoxycillin/clavulanic acid, 27% with piperacillin, 59% with ofloxacin, and 108% with cefoperazone. The ratios for AP were 7%, 23%, 26%, 52%, and 70%, respectively. T/S ratios were similar for NR and AP except for amikacin, for which the T/S ratio was lower in AP than in NR (P = 0.02). Pancreatic tissue concentrations of antibiotics with high penetration rates (cefoperazone and ofloxacin) were sufficient to inhibit most of the pathogens expected during acute pancreatitis. The concentrations of the other antibiotics were less than the minimal inhibitory concentrations (MIC) for common potential pathogens in pancreatic infection. CONCLUSIONS: Cefoperazone and ofloxacin showed the best pancreatic penetration of the five antibiotics tested. The high concentrations of these antibiotics in the pancreatic tissue would have enabled efficient antibacterial activity against most of the potential pathogens causing pancreatic infection. An early stage of acute necrotizing pancreatitis did not have a major effect on the pancreatic concentrations of the antibiotics.     

Amikacin, ceftazidime, and flucloxacillin against suspended and adherent Pseudomonas aeruginosa and Staphylococcus epidermidis in an in vitro model of infection.

Bacterial inocula were exposed as suspended cultures or as adherent biofilms on glass beads in a novel in vitro model of infection to oscillating drug concentrations mimicking human serum kinetics during clinical treatment. Amikacin was given once or thrice daily alone or in combination with ceftazidime or flucloxacillin against Pseudomonas aeruginosa or Staphylococcus epidermidis. Killing of adherent bacteria was significantly reduced during single-drug treatment compared with suspended bacteria (P less than .001), and beta-lactams were more active than amikacin against both suspended and adherent bacteria (P less than .01). Amikacin-beta-lactam combinations killed the inocula more rapidly and were consistently bactericidal against both suspended and adherent pathogens (P less than .05). Once-daily dosing of amikacin produced greater initial killing than thrice daily dosing (P less than .05), but both regimens were similarly effective after 48 h. The differences in antibiotic activity against suspended and adherent bacteria may relate to clinical failures in the treatment of foreign-body infections by bacteria sensitive to the administered antibiotics, as determined by standard susceptibility tests.     

Comparative antimicrobial susceptibility of aerobic and facultative bacteria from community-acquired bacteremia to ertapenem in Taiwan

Background  

Ertapenem is a once-a-day carbapenem and has excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. The susceptibility of isolates of community-acquired bacteremia to ertapenem has not been reported yet. The present study assesses the in vitro activity of ertapenem against aerobic and facultative bacterial pathogens isolated from patients with community-acquired bacteremia by determining and comparing the MICs of cefepime, cefoxitin, ceftazidime, ceftriaxone, ertapenem, piperacillin, piperacillin-tazobactam, ciprofloxacin, amikacin and gentamicin. The prevalence of extended broad spectrum β-lactamases (ESBL) producing strains of community-acquired bacteremia and their susceptibility to these antibiotics are investigated.     

Monitoring of hearing during treatment of leukaemia with special reference to the use of amikacin

Abstract. Thirty-nine patients with leukaemia were followed audiometrically during treatment with broad-spectrum antibiotics. Amikacin was given during neutropenic febrile episodes. Five patients reported a deterioration of the hearing function after termination of amikacin treatment. Significant hearing threshold loss occurred in 20 patients (51%). The hearing threshold changes were small in general, except for two patients who exhibited bilateral hearing threshold changes in the frequency range 0.5–8 kHz. Using multiple linear regression analysis 22% of the changes in hearing thresholds was estimated to be related to old age, an increased trough concentration of amikacin and an impaired pretreatment hearing state. Factors found not to influence the hearing thresholds were maximum peak concentration of amikacin, cumulative duration of therapy, pretreatment renal dysfunction and concomitant use of vancomycin. It is concluded that administration of amikacin for repeated treatment courses is associated with a low incidence of serious changes in hearing function.     

Comparison of in vitro antimicrobial activities of ofloxacin, levofloxacin, ciprofloxacin, and sparfloxacin against various mycobacteria

In vitro antimicrobial activities of ofloxacin (OFLX), levofloxacin (LVFX), ciprofloxacin (CPFX), and sparfloxacin (SPFX) were compared against various mycobacteria using the agar dilution method with 7H11 medium, and the following results were obtained. (1) These four new quinolones showed excellent antimicrobial activities against M. tuberculosis, M. kansasii, and M. fortuitum. (2) SPFX was most active against slowly growing mycobacteria. The activity against M. tuberculosis was in the order of SPFX > CPFX > LVFX > OFLX. The activity against M. kansasii was in the order of SPFX > LVFX > OFLX > or = CPFX. (3) On the other hand, CPFX was most active against rapidly growing mycobacteria. The activity against M. fortuitum was in the order of CPFX > SPFX > LVFX > OFLX. Considering the in vitro antimicrobial activities and the pharmacokinetics of these four drugs, they could achieve favorable clinical outcomes for all the patients with pulmonary infection due to M. tuberculosis or M. fortuitum and some of the patients with pulmonary infection due to M. kansasii or M. chelonae.     

O(6)-alkylguanine-DNA alkyltransferase DNA repair in mycobacteria: pathogenic and non-pathogenic species differ

SETTING: DNA repair genes assist the organism in maintaining DNA integrity in the face of environmental (mutagenic) stress. The genome sequences of M. tuberculosis and M. bovis demonstrate sequences suggestive of an O(6)-alkylguanine-DNA alkyltransferase DNA repair activity similar to that seen in almost all other bacterial and eukaryotic organisms. The near ubiquitousness of this gene implies an important function. OBJECTIVE: Our aim was to ascertain whether mycobacteria exert an alkyltransferase response to mutagen (streptozotocin) stimulation and whether alkyltransferase activity is essential for mycobacterial survival. DESIGN: Alkyltransferase activity in slow- and fast-growing mycobacterial species was determined in the presence and absence of sublethal concentrations of an alkylating agent streptozotocin. The intracellular survival and response to anti-tuberculosis drugs of an alkyltransferase knockout strain of M. bovis BCG was also determined. RESULTS: We demonstrate the presence of O(6)-alkylguanine alkyltransferase (cellular methyltransferase activity) in mycobacterial species and that there is an inducible and constitutive form in fast-growing mycobacteria (M. smegmatis), whereas only the constitutive form exists in the pathogenic or slow-growing species (M. bovis BCG) under the conditions tested. The overall activity of the constitutive form is high. We also show that intracellular growth of M. bovis BCG in macrophages is reduced when the alkyltransferase gene is absent. The presence of alkyltransferase activity appears to assist the organism in reducing the effects of isoniazid, since interruption of the gene confers sensitivity to the drug. CONCLUSIONS: We conclude that for the slow-growing mycobacteria, an inducible response is not essential as their ecological niche is stable and protected, but that the presence of the alkyltransferase activity confers a growth advantage in macrophages and offers some protection against antibiotics.     

Antimycobacterial activity of some potential chemotherapeutic compounds

Fourteen compounds were tested in vitro for activity against Mycobacterium intracellulare and other pathogenic mycobacteria. Only clofazimine and chaulmoogric acid showed significant activity against M. intracellulare. In view of known minimal side effects of clofazimine further studies are warranted for this drug in chemotherapy of M. intracellulare infections.     

Efficacy of common antiseptics against mycobacteria.

SETTING AND OBJECTIVE: Antiseptics are frequently used to prevent mycobacterial infection; however, the reported activities of a number of antiseptics against mycobacteria are not always consistent. The aim of this study was to determine those antiseptics that are useful against mycobacteria. DESIGN: Evaluation of antiseptic activity against mycobacteria in vitro. RESULTS: The effects of different antiseptics on mycobacteria (Mycobacterium avium, M. kansasii and M. tuberculosis) were examined. At concentrations of 0.05%, povidone-iodine (PVP-I) killed 99% or more of all strains tested within 15 seconds, while 0.5% chlorhexidine gluconate and 0.1% benzalkonium chloride showed no bactericidal activity against mycobacteria. M. kansasii and M. tuberculosis were killed after exposure to cresol for 60 seconds at concentrations of 1.0%, but M. avium was unaffected even after 60 seconds. While M. kansasii and M. tuberculosis were killed by treatment with 2.0% glutaraldehyde for 5 minutes, M. avium was highly resistant to this agent. CONCLUSION: PVP-I seems to be a useful antiseptic against mycobacteria. The measured activity of antiseptics should be interpreted carefully, due to the potential for interference by artifacts.     

Influence of subinhibitory concentrations of cephalosporins on the serum sensitivity of Pseudomonas aeruginosa

The effect of sublethal concentrations of antibiotics on the serum sensitivity of Pseudomonas aeruginosa was examined. Cefepime, ceftazidime, and imipenem but not amikacin nor ciprofloxacin increased the serum bactericidal activity of pooled normal human serum. Killing was both serum- and antibiotic dose-dependent. Increased sensitivity to the bactericidal action of serum in the presence of cefepime was observed for several different clinical isolates. With the use of C8-deficient sera, the late components of the complement pathway were shown to be essential for bacterial killing. A significant increase in the amount of [125I]C9 based on bacterial mass was observed with bacteria incubated with cefepime compared with non-antibiotic- or amikacin-treated controls. No major change in the amount of type of lipopolysaccharide was observed when cefepime-treated and control bacteria were compared. The data show that cefepime and other cephalosporins at sublethal concentrations increase the complement-mediated bactericidal activity of serum against P. aeruginosa.