• Tuberculosis and Respiratory Diseases
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• 제57권5호
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• pp.405-410
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• 2004

배 경 : 현재 moxifloxacin은 기존의 quinolone 제제들에 비하여 항결핵효과가 크다고 알려지면서 다제내성 결핵에 많이 사용되어 왔지만 moxifloxacin과 기존의 quinolone간의 교차내성에 대한 보고가 없는 상황에서 기존의 quinolone에 내성인 균주에 대한 moxifloxacin의 효과를 예측하기 어려웠다. 이에 본 연구를 통하여 moxifloxacin과 ofloxacin간의 교차내성을 알아봄으로써 ofloxacin 내성 균주에 대한 moxifloxacin의 항 결핵 효과를 알아보고자 하였다. 방 법 : 2003년 3월부터 2004년 3월까지 폐결핵 치료를 위해서 국립마산병원에 방문 또는 입원하였던 환자들의 객담에서 분리된 M. tuberculosis isolate에 대한 약물감수성 검사상 ofloxacin에 대한 본원 임상 검사실의 내성기준 농도인 $2.5{\mu}g/m{\ell}$의 농도에 내성을 보인 균주 37개와 감성을 보인 균주 16개를 대상으로 하여 ofloxacin 및 moxifloxacin 각각에 대한 MIC를 비례법을 이용하여 조사하였다. 결 과 : Ofloxaicn 감성균주들에 대한 $MIC_{50}$과 $MIC_{90}$은 ofloxacin에서 모두 $1.25{\mu}g/m{\ell}$, moxifloxacin에서는 각각 $0.31{\mu}g/m{\ell}$과 $0.63{\mu}g/m{\ell}$였다. ofloxacin 내성균주들에 대한 $MIC_{50}$은 ofloxacin에서 $10{\mu}g/m{\ell}$ 이상, moxifloxacin에서 $5{\mu}g/m{\ell}$였으며 $MIC_{90}$은 ofloxacin과 moxifloxacin 모두에서 $10{\mu}g/m{\ell}$이상의 값을 보였다. 약물 농도 $2.5{\mu}g/m{\ell}$을 기준으로 한 moxifloxacin의 ofloxacin에 대한 교차 내성률은 67.6%로 나타났다. 결 론 : moxifloxacin은 $10{\mu}g/m{\ell}$의 농도에서 ofloxacin 내성균주의 82.4%(28/34)에서 항결핵 효과가 있었으나 ofloxacin 내성을 포함하는 다제내성 결핵환자에게 사용하기 위해서 좀 더 많은 연구가 필요할 것으로 사료된다.

• Tuberculosis and Respiratory Diseases
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• 제52권2호
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• pp.128-136
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• 2002

연구배경 : 다제내성 결핵 환자에서 fluoroquinolone계 약물이 빈번하게 처방되고 있음에도 불구하고, 이의 약동학적 특성에 대한 연구가 부족한 실정이다. 그러므로, 본 연구에서는 fluoroquinolone계 약물의 하나인 ofloxacin을 복용하고 있는 다제내성 결핵 환자에서의 ofloxacin의 약동학적 특성을 분석하였고, 아울러 ofloxacin의 약동학적 특성을 전신쇠약 상태와 연관지어 분석하였다. 방 법 : 300 mg b.i.d. 의 ofloxacin 용법을 포함하여 prothionamide, cycloserine, para-aminosalicylic acid, kanamycin 및 streptomycm 등의 2차 항결핵제제를 복용 중인 20명의 다제내성 결핵 환자를 대상으로 하였다. 전신쇠약 상태가 ofloxacin의 약동학에 미치는 영향을 평가하기 위하여 body mass indes (BMI)에 따라 환자를 두 군 (A 군 ; 18.5 $\leq$ BMI < 23, B군 : < 18.5)으로 나누어 두 군간의 ofloxacin의 항정상태 약동학적 특성을 비교분석하였다. 한 달 이상의 고정용법으로 항정상태에 이른 피험자에서 약동학 연구를 위하여 혈액을 경시적으로 13회 취하였고, 뇨 시료도 24 사간까지 취하였다. 혈장 및 뇨의 ofloxacin 농도를 HPLC를 이용하여 측정한 후 각각의 약동학적 분석을 시행하였다. 결 과 : Ofloxacin 의 AUC는 B군에서 $31.4{\pm}8.9{\mu}g/ml{\cdot}h$로 A군의 24.1+6.2 ${\mu}g/ml{\cdot}h$보다 유의하게 큰 것으로 나타났다(p<0.05). 항정상태에서 A군의 ofloxacin의 청소율 (Cl/F)은 $0.16{\pm}0.03$ L/h/kg로 산출되었고, B군에서는 $0.14{\pm}0.03$ L/h/kg로 나타났다. Ofloxacin의 반감기($t_{1/2}$)는 두 군간에 차이를 보이지 않았다(A군 : $5.3{\pm}0.8$시간, B군 $5.7{\pm}0.9$시간)으며 다른 약동학적 경수들도 두 군간의 유의한 차이를 보이지 않았다. 결 론 : 이상의 연구결과는 정상 피험자에 비하여 다제내성 결핵 환자에서 ofloxacin의 약동학적 특성이 유의하게 다르지 않음을 나타내고 있다. 한편, 만성 다제내성 결핵 환자의 전신쇠약 정도는 혈장 ofloxcaicn의 농도에 변화를 유발하는 것으로 기대된다.

• Archives of Pharmacal Research
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• 제21권6호
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• pp.671-676
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• 1998

Five hundred and seventy clinical strains of Pseudomonas aeruginosa were isolated from August 1993 to August 1994 in Korea and screened for their resistance to ciprofloxacin, norfloxacin, and ofloxacin. Among these, two P. aeruginosa strains (PA150 and PA300) were selected based on their strong resistance (MICs > 50mcg/ml) to all three quinolones. The susceptible strain as well as two resistant strains had proton gradient-dependent efflux system. Efflux system in PA300 showed different specificities to ofloxacin and ciprofloxacin while PA150 had less permeability for ofloxacin. Ofloxacin had a less inhibitory action on DNA synthesis in permeabilized cells of PA150 and PA300 than 1771M. When quinolone resistance determining region (QRDR) in gyrA was sequenced, PA300 had one missense mutation, Asn 116Tyr, which was newly reported in this work. The results showed that PA150 became ofloxacin resistant by reduced ofloxacin accumulation due to the existence of efflux system and low permeability, while resistance of PA300 was due to the efflux system and a mutation in QRDR of gyrA -the target site of quinolone.

• 대한의생명과학회지
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• 제11권4호
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• pp.465-471
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• 2005

Ofloxacin has antimycobacterial activity that possibly contributes a pivotal role in the second-line drug regimens that are used for the treatment of multidrug-resistant tuberculosis. However, in some communities, the resistance rate of Mycobacterium tuberculosis to this agent is surging. Therefore, a rapid and accurate method that can be used to determine the resistance of M tuberculosis to the ofloxacin can be very useful for effective treatment of the patients. As an effort to develop such a method, this study was set up to reveal general types of mutations that are related to ofloxacin resistance of M tuberculosis. From previous studies, it has been well known that ofloxacin resistance is associated with mutations in a gene encoding the gyrase A subunit protein. In this study, we obtained 43 ofloxacin-resistant and 50 ofloxacin-susceptible M tuberculosis clinical isolates from Masan National TB Hospital, and sequences of DNA fragment of 320 bp, region of gyrA corresponding to the ofloxacin resistance-determining region were analyzed. In brief, the results showed that a total of seven mutation types were found at gyrA. Theses mutations were all clustered within nucleotides 2574 to 2586 of the gyrA gene (codons 88 to 94). Codon 94 was the most frequently substituted site. Twenty-four of the 43 isolates had mutations at this position resulting in a total of five different types of amino acid changes $(Asp{\to}Ala,\;Asp{\to}Gly,\;Asp{\to}His,\;Asp{\to}Tyr,\;and\;Asp{\to}Asn)$. Five isolates contained a mutation at codon 90 resulting $Ala{\to}Val$ change. Four isolates had mutations at codon 91 causing a $Ser{\to}Pro$ change at this site. Two isolates contained a mutation at codon 88 and each of them resulted in different types of amino acid changes $(Gly{\to}Cys,\;Gly{\to}Ala)$. On the other hand, polymorphic site at codon 95 was found in both ofloxacin-resistant and ofloxacin-susceptible isolates. From these results, we concluded that the rate of mutations present in gyrA among ofloxacin-resistant M. tuberculosis in Korea is similar to the general rates of mutations found throughout the world. Subsequently, an oligonucleotide probe was designed based on the results of sequence analysis and was used to develop a dot blot hybridization assay system to determine ofloxacin-resistance of M tuberculosis. To evaluate this probe, dot-blot hybridization was carried out using other 57 clinical isolates, and the results showed that the dot-blot hybridization assay is good for detecting sequence alterations atgyrA gene.

• 미생물학회지
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• 제38권4호
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• pp.265-265
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• 2002

Iron increased the susceptibilities of clinical isolates Pseudomonas aeruginosa to quinolones. In the presence of iron, increased susceptibilities to ofloxacin were observed in twenty-six out of thirty isolates and with no change in four isolates. In the case of norfloxacin, iran increased susceptibilities of twelve isolates but did not render any change in eighteen isolates. In the case of ciprofloxacin, iron decreased the MICs (Minimal Inhibitory Concentration) of twenty isolates, increased the MIC of one isolate, and did net change the MICs of nine isolates. To find out how iron increased susceptibility to ofloxacin, bacterial cells were grown in Muller Hinton (MH) media and succinate minimal media (SMM) to induce iran acquisition systems and the intracellular ofloxacin concentrations were assayed in the presence of iron. The addition of iron to the media decreased the MICs of cells whether they were grown in MH or SMM. Siderophores, carbonyl cyanide m-chlorophenylhydrazone (an inhibiter of proton motive force), and ouabain (an inhibitor of ATPase) did not decrease the effect of iron. Results suggested that the increase in the intracellular ofloxacin concentration by iron is accomplished not by decreasing the efflux but by increasing the of ofloxacin permeability.

• Archives of Pharmacal Research
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• 제15권3호
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• pp.208-210
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• 1992

Comparative bioavailability of two tablet dosage forms of ofloxacin (either as Hoechst (India) or Ranbaxy preparation ) was investigated. In a randomized cross-over study, eitht healthy human volunteers received single 200 mg dose of film coated ofloxacin in fasting state. The concentration of ofloxacin in the collected saliva and serum samples were measured by high performance liquid chromatography. No significant difference in bioavailability of both preparations was judged from various serum and seliva pharmacokinetic parameters such as peak concentration, time to peak concentration and are under the curves. Intersubject variation was also found to be insignificant.

• 한국임상약학회지
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• 제10권1호
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• pp.38-41
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• 2000

A high-performance liquid chromatographic method with fluorometric detection was evaluated for analysis of ofloxacin in plasma. Biological fluids (plasma, $200\;{\mu}L$) were prepared for assay by protein precipitation with chlorofurm. The detection of ofloxacin and triamterene as an internal standard were performed at 358 nm for excitation and 495 nm for emission. The HPLC separation was carried out on Ultrasphere ODS column (4.6 mm${\times}25\;cm,\;5\;{\mu} m$) with acetonitrile $(45\%)$-phosphoric acid $(1.5\%)\;containing\;0.3\%$ sodium laurylsulfate as the mobile phase. The flow-rate was 1.0 mL/min. The calibration graphs were linear from 3.0 to 80 ng/mL with r=0.998. The minimal detectable concentration in plasma was 1.5 ng/mL. The proposed technique is reproducible, selective, reliable and sensitive.

• 약학회지
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• 제43권1호
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• pp.128-130
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• 1999

In vitro activity of commonly used antimicrobial agents against several clinical isolates were studied. In the case of E. coli, the MICs at which 90% of the bacteria are inhibited of ampicillin, Unasyn, cefazoline, cefotaxim, carbenicillin, gentamicin and ofloxacin were 100<, 100, 25, 0.2, 100<, 3.13, and $12.5{\;}\mu\textrm{g}/m$ , respectively. In the case of K . pneumoniae, the MICs at which 90% of the bacteria are inhibited of ampicillin, Unasyn, crfazoline, cefotaxim, carbenicillin, gentamicin and ofloxacin were 100<, 12.5, 100<, 0.1, 100<, 1.6, and $0.4{\;}\mu\textrm{g}/m$ , respectively. In the case of Enterobacter sp, the MICs at which 90% of the bacteria are inhibited of ampicillin, Unasyn, cefazoline, cefotaxim, carbenicillin, gentamicin and ofloxacin were 100<, 100, 100<, 6.25, 100<, 100 and $1.57{\;}\mu\textrm{g}/m$ , respectively. In the case of Acinetobacter sp, the MICs at which 90% of the bacteria are inhibited of ampicillin, Unasyn, cefazoline, cefotaxim, carbenicillin, gentamicin and ofloxacin were 100<, 100<, 100<, 100<, 100< 100< and $50{\;}\mu\textrm{g}/m$ , respectively. In the case of Pseudomonas sp, the MICs at which 90% of the bacteria are inhibited of ampicillin, Unasyn, cefazoline, cefotaxim, carbenicillin, gentamicin and ofloxacin were 100<, 100<, 100<, 50, 100<, 25 and $25{\;}\mu\textrm{g}/m$, respectively. In the case of S. aureus, the MICs at which 90% of the bacteria are inhibited of ampicillin, Unasyn, cefazoline, cefotaxim, carbenicillin, gentamicin and ofloxacin were 50, 50, 100<, 100<, 50, 50, and $100{\;}\mu\textrm{g}/m$, respectively.

• Journal of Microbiology
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• 제38권4호
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• pp.265-269
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• 2000

Iron increased the susceptibilities of clinical isolates Pseudomonas aeruginosa to quinolones. In the presence of iron, increased susceptibilities to ofloxacin were observed in twenty-six out of thirty isolates and with no change in four isolates. In the case of norfloxacin, iran increased susceptibilities of twelve isolates but did not render any change in eighteen isolates. In the case of ciprofloxacin, iron decreased the MICs (Minimal Inhibitory Concentration) of twenty isolates, increased the MIC of one isolate, and did net change the MICs of nine isolates. To find out how iron increased susceptibility to ofloxacin, bacterial cells were grown in Muller Hinton (MH) media and succinate minimal media (SMM) to induce iran acquisition systems and the intracellular ofloxacin concentrations were assayed in the presence of iron. The addition of iron to the media decreased the MICs of cells whether they were grown in MH or SMM. Siderophores, carbonyl cyanide m-chlorophenylhydrazone (an inhibiter of proton motive force), and ouabain (an inhibitor of ATPase) did not decrease the effect of iron. Results suggested that the increase in the intracellular ofloxacin concentration by iron is accomplished not by decreasing the efflux but by increasing the of ofloxacin permeability.

• Journal of Pharmaceutical Investigation
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• 제35권6호
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• pp.417-422
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• 2005

This study was aimed to design and formulate the moisture-activated patches containing ofloxacin and lidocaine for antibacterial and local anesthetic action. The solubility of lidocaine at $32^{\circ}C$ in various vehicles decreased in the rank order of PG $759.5{\pm}44.5\;mg/mL$ > PGL > IPM > PEG 300 > PEG 400 > Ethanol > PGMC > DGME > PGML > OA > $Captex^{\circledR}\;300$ > $Captex^{\circledR}\;200$ > water $(4.0{\pm}0.1\;mg/mL)$. Ofloxacin revealed very low solubility, which the highest solubility was obtained from PEG 400 $(18.7{\pm}6.3\;mg/mL)$ among the vehicles used. The addition of lactic acid increased the solubility of ofloxacin dramatically; the solubility at 5% lactic acid was $133.7{\pm}9.7\;mg/mL$. As $2-hydroxypropyl-{\beta}-cyclodextrin$ was added at the concentrations of 40, 80, 120, 160 and 200 mM, the solubilities of lidocaine and ofloxacin were enhanced up to three and two times, respectively, with concentration-dependent pattern. Gel intermediates for filmtype patches were prepared with mucoadhesive polymer, viscosity builders, lidocaine or ofloxacin at pH values from 5 to 7. Gels were cast onto a release liner and dried at room temperature. Dried patch was attached onto an adhesive backing layer, thus forming a patch system. Patches containing a single drug component were characterized by in vitro measurement of drug release rates through a cellulose barrier membrane. The release study was carried out at $37^{\circ}C$ using a Franz-type cell. Receptor solutions were isotonic phosphate buffers (pH 7.4). Samples $(100\;{\mu}L)$ were taken over 24 hours and quantitated by a verified HPLC method. The releases from all tested were proportional to the square root of time. The release rates were 0.9, 157.3 and $281.7\;{\mu}g/cm^{2}/min^{1/2}$ for the lidocaine patches and 19.8,37.2 and $50.7\;{\mu}g/cm^{2}/min^{1/2}$ for the ofloxacin patches at the concentrations of 0.3, 0.5 and 1 %, respectively. The release rates were dose dependent in both drug patches $(R^{2}\;=\;0.9077\;for\;lidocaine;\;R^{2}\;=\;0.9949\;for\;ofloxacin)$ and those were also thickness-dependent $(R^{2}\;=\;0.9246\;for\;lidocaine;\;R^{2}\;=\;0.9512\;for\;ofloxacin)$.