Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.     

哌拉西林/他唑巴坦联合阿米卡星治疗绿脓杆菌肺炎疗效分析

目的:观察哌拉西林/他唑巴坦联合阿米卡星治疗绿脓杆菌肺炎的疗效.方法:对我科收治的绿脓杆菌肺炎100例病人采用哌拉西林/他唑巴坦联合阿米卡星治疗,静脉滴注剂量为哌拉西林/他唑巴坦4.5 g,q 8 h,阿米卡星400 mg,qd,疗程7-10 d.结果:总有效率为81%,细菌清除率为72%,不良反应率低.结论:哌拉西林/他唑巴坦联合阿米卡星是治疗绿脓杆菌肺炎的有效选择.     

Piperacillin/Tazobactam Monotherapy Versus Piperacillin/Tazobactam Plus Amikacin as Initial Empirical Therapy for Febrile Neutropenia in Children with Acute Leukemia

The purpose of this study is to compare the efficacy and safety of piperacillin/tazobactam (PIP/TAZO) versus PIP/TAZO plus amikacin in febrile neutropenic children with acute leukemia (AL). Children with AL who had febrile neutropenic episodes were randomized to treatment with PIP/TAZO versus PIP/TAZO plus amikacin. Modification was defined as addition of other antimicrobials and/or antifungal agents to the empirical therapy. Protocol failure was defined as withdrawal of the empirical regimen and introduction of other antimicrobials due to failure in controlling infection. Seventy-two febrile episodes of 42 patients with a median age of 4.5 years (3.5 months to 19 years) were evaluated. There were 37 and 35 episodes in PIP/TAZO and combination arms, respectively. Success without modification, with modification, protocol failure, duration of treatment were 45.9%, 35.1%, 18.9%, and 10 days in PIP/TAZO arm and 42.9%, 37.1%, 20%, and 12 days in combination arm, respectively (P > .05). There was no significant difference between the empirical therapy arms regarding median duration of neutropenia and defervescence of fever. Empirical therapy was substituted by other drugs in 6 and 5 episodes in PIP/TAZO and combination arms, respectively. There was no infection-related death. There was reversible increase in serum creatinine in 1 episode on the combination arm. Monotherapy with PIP/TAZO was effective and safe for initial empirical treatment of febrile neutropenic episodes in children with AL. However, local bacterial resistance patterns should be considered in daily practice. Combination of amikacin with PIP/TAZO did not improve treatment success, but it may increase nephrotoxicity.     

Comparative In- Vitro Activity of Fourteen Antibiotics Against Clinical Isolates of Enterococci

Summary

The in-vitto antibacterial activities of fourteen antimicrobial agents, including ampicillin, amikacin, Augmentin, ceftazidime, cefotaxime, ceftriaxone, ciprofloxacin, erythromycin, gentamicin, penicillin G, piperacillin, rifampicin, streptomycin and vancomycin, were compared against 195 enterococcal strains isolated from clinical specimens received at the King Abdulaziz University Hospital in Saudi Arabia. The antibacterial susceptibility was determined by the minimal inhibitory concentration (MIC) using an agar dilution method. Ampicillin, Augmentin and vancomycin exhibited the greatest activity, inhibiting 90% of the tested strains (MIC90) at 2 μg/ml, followed by penicillin G and piperacillin with MIC90 of 4 μg/ml. Erythromycin, third generation cephalosporins, aminoglycosides and rifampicin, on the other hand, had poor activity against enterococci with MIC90s well above the obtainable serum concentrations. The clinical implications of resistance to aminoglycosides and the alternative antimicrobial therapy in serious entrococcal infections are discussed in the text.     

十一种抗菌药对五种细菌的抗生素后效应

目的：测定不同类别抗菌药对5种细菌的抗生素后效应（PAE）。方法：以肉汤稀释法测定抗菌药的最低抑菌浓度,PAE实验采用洗涤法去除抗菌药,以活菌落计数法测定菌液浓度,作生长曲线、计算PAE。结果：大环内酯类红霉素、阿奇霉素、克拉霉素及罗红霉素对金黄色葡萄球菌的PAE为3．10－4．15h,对肺炎链球菌的PAE为1．85－3．3h,明显较其他抗菌药的PAE为长（P＜0．01）。大环内酯类抗菌药对流感嗜血杆菌的PAE为1－4h,其中阿奇霉素的PAE达4h。环丙沙星、阿米卡星对大肠杆菌及肺炎克雷伯菌的PAE为1．38－2．00h,明显较哌拉西林、头孢唑啉或头孢噻肟的PAE（0．1－0．5h)为长（P＜0．01）。结论：各类抗菌药对细菌的PAE长短不一,PAE作为一个药效学指标,对抗菌药给药方案的制订及其合理应用有一定的参考价值。     

烧伤休克期家兔丁胺卡那霉素药动学的改变

５０只家兔烫伤前和烫伤后静脉注射丁胺卡那霉素（１０ｍｇ／ｋｇ）的药动学资料比较结果表明，２０～３０％体表面积三度烫伤后６ｈ、１２ｈ、２４ｈ和３６ｈ给药的４０只补液家兔的丁胺卡那霉素药动学参数均表现为，半衰期（ｔ＿１／２）延长、表观分布容积（Ｖｄ）增加，清除率（ＣＬ）和曲线下面积（ＡＵＣ）改变不明显；１０只烫后６ｈ给药的不补液家兔的药动学参数则为：ｔ＿１／２会延长、Ｖｄ改变不明显、ＣＬ下降和ＡＵＣ增加。本研究揭示了烧伤休克期丁胺卡那霉素药动学变化的特点，为临床合理用药提供实验依据。     

Disseminated Mycobacterium abscessus subspecies massiliense infection and subsequent prosthetic joint infection in a hemodialysis patient: A case report

A 74-year-old man with diabetic nephropathy undergoing dialysis after total knee arthroplasty presented to our hospital with dyspnea and abnormal behavior such as wearing his pants on his head. The patient was in shock with ventricular tachycardia. Urine and blood cultures showed MAM with sterile pyuria. We administered amikacin and imipenem cilastatin, but repeated cultures were persistently positive. Although we initially chose not to administer azithromycin because of a higher risk of fatal arrhythmia, we had no choice but to administer azithromycin because of treatment failure. Upon close monitoring, we observed no arrhythmia, and the blood cultures became negative. The patient was discharged on day 106 without any symptoms. However, 2 months after discontinuation of antibiotics, he was readmitted and diagnosed with prosthetic joint infection due to MAM. He could not undergo total knee arthroplasty resection because of his low tolerance to surgery. We re-administered same antibiotics, and repeated draining and cleaning of his left knee for several weeks. The inflammation in the knee joint gradually improved, and the patient was discharged while treatment with azithromycin and amikacin was continued. After being discharged, the patient did not experience recurrent disease for at least 6 months.Our case suggests that MAM can cause sterile pyuria and infection in a patient with diabetic nephropathy. The macrolide agent is a key drug for MAM infection, and repeated joint lavage in addition to administering antibiotics may be an alternative treatment for prosthetic joint infection in patients with intolerance to surgery.     

紫外分光光度法测定脂质体中阿米卡星的含量

应用紫外分光光度法 (经Hantzsch衍生化 )测定脂质体中阿米卡星的含量 .平均回收率为(10 0 5± 1 7) % (n =5 ) ,线性范围为 10～ 6 0 μg/mL .方法准确度高、重现性好 .     

The Efficacy of Mezlocillin-Amikacin Combination in Febrile Neutropenic Children with Oncologic Disease

Summary

The efficacy of mexlocillin-amikacin combination as empirical therapy for febrile neutropenic patients was studied in 30 children (21 males, 9 females) with various oncologic diseases aged 1-15 years (mean age 7.3±4.4) in the Istanbul Medical School, Oncologic Disease Research and Treatment Center, and Department of Pediatric Hematology-Oncology between January 1 and May 31, 1988.

The response rate was 76.6%. Profound persistent granulocytopenia (fewer than 100 ml) was present in 70% of the patients. In 63.3% of patients, the infections were microbiologically documented (60%) gram( + ) and 40% gram( - ).

The combination was well tolerated with hepatic and/or renal disturbances in 8 cases (26.6%). We conclude that mezlocillin-amikacin is an effective empirical combination in the initial treatment of infections in febrile neutropenic children with various oncologic diseases.