Drug monitoring and individual dose optimization of antimicrobial drugs: oxazolidinones

Introduction: Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials.

Areas covered: In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug-related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers.

Expert opinion: Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven.     

Comparing the ocular surface effects of topical vancomycin and linezolid for treating bacterial keratitis

Background: Vancomycin is the gold standard in combination therapy for severe and resistant gram-positive keratitis and in particular for Methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to report the ocular surface toxicity and scoring in patients whose treatment shifted to topical linezolid/ceftazidime from topical vancomycin/ceftazidime due to their vancomycin intolerance.

Methods: A retrospective, interventional case series of bacterial keratitis was treated with topical linezolid (one drop of 0.2% solution per eye), administered hourly until epithelization and then gradually decreased. The number and extent of punctate epithelial erosions were noted across the entire surface of the cornea. Ocular discomfort was assessed by means of (a) patient-reported pain upon instillation of the medication (vancomycin/linezolid), (b) reported burning sensation between doses and (c) reported foreign-body sensation. No ocular surface toxicity related to linezolid use was noted. Patients were followed for at least 2 months after treatment between April and December 2013.

Results: Of the seven patients included in the study (age range: 2–88 years; five females, two males), complete epithelization and resolution was achieved in five patients. One patient was treated with linezolid after penetrating keratoplasty. The second culture of another patient with impending perforation despite linezolid/ceftazidime therapy yielded Fusarium spp., so he underwent tectonic keratoplasty. The mean ocular surface score was 9.4?±?1.6 during vancomycin treatment and 5.9?±?1.3 during linezolid treatment after discontinuation of vancomycin. The topical linezolid score was significantly lower (p?=?0.027).

Conclusions: Topical linezolid may be better tolerated, according to the mean ocular surface score, than topical vancomycin by some patients and can be considered an alternative for patients who do not well tolerate vancomycin.     

老年患者应用利奈唑胺的合理性和安全性评价

目的：对复旦大学附属中山医院老年患者临床应用利奈唑胺的合理性进行分析,并统计不良反应的发生情况,为老年患者安全合理用药提供参考。方法：运用回顾性研究方法,选取2018年8月至2020年8月在复旦大学附属中山医院使用利奈唑胺治疗的老年患者,收集患者的基本信息、感染部位、病原菌的种类、实验室检查指标、合并疾病和合并用药等情况,根据药品的说明书和相关指南设计调查表,对老年患者中利奈唑胺的使用情况进行合理性评价,评估其疗效和不良反应,并对血药浓度监测情况进行统计分析。结果：共纳入有效病例329例,利奈唑胺临床应用的合理率为81.8%,不合理原因主要有无指征用药、疗程不当、选药起点过高以及联用药物不适宜等。临床治疗有效率为69.3%,病原菌清除率为59.6%。利奈唑胺用药期间主要的不良反应为血小板减少（20.4%）和血红蛋白减少（11.9%）。31名老年患者进行利奈唑胺的血药浓度监测,血药浓度的监测率为9.4%,谷浓度维持在2~8 mg·L^-1的有11例（35.5%）,谷浓度＞8 mg·L^-1的有18例（58.1%）,谷浓度<2 mg·L^-1的有2例（6.4%）。结论：利奈唑胺临床应用的合理性有待提高,临床医师应严格把握用药适应证及合并用药的合理性来促进其临床使用。此外,临床用药期间还应加强利奈唑胺的血药浓度监测来提高老年患者用药的安全性。     

2例利奈唑胺中介粪肠球菌血流感染的毒力及耐药机制

目的对血流感染患者临床分离的利奈唑胺中介粪肠球菌的毒力因子及耐药机制进行初步研究。方法从2例血流感染患者血标本中分离2株利奈唑胺中介粪肠球菌,分析患者治疗经过,2株分离菌编号为A、B,测定其对利奈唑胺和万古霉素的最低抑菌浓度(MIC),采用聚合酶链反应(PCR)扩增毒力基因(esp、asa1、gelE、ace、agg、efaA、cylA、hyl)和利奈唑胺耐药相关基因,包括23SrRNA V区基因、cfr、cfr(B)及optrA基因片段,其中23SrRNA V区基因扩增产物送测序并分析有无突变位点。结果 2例患者培养出利奈唑胺中介粪肠球菌后均使用利奈唑胺治疗控制了临床症状。菌株A、B对万古霉素、替考拉宁、氨苄西林、呋喃妥因敏感,对利奈唑胺中介(MIC均为4μg/mL),对万古霉素敏感(MIC分别为1μg/mL和4μg/mL)。2株菌均含有多种毒力因子,菌株A仅cylA、hyl为阴性,菌株B仅hyl、esp为阴性,其余毒力基因均为阳性。菌株A的23SrRNA V区存在G2621T突变,菌株B未发现突变位点。菌株A和B耐药基因cfr、cfr(B)、optrA均为阴性。结论此研究中血流感染患者分离的利奈唑胺中介粪肠球菌对万古霉素和氨苄西林敏感,虽治疗结果提示利奈唑胺仍有效,但临床中选用利奈唑胺治疗需谨慎。靶位突变是该类药物重要的耐药机制,临床中治疗该类药物不敏感粪肠球菌感染需足够重视,其治疗策略仍需进一步探讨。     

2011—2015年四川省金黄色葡萄球菌对万古霉素及利奈唑胺耐药性变迁

目的了解四川省金黄色葡萄球菌对万古霉素、利奈唑胺耐药情况,为临床抗感染治疗提供参考依据。方法收集四川省71所医院2011-2015年临床分离的金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌（MRSA）,并计算每年万古霉素与利奈唑胺对金黄色葡萄球菌、MRSA的最低抑菌浓度（MIC）值。结果5年共收集51 976株金黄色葡萄球菌,包括MRSA 14 361株,MRSA检出率由2011年的36.02%下降至2015年的25.56%,呈下降趋势(χ2=160.72,P＜0.05）。2011-2015年万古霉素对金黄色葡萄球菌的MIC50值分别为：1、0.5、0.5、1、1 μg/mL,MIC90值由1 μg/mL上升至2 μg/mL;利奈唑胺MIC50值均为2 μg/mL,MIC90值由2 μg/mL上升至4 μg/mL。2011-2015年万古霉素对MRSA的MIC50、MIC90值变化较明显,分别由0.5、1 μg/mL上升至2 μg/mL;利奈唑胺MIC50值均为2 μg/mL,MIC90值由2 μg/mL上升至4 μg/mL。结论MRSA的检出率有下降趋势,但万古霉素、利奈唑胺对其MIC50及MIC90值总体有上升趋势,需继续加强细菌耐药监测,为临床合理应用抗菌药物提供帮助。     

Recent progress with oxazolidinone antibacterial agents

The oxazolidinone class of antibiotics represents a promising advance in the battle against multiply resistant Gram-positive bacterial infections. Numerous companies have been involved in this area of research and Pharmacia has recently brought the first member of this class, linezolid (Zyvox^®), to market for the treatment of sensitive and resistant Gram-positive bacterial infections. During the last few years, advancements have been made by several firms in expanding oxazolidinone SAR as well as the spectrum of activity to include the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.     

The oxazolidinones as a new family of antimicrobial agent

The oxazolidinones are a new chemical class of synthetic antimicrobials characterized by a unique mechanism of protein synthesis inhibition. Linezolid is the first compound of this class and has recently received approval for the treatment of community- and hospital-acquired pneumonia and skin and skin structure infections. In vitro tests demonstrate that linezolid possesses a significant activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate strains (VISA) and penicillin-resistant pneumococci (PRPN). Combined with other drugs linezolid interacts favourably against many important pathogens and it is able to affect some bacterial virulence factors as well as produce a postantibiotic effect.
Results from experimental models of infection reveal linezolid to be highly active in vivo against infections due to Gram-positive pathogens.
Linezolid may be administered either intravenously or orally with oral bioavailability of approximately 100% and limited adverse effects. The clinical efficacy of linezolid has been investigated in several phase II and III trials. Linezolid has been proved to be useful in severe infections sustained by multiresistant Gram-positive micro-organisms. Synthesis of the second-generation oxazolidinones with improved potency against Gram-positive and negative bacteria is currently under way.     

Efficacy and safety of linezolid in liver transplant patients

S. Radunz, B. Juntermanns, G.M. Kaiser, J. Treckmann, Z. Mathe, A. Paul, F.H. Saner. Efficacy and safety of linezolid in liver transplant patients
Transpl Infect Dis 2011: 13: 353–358. All rights reserved Abstract: Bacterial infections are the main cause of death within the first year after liver transplantation, and the increased incidence of multidrug‐resistant gram‐positive pathogens has created a major challenge in the treatment of these patients. Linezolid, the first US Food & Drug Administration‐approved oxazolidinone, offers a valuable novel treatment option for serious gram‐positive infections. Linezolid is relatively non‐toxic but prolonged treatment with linezolid was associated with thrombocytopenia. Here we report on the experience of linezolid treatment in adult liver transplant patients, who are at an increased risk for thrombocytopenia because of hypersplenism. From November 2003 until December 2009, we evaluated the clinical course of 46 liver transplant patients (27 male/19 female) in our surgical intensive care unit. For proven or probable gram‐positive infection, all patients received linezolid 600 mg intravenously every 12 h. On clinical improvement, treatment was changed to oral linezolid 600 mg twice daily. Treatment duration was 11 ± 7 days. Treatment indications were pneumonia (n=8), blood stream infection (n=30), and surgical site/abdominal infection (n=3). Clinical cure was achieved in 43 out of 46 patients. During the course of treatment, no cases of severe thrombocytopenia occurred and a statistically significant platelet count increase was seen from day 1 (110 ± 73/nL) to day 7 (165 ± 116/nL) and day 14 (180 ± 140/nL). We did not observe any further adverse events, especially no severe neurological complications (e.g., serotonin syndrome) or signs of lactate acidosis. Two patients died from uncontrolled vancomycin‐resistant Enterococcus faecium sepsis with septic shock and one due to uncontrolled methicillin‐resistant Staphylococcus aureus pneumonia. These deaths were considered to be unrelated to linezolid treatment, and linezolid was regarded as the optimal treatment choice in these patients. A subgroup analysis of patients treated for >14 days revealed no statistically significant differences when compared with patients on shorter treatment. In particular, no cases of thrombocytopenia occurred during longer treatment. In conclusion, linezolid is a safe and effective treatment for adult liver transplant patients with gram‐positive infections.     

Effect of a serum lactate monitoring recommendation policy on patients treated with linezolid

Lactic acidosis is one of the most fatal adverse effects of linezolid, an antibiotic used to treat serious infections caused by antibiotic-resistant bacteria. However, the measures to prevent lactic acidosis have not been well established.We performed a retrospective study to analyze the impact of applying a serum lactate monitoring recommendation policy in patients treated with linezolid.Since September 2011, we have recommended inpatient monitoring of serum lactate levels in patients treated with linezolid at our hospital. Patients were divided into two groups according to whether they were seen during the non-recommendation or recommendation periods. The frequency of serum lactate monitoring, linezolid-induced lactatemia, lactic acidosis, critical illness, and death were compared between the two periods.After September 2011, adherence to the recommendation to monitor serum lactate increased from 6.1% to 60.1%. No difference was observed in the incidence of linezolid-induced lactatemia and lactic acidosis between the two periods. However, there was a significant difference in the incidence of linezolid-induced critical illness between the non-recommendation and recommendation periods (3 vs 0 cases, P = .044).In patients treated with linezolid, serum lactate monitoring led to early detection of lactatemia, thus enabling rapid rescue. We recommend regular monitoring of serum lactate in all patients treated with linezolid.