Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a randomised, multicentre trial

We report on 232 patients undergoing autologous haematopoietic stem cell transplantation (ASCT) entered into a multicentre, randomised trial comparing the efficacy and tolerability of meropenem (MPM) with that of piperacillin/tazobactam (P/T) as empirical antimicrobial first-line therapy for febrile neutropenia. In 27.6% of patients in the MPM group and 22.4% in the P/T group, therapy was initially supplemented with a glycopeptide for venous catheter infection or bacteraemia because of coagulase-negative staphylococci. Complete response rate after 72 h was 63.8% in the MPM group and 49.6% in the P/T group (P = 0.034). Overall complete response rate after treatment modification was 94.0% in the MPM group and 93.1% in the P/T group. Median time to defervescence was 2 d in the MPM group and 3 d in the P/T group. The most frequently isolated pathogens were Gram-positive cocci. Treatment was well tolerated in both groups. One patient (0.4%) died from infection. Empirical first-line therapy with MPM as well as with P/T is safe and effective in febrile episodes emerging after ASCT. Higher response rates to primary treatment can be achieved with MPM.     

神经外科重症患者美罗培南迟发型过敏反应1例及处置经验

美罗培南是神经外科重症感染的常用药物,抗感染疗效确切,但有关不良反应报道的资料较少,特报道1例美罗培南迟发型过敏反应病例及处置经验,回顾并附以皮疹图片资料,以供临床参考.     

Competing off-loading mechanisms of meropenem from an l,d-transpeptidase reduce antibiotic effectiveness

The carbapenem family of β-lactam antibiotics displays a remarkably broad spectrum of bactericidal activity, exemplified by meropenem’s phase II clinical trial success in patients with pulmonary tuberculosis, a devastating disease for which β-lactam drugs historically have been notoriously ineffective. The discovery and validation of l,d-transpeptidases (Ldts) as critical drug targets of bacterial cell-wall biosynthesis, which are only potently inhibited by the carbapenem and penem structural classes, gave an enzymological basis for the effectiveness of the first antitubercular β-lactams. Decades of study have delineated mechanisms of β-lactam inhibition of their canonical targets, the penicillin-binding proteins; however, open questions remain regarding the mechanisms of Ldt inhibition that underlie programs in drug design, particularly the optimization of kinetic behavior and potency. We have investigated critical features of mycobacterial Ldt inhibition and demonstrate here that the covalent inhibitor meropenem undergoes both reversible reaction and nonhydrolytic off-loading reactions from the cysteine transpeptidase Ldt_Mt2 through a high-energy thioester adduct. Next-generation carbapenem optimization strategies should minimize adduct loss from unproductive mechanisms of Ldt adducts that reduce effective drug concentration.

The β-lactam family of antibiotics act by inhibiting biosynthesis of the peptidoglycan (PG) portion of the bacterial cell wall canonically by irreversible, covalent inhibition of penicillin-binding proteins (PBPs) (1). The PBPs known as d,d-transpeptidases (Ddts) generate 4 → 3 cross-links between amino acids in PG stems, while those known as d,d-carboxypeptidases hydrolyze the PG peptide stem C-terminal d-alanyl-d-alanyl amide bonds (2). The PBPs were long thought to be the sole target of β-lactams. However, in 1974, mycobacterial PG was shown to additionally contain 3 → 3 cross-links (3), and Streptococcus faecalis membrane preparations were demonstrated to catalyze l,d-type 3 → 3 cross-linking reactions in a penicillin-insensitive manner (4). The first characterized l,d-transpeptidase (Ldt) enzyme, Ldt_fm, was identified in Enterococcus faecium in 2005 (5), and the dominant cross-link type in mycobacteria was demonstrated to be of type 3 → 3 soon after (6). Discovery of the primary l,d-transpeptidase in Mycobacterium tuberculosis, Ldt_Mt2, and its validation as a drug target followed (7). Ldts are widespread in bacteria; both pathogenic and harmless mycobacterial species contain multiple paralogues (8). The Ldt and PBP families display convergent evolution of PG transpeptidase activity: the PBPs use a serine nucleophile to cross-link cell walls, and the alternately folded Ldts catalyze cross-linking reactions with an active-site cysteine. Within the β-lactam class of drugs, only the related carbapenem and penem classes potently inhibit l,d-transpeptidases (9–12). Carbapenems have been in clinical use since the approval of imipenem in 1985 (13) and were identified as antimycobacterial compounds in 2009 (14), a unique property among β-lactams. A phase II clinical trial has demonstrated that meropenem, in combination with amoxicillin and clavulanic acid, is effective at reducing mycobacterial burden in adults with pulmonary tuberculosis over 14 d (15), and a clinical trial is underway for use of meropenem in adults with rifampin-resistant tuberculosis (https://clinicaltrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT03174184","term_id":"NCT03174184"}}NCT03174184). However, key mechanistic questions about the mode of action of carbapenems antimycobacterial activity remain open.Based on mechanistic studies with PBPs, β-lactams were initially assumed to undergo an irreversible reaction, in which the only pathway to regenerate active enzyme after drug acylation is hydrolysis and thus destruction of the covalent warhead of the antibiotic (16, 17). Kinetic models of carbapenem Ldt inactivation have been built upon the assumption of irreversibility (10, 18). However, universal irreversibility of β-lactam acylation of enzymes has been challenged by the discovery of the reversible action against Ldts of the cephalosporin nitrocefin. Ldt–carbapenem reversibility requires re-formation of a β-lactam ring in the active site of an enzyme, an energetically challenging reaction but precedented in the light of nitrocefin-reversibility and biosynthesis of certain β-lactam containing natural products (19).Four distinct enzyme catalyzed mechanisms of β-lactam ring closure are known from natural product biosynthesis. Penicillins and cephalosporins form their bicycle within one nonheme iron-dependent enzyme, powered by the exergonic reduction of diatomic oxygen to water (20). The three remaining mechanisms are nonoxidative, transacylation reactions (Fig. 1). Carbapenems, clavams, and tabtoxinine are synthesized from an asparagine synthetase homolog, in which ATP is consumed to produce an AMP-adenylate, primed for intramolecular attack of an amine to generate the four-membered ring (21–23). The β-lactam in carbapenems is synthesized through a carbapenam intermediate prior to desaturation of the five-membered ring and, to our knowledge, there is little precedence, synthetically or biosynthetically, for direct ring closure of a desaturated pyrroline to form a strained carbapenem directly. A monocyclic β-lactam family, the nocardicins, exploit a high-energy pantetheine thioester bond, seen in most nonribosomal peptide synthetase (NRPS) intermediates, to close their ring in a condensation domain (24). The other family of monocyclic β-lactams, monobactams, also form their eponymous rings while bound to an NRPS but on an atypical type 1 thioesterase (T1 TE) bearing a catalytic cysteine. The cysteine of the monobactam T1 TE catalyzes product release from the NRPS system by β-lactam formation instead of the hydrolysis or unstrained macrocyclization reactions characteristically observed for serine T1 TEs (25). Interestingly, replacement of the catalytic cysteine of the monobactam sulfazecin T1 TE with serine reverts the TE into a hydrolase, emphasizing the need for a high-energy intermediate, such as a thioester, to enable β-lactam formation (26).Open in a separate windowFig. 1.Key four-membered ring formations. In monocyclic β-lactams, the azetidinone ring is formed in A by a condensation domain while attached as thioesters to peptidyl carrier proteins in the case of nocardicin G (the nocardicins), or (B) a thioesterase as shown in sulfazecin (the monobactams). (C) Nitrocefin re-forms its β-lactam in the active site of Ldt_fm using its conjugated, anionic amine to substitute the enzyme thioester. (D) The obafluorin β-lactone ring is formed on a thioester. The meropenem-derived lactone (E) is formed by attack of the C6 hydroxyethyl group into the ester of class D, serine β-lactamases (SBLs). The condensation domain responsible for monocyclic β-lactam formation is depicted as a green circle, labeled C₅, as it is in the “module” responsible for incorporating the fifth amino acid in nocardicin G biosynthesis. The two peptidyl carrier proteins that deliver nocardicin biosynthetic intermediate to the condensation domain within module 5 are represented as cyan rectangles labeled PCP₄ and PCP_5. The thioesterases used to form the sulfazecin β-lactam and obafluorin β-lactone is a green circle labeled “TE.” The l,d-transpeptidase from E. faecium, Ldt_fm, is an orange circle. The C3′ position of nitrocefin is labeled with a black arrow. The class D β-lactamase is depicted as a green circle labeled “SBL.”The Ldt from E. faecium (Ldt_fm) reacts reversibly with nitrocefin, which, unlike most cephalosporins, does not have a C3′ leaving group to drive the reaction forward irreversibly (27). Instead, the C3′ sidechain contains a conjugated chromogen that remains deprotonated, giving a colorimetric signal concurrent with β-lactam scission. This resonance-stabilized anion can attack back into the Ldt thioester, re-forming nitrocefin’s original β-lactam ring, and releasing itself from Ldt_fm, the sole characterized reversible reaction of a β-lactam with a transpeptidase (28). In contrast, Ldt_fm was proposed to be irreversibly inhibited by carbapenems due to apparent rapid protonation of the pyrroline nitrogen in the ring-open enzyme–adduct form (28–30). However, the pK_a of the nitrogen of a pyrolline-2-carboxylic acid is 6.2 (31) and, while this study was done on a small molecule in solution rather than an enzyme adduct, it is reasonable that a portion of the pyrroline nitrogens in the ensemble of Ldt–carbapenem adducts remain unprotonated for nucleophilic β-lactam ring closure in our reaction conditions at pH 8.0. Analogous to biosynthesis of the monocyclic β-lactams, the Ldt cysteine nucleophile forms a thioester upon drug acylation, rather than a more stable PBP oxyester. Given the resemblance among the Ldt–carbapenem thioester adduct, the biosynthetic thioester intermediates, and the Ldt_fm–nitrocefin adduct, we reasoned that, although strained, carbapenem drugs may have a reversible mechanism of action with Ldt enzymes through re-formation of the β-lactam ring. Chemically, this proposal would follow from the principle of microscopic reversibility.The β-lactone family of natural products is chemically related to the β-lactam family, and the known biosyntheses are analogous. They may proceed through AMP-adenylates on β-lactone synthetases (32), as in carbapenems and clavams, or in obafluorin biosynthesis, a T1 TE thioester on an NRPS (33), thus mirroring monobactam biosynthesis. The class D β-lactamases, a family of serine-based β-lactamases, are notable for both their ability to degrade carbapenem drugs and the unusual carbapenem β-lactone formation, which, along with hydrolysis, defines their mechanism of antibiotic degradation (34). Meropenem’s nucleophilic hydroxyethyl combined with a 1-β-methyl capable of directing a conformation favoring 4-exo-trig cyclization sets the stage for kinetically favorable β-lactone ring formation while meropenem is bonded to an enzyme, and, in the case of Ldt–meropenem adducts, the Ldt thioester lowers the energy barrier for β-lactone formation further.     

注射用比阿培南治疗呼吸系统、泌尿系统细菌感染的随机对照多中心临床研究

目的 评价注射用比阿培南治疗呼吸系统和泌尿系统细菌感染的疗效和安全性。方法 采用多中心、随机、盲法、阳性药物平行对照试验方法,共入选288例呼吸系统和泌尿系统感染患者,随机分别接受比阿培南（试验组,144例）或美罗培南（对照组,144例）的治疗,统计两组的临床治愈率、细菌学疗效和不良反应发生率并进行比较。结果 试验组和对照组临床治愈率分别为95.10%（136/143）和92.25%（131/142）,呼吸系统感染治愈率分别为93.06%（67/72）和94.29%（66/70）,泌尿系统感染治愈率分别为97.18%（69/71）和90.28%（65/72）;试验组和对照组细菌清除率分别为88.00%（66/75）和92.65%（63/68）,呼吸系统感染细菌清除率分别为83.33%（30/36）和90.62%（29/32）,泌尿系统感染细菌清除率分别为92.31%（36/39）和94.44%（34/36）;两组间临床治愈率、细菌学疗效比较差异无统计学意义（P>0.05）;试验组不良反应发生率为2.08%（3/144）,对照组为8.33%（12/144）,两组间比较差异有统计学意义（P=0.030 6）。非劣效性检验结果显示,试验组的细菌清除率和综合疗效非劣于对照组成立。结论 比阿培南治疗呼吸系统感染和泌尿系统感染的疗效与美罗培南相仿,安全性更好。     

1例多重耐药鲍曼不动杆菌颅内感染病例讨论

目的通过对1例多重耐药鲍曼不动杆菌颅内感染患者成功抗感染治疗的分析讨论,促进专科临床药师树立对专科治疗、营养、生命支持等治疗的整体观理念。方法分析讨论1例多重耐药的鲍曼不动杆菌颅内感染患者抗感染治疗过程。结果美罗培南虽然药敏显示耐药,但前期治疗有效,根据其药动学／药效学（PK／PD）,持续泵入,延长给药时间,加上甘露醇降低颅内压等治疗,抗感染治疗效果明显。结论抗感染效果不仅仅由抗菌药物决定,有效的综合治疗诸如患者的营养改善、内环境稳定等决定抗感染最终的治疗效果。     

美罗培南治疗血液肿瘤伴发热及中性粒细胞减少患儿的疗效分析

目的初步探讨美罗培南对血液系统肿瘤伴发热及中性粒细胞减少患儿的疗效及安全性。方法收集2012年7月至2013年10月湖南省儿童医院住院的血液系统肿瘤伴中性粒细胞减少及初次发热经美罗培南治疗患儿的病例资料,分析美罗培南的疗效及安全性。并根据不同肿瘤类别、中性粒细胞绝对数减少程度分组比较。结果共55例纳入研究,微生物学检测确诊及临床确诊感染的病例分别为22例(40.0%)、24例(43.6%)、未知感染源者9例(16.4%)。实体瘤患儿的发热性中性粒细胞减少(FN)持续时间及住院时间较白血病患儿短(P<0.05),治疗有效率差异无统计学意义;ANC≥0.2×109·L-1组的FN持续时间及住院时间较ANC<0.2×109·L-1组患儿短(P<0.05),治疗有效率高于后者;未出现不良反应、总有效率89.1%(49/55)。结论应用美罗培南治疗血液系统肿瘤伴发热及FN患儿安全有效,可作为临床医师初期经验性抗菌药物选用的药物。     

Carbapenems in the USA: focus on doripenem

The threat of antibacterial resistance continues to increase globally, and therapeutic options for the treatment of some serious infectious diseases are diminishing. The carbapenems are a potent class of broad-spectrum drugs, and their stability against hydrolysis by many important β-lactamases make them an important weapon in the treatment of β-lactamase-producing bacterial pathogens. This review focuses on four carbapenems of clinical importance in the USA: imipenem, meropenem, ertapenem and doripenem. After a historical review of carbapenem development, these four carbapenems are evaluated based on their mechanism of action, spectrum of activity, potency, pharmacodynamics, clinical pharmacokinetics, clinical profiles and toxicity issues.     

美罗培南在化脓性脑膜炎新生儿血浆和脑脊液中药动学和药效学的关联研究

目的 探讨美罗培南在化脓性脑膜炎的新生患儿血浆和脑脊液中的药动学和药效学的关联。方法 试验招募2016年5月—2021年5月在扬州大学附属医院诊断为化脓性脑膜炎的58例新生儿患者,均获得血浆样品,其中17人获得脑脊液样品。出生后2～4周的新生儿以及4～6周的婴幼儿使用8 h的剂量间隔,美罗培南使用剂量为40 mg·kg^-1,输注时间超过30 min。使用带有DIGITAL FORTRAN编译器的NONMEM软件包分析数据。超高效液相色谱联用串联质谱（UHPLC-MS/MS）测定血浆和脑脊液中的美罗培南浓度。使用最终模型估计值的蒙特卡罗模拟（n＝1 000）用于生成不同给药方案的游离血药浓度水平维持在目标菌群的最低抑菌浓度（MIC）之上的时间（fT＞MIC）占1个给药间隔的百分比（% fT＞MIC）和最小抑菌浓度（MIC）值：1、2、4、8 mg·L^-1。结果 美罗培南在血浆中的峰浓度（C_max）、曲线下面积（AUC）、清除率（CL）、表观分布容积（V_d）高于脑脊液中的各项数据,差异有统计学意义（P＜0.05）;血浆中的半衰期（t_1/2）低于脑脊液,差异有统计学意义（P＜0.05）。用蒙特卡罗模拟10 000例患者目标获得概率,随着MIC值增加,血浆目标获得概率降低;血浆中40%最低抑菌浓度（MIC）的时间百分比（40% TMIC）、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。随着MIC值增加,脑脊液目标获得概率降低;脑脊液中40% TMIC、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。结论 模拟试验表明,当MIC为2 μg·mL^-1时,美罗培南在血浆中的目标获得概率可以达标,其在脑脊液中的目标获得概率不能达标,治疗时需要增加美罗培南的剂量或缩短给药间隔,以达到治疗目标。     

胸腺肽联合美罗培南治疗革兰阴性杆菌重症下呼吸道感染临床疗效观察

目的评价胸腺肽联合美罗培南治疗革兰阴性杆菌重症下呼吸道感染的临床疗效和安全性。方法将84例革兰阴性杆菌重症下呼吸道感染患者随机分为胸腺肽联合美罗培南治疗组41例（A组）和美罗培南治疗对照组43例（B组）,疗程均为7~14天。比较两组临床疗效、美罗培南使用时间、细菌学改变及不良反应情况。结果 A、B组的临床有效率分别为85.4%、79.1%,差异无统计学意义（P〉0.05）;A组的治疗时间短于B组,（8.6±3.6）天vs（12.5±3.4）天（P〈0.05）;A、B组的细菌清除率87.5%、81.4%,差异无统计学意义（P〉0.05）。A组的二重感染率低于B组,（3.1%vs 25.0%,P〈0.05）。结论胸腺肽联合美罗培南治疗革兰阴性杆菌重症下呼吸道感染安全、有效,可减少二重感染发生、缩短美罗培南治疗时间。