NEJM述评：阿奇霉素和其他抗菌药的肠胃风险！

根据IMS肥胖病患者系统连续性Corporation数据集，2011年纽约地区约4.3千万（约1/8人口）施打过病房药药中会的大环内芳香烃抗生素于在头孢。鉴于其癌病患者后果，这一年，我们在旧金山食品和用药管理局（FDA）维持原判了于在头孢及其他已批准的选择连续性类杀菌药的表单说明了，从发表的系统连续性调查报告及上市后监测调查报告来看，这种后果已似乎都与当明显。在维持原判的为基础，考虑其起因的QT外期该线和与之都与关的尖端扭转型室速，FDA批准了对于在头孢表单说明了的改动。修订后的表单说明了不决定对已知险恶心理因素的病患者适用于在头孢，如QT外期该线，极低钾血病患者，极低镁血病患者，心动过缓，或适用某些抗心力衰竭用药，之外IA类（如奎尼夫，普鲁卡因酯）和三类可以该线QT外期的用药（如，多非利特，酯碘醛，戈他洛尔）。在2013年3月为反映一项诊疗系统连续性结果：于在头孢可以该线矫正的QT外期，FDA宣告，对于在头孢表单说明了已作进一步的修订。

在2012年一项扩展到乔治亚州照护补助金病人的检视连续性系统连续性中会，Ray 等人量化了与于在头孢区别的心血管疾病或许丧命后果并将其与适用其他的杀菌药或不适用都与比之下。系统连续性说明，无论是从任一或许还是癌病患者或许看，与于在头孢区别的丧命的后果都大于阿莫西林。每21000个适用于在头孢的病房病人中会就有数人发生心血管疾病丧命，将近那些适用阿莫西林的同数量病房病人。根据癌病患者的险恶心理因素，于在头孢较阿莫西林过较低的后果心理因素很杂，系统连续性人员预估，在较低心血管疾病后果病患者中会每4100适用于在头孢的病患者中会就有将近一个死于心血管疾病心理因素，而在极低心血管疾病后果病患者中会丧命部将差不多1/100,000。

这项由Ray等人顺利完成的系统连续性有一定的局限连续性，它只是一种内在的检视，而非不确定连续性的诊疗系统连续性。值得注意是，非不确定连续性系统连续性不能也就是说的似乎连续性就是与管控用药病患者都与比之下，一些私自审计的病患者以一些关键但未被挖掘出的方式施打用药，从而加剧结果偏差。这种参杂似乎是比较偏差起因，不只能假定于施打杀菌药及未施打杀菌药病患者外，也假定于施打多种不同的杀菌药病患者之外。虽然Ray等人适用了适当的系统连续性方法以解决问题潜在的参杂，但我们无法确信这些方法是否十分有效。通过系统连续性多种不同的数据集分组重复使用笔记的结果，将为施打于在头孢的病患者减少癌病患者的丧命部将这一挖掘出提供愈来愈多的具体度。

尽管有这样的劝诫，由雷等人得出结论的结果值得受到重视。该结果的着重点是后果的小时受到限制Mode：因任何或许与心血管疾病病因与于在头孢都与关的丧命部将减少小时跨度小时为1?5天，反映了典型的于在头孢5天给药适用期（例如，希舒美Z-PAK）。在6至10天，心血管疾病或许丧命的后果增大不必显现。此Mode与于在头孢血药浓度达峰小时及随之而来的QT外期该线后果是一致的。不管是否将适用于在头孢用药与阿莫西林及与不适用杀菌用药都与比之下，增大后果都有非常大的统计学普遍性。此外，检视到的过较低丧命部将只能出自于癌病患者丧命，尤其是肺脏暴毙;虽然肺脏连续性暴毙可以是心力衰竭都有的其他或许引来，在此类别中会丧命部将减少预想类型一般为心力衰竭血案与 引来QT外期该线的用药。此外，假定癌病患者病患者与于在头孢都与关的后果愈来愈较低且构成用药都与关连续性心力衰竭。

由Svanstrom和他的同事（在1704至1712页）适用冰岛国家政府护理数据集顺利完成的一项另行系统连续性挖掘出，适用于在头孢和青头孢V在5天内的心血管疾病丧命后果并都将（都与对后果，0.93;95％具体区外[CI]，0.56至1.55）。然而，在95％的置信区外的上限，不也就是说后果将增至55％。如Svanstrom等人所说，在丧命基线后果和癌病患者险恶心理因素方面，他们系统连续性的人口多种不同于Ray等人。上都来看，冰岛的病患者比乔治亚州的照护补助金病患者有着愈来愈容易的心血管疾病肥胖病患者。对假定癌病患者文化史的病患者顺利完成亚分组系统连续性时，于在头孢vs青头孢V的后果比大于1，但该区别连续性无统计学普遍性（都与对险恶度为1.35，95％CI，0.69 - 2.64）。 svanstrom等人揭示道：他们的结果与Ray等人的结果并不冲突。都与反，对癌病患者丧命部将的影响似乎只能限与患有癌病患者的病患者。

当然，我们必须对诊疗获利与任何检视到的用药都与关连续性后果顺利完成衡量，因此，对仍未反映在 Ray等人系统连续性的后果数据集中会的于在头孢具体获利的似乎其所顺利完成适当考虑。例如，其他系统连续性说明，选择连续性类用药在社区给予败血病患者用药中会就上都生存期而言优于其他杀菌药。在新西兰都只的一项检视连续性系统连续性中会，系统连续性人员事件调查了2973个社区给予败血病患者的病房病人，与那些做氟化物类固醇类用药病人都与比之下做选择连续性类用药病患者30天丧命部将显着降极低（校正都为0.28，95％CI，0.09?0.86）。都只的对观测系统连续性的一项荟萃系统连续性说明：在社区给予败血病患者住院病患者中会广泛其所用选择连续性类用药都与对于广泛其所用非选择连续性类用药病患者在丧命部将上假定着25％非常大统计学区别连续性。这些系统连续性结果，其所考虑其观测系统连续性的受到限制连续性，不一定与Ray等人的结果都与矛盾。舍弃5天的与于在头孢都与关的癌病患者丧命后果，这种用药似乎会减少因肺炎起因的一直丧命部将（例如，将近30天）。在乔治亚州照护补助金的病人广泛其所用于在头孢用药肺炎不是常规的处理方式。

诊疗精神科须考虑不只能于在头孢，其他备选杀菌药也有潜在的致心力衰竭作用。先前的系统连续性说明：吲哚的适用和心源连续性暴毙之外假定区别，与细胞色素P-4503A同工酶（代谢吲哚）抑制剂同用时会减慢。吲哚和克拉头孢表单说明了忠告之外QT外期该线和心力衰竭。所有氟化物类固醇类产品的表单说明了同样有关于QT外期该线的忠告，格帕沙星就是因为这种后果从市场上后撤。都只的一项关于新西兰魁北克省老年区内检视连续性系统连续性显示：病房氟化物类固醇类用药的适用和更为严重心力衰竭（定义为出院诊断为室连续性心力衰竭、马上或自发的丧命）假定区别。虽然雷等人的挖掘出：于在头孢癌病患者丧命后果比环丙沙星愈来愈大，他们挖掘出适用右氧氟化物沙星与于在头孢的后果都与似。笔记用证据推论了这种都与似连续性，右氧氟化物沙星可致心力衰竭，然而，右氧氟化物沙星致心力衰竭与新西兰的系统连续性未区别连续性通过系统连续性从2002年到2011年十年外约3200病房精神科顺利完成的一项Encuity系统连续性的数据集，我们事件调查了病房于在头孢最类似的止痛。在所有年龄分组的病患者中会，于在头孢最类似的两种止痛为慢连续性鼻窦炎和支气管炎。表中会显示了在旧金山对于这些止痛的最常用杀菌用药。在此期外于在头孢是病房用药支气管炎的除此以外用药（即使阿莫西林与阿莫西林-克拉维酸联合）。对于慢连续性鼻窦炎，于在头孢的适用只能次于阿莫西林排名第二。由于止痛由药医师调查报告，这些数据集使我们无法审计诊断确定且即将做用药的接种。

在决定药时某种程度考虑杀菌药用药的后果和获利。药理和系统连续性数据集指出：适用于在头孢，选择连续性类，氟化物类固醇类起因的QT外期该线的一个潜在更为严重连续性就是致命连续性心力衰竭。这种似乎连续性使精神科在考虑适用杀菌药药时，尤其是对已假定心血管疾病险恶心理因素或诊疗病患者状，适用杀菌用药用药的获利有限的病患者，其所暂时停用。 与于在头孢都与关的拓展阅读：

In a 2012 observational study involving Tennessee Medicaid patients, Ray et al.1 quantified the risk of death from cardiovascular causes associated with azithromycin as compared with other antibacterial drugs or nonuse. The study showed that the risks of death, both from any cause and from cardiovascular causes, associated with azithromycin were greater than those associated with amoxicillin. For every 21,000 outpatient prescriptions written for azithromycin, one cardiovascular death occurred in excess of those observed with the same number of amoxicillin prescriptions. The excess risk over amoxicillin varied considerably according to cardiovascular risk factors; the researchers estimated that there was one excess cardiovascular death per 4100 prescriptions among patients at high cardiovascular risk but less than one per 100,000 among patients with lower cardiovascular risk.

The study by Ray et al. has limitations that are intrinsic to observational, nonrandomized clinical studies. In particular, nonrandomized studies cannot exclude the possibility that patients receiving a drug under evaluation differ from control patients in some important but undetected way, causing bias in the results. Such confounding may bias comparisons not only between patients receiving antibacterial drugs and those receiving no antibacterials but also between patients receiving different antibacterials. Although Ray et al. used appropriate ytic methods to address potential confounding, we cannot know for certain whether these methods were fully successful. Replication of the authors' results, through ysis of a distinct data set, would provide more confidence in the finding of increased cardiovascular mortality among patients receiving azithromycin.

Despite such ceats, the results presented by Ray et al. warrant serious attention. A chief strength of the results is the time-limited pattern of the risk: the azithromycin-associated increase in the rates of death from any cause and from cardiovascular causes spanned days 1 through 5, reflecting the typical 5-day duration of azithromycin administration (e.g., Zithromax Z-Pak). On days 6 through 10, an elevated risk of death from cardiovascular causes was no longer detected. This pattern is consistent with the timing of peak plasma azithromycin concentrations and the concomitant risk of QT-interval prolongation. The elevated risk was statistically significant, regardless of whether azithromycin treatment was compared with amoxicillin or with nonuse of an antibacterial drug. Furthermore, the observed excess mortality was attributable solely to cardiovascular deaths and, in particular, to sudden cardiac death; although sudden cardiac death can result from causes other than arrhythmias, an increase in deaths in this category would be the pattern expected from an arrhythmogenic, QT-interval–prolonging drug. Also, the azithromycin-associated risk was higher among patients with cardiovascular disorders, which is consistent with a drug-related arrhythmia.

A new study by Svanström and colleagues (pages 1704–1712), using Danish national health care data, found no difference between azithromycin and penicillin V in the 5-day risk of cardiovascular death (relative risk, 0.93; 95% confidence interval [CI], 0.56 to 1.55). However, the upper bound of the 95% confidence interval does not exclude an increased risk of as much as 55%. As Svanström et al. point out, the population they studied differed from that studied by Ray et al. with respect to the baseline risk of death and cardiovascular risk factors. Overall, the Danish patients had better cardiovascular health than the Tennessee Medicaid patients. In a subgroup ysis of patients with a history of cardiovascular disease, the risk ratio for azithromycin versus penicillin V was greater than 1, though the difference was not statistically significant (relative risk, 1.35; 95% CI, 0.69 to 2.64). Svanström et al. conclude that their results do not conflict with those of Ray et al. Rather, the effect on cardiovascular mortality may be limited to patients with cardiovascular disease.

One must, of course, weigh any observed drug-associated risk against clinical benefits, so it's appropriate to consider the possibility that certain offsetting benefits of azithromycin may not he been reflected in the risk data yzed by Ray et al. For example, other studies he suggested that macrolides he an advantage over other antibacterial agents in terms of overall survival from community-acquired pneumonia. In a recent Canadian observational study, researchers followed 2973 outpatients with community-acquired pneumonia and found significantly lower 30-day mortality among patients receiving macrolides than among those receiving fluoroquinolones (adjusted odds ratio, 0.28; 95% CI, 0.09 to 0.86).2 A recent meta-ysis of observational studies showed a statistically significant 25% difference in mortality among hospitalized patients with community-acquired pneumonia foring macrolides over nonmacrolide antibacterials.3 Such findings, which must be considered with due regard for the limits of observational studies, do not necessarily contradict the results of Ray et al. Past the 5-day period of risk of azithromycin-associated cardiovascular death, the drug might reduce the longer-term (e.g., more-than-30-day) rate of death due to pneumonia. Pneumonia was an uncommon indication among the Tennessee Medicaid patients treated with azithromycin.

Clinicians must consider the arrhythmogenic potential not only of azithromycin but also of potential alternative antibacterial drugs. An earlier study showed an association between the use of erythromycin and sudden cardiac death, augmented by concomitant use of inhibitors of the cytochrome P-450 3A isozymes that metabolize erythromycin.4 Labels for erythromycin and clarithromycin include warnings regarding QT-interval prolongation and arrhythmias. All labels for fluoroquinolone products similarly he warnings regarding QT-interval prolongation, and grepafloxacin was withdrawn from the market because of that risk. A recent observational study of elderly residents of Quebec, Canada, showed an association between outpatient fluoroquinolone use and serious arrhythmias (as defined by hospital discharge diagnoses of ventricular arrhythmia or sudden or unattended death).5 And although Ray et al. found the risk of cardiovascular death to be greater with azithromycin than with ciprofloxacin, they found the risk with levofloxacin similar to that with azithromycin. The authors interpreted this similarity as evidence that levofloxacin may be proarrhythmic; however, levofloxacin was not implicated as proarrhythmic in the Canadian study.

We investigated the most common ambulatory indications for azithromycin by yzing data from a survey conducted by Encuity Research of approximately 3200 office-based physicians for the decade from 2002 through 2011. Across all age groups of patients, the two most common indications for azithromycin were chronic sinusitis and bronchitis. The table

The risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they're considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.