akinohanayuki ブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.


結構 遭遇するO157
夏祭りで悲しきあるある O157
抗菌薬やるの?やらないの? O157



Enterohemorrhagic Escherichia coli (EHEC) are strains capable of producing Shiga toxin and typically cause bloody diarrhea. The incubation period between exposure to EHEC and the onset of symptoms is typically three to four days (range one to nine days). Clinical manifestations may include history of bloody diarrhea, a visibly bloody stool specimen, no reported fever, a peripheral white blood cell count above 10,000/microL, and abdominal tenderness.
Hemolytic-uremic syndrome (HUS) is the major systemic complication of EHEC infection. HUS is characterized by the triad of acute renal failure, microangiopathic hemolytic anemia, and non-immune thrombocytopenia; these typically begin 5 to 10 days after the onset of diarrhea. HUS generally complicates 6 to 9 percent of EHEC infections overall and about 15 percent of EHEC infections in children under age 10; for reasons that are not fully known, the incidence of HUS was substantially higher in the outbreak of E. coli O104:H4 infection in Europe in the summer of 2011.
Screening for E. coli O157:H7 in stool may be performed with sorbitol-MacConkey (SMAC) agar, as the organism ferments sorbitol slowly. Sorbitol-negative (translucent) colonies can be confirmed as E. coli biochemically and then tested for reaction with antisera to the O157 antigen. Strains presumptively identified as E. coli O157:H7 should be sent to a reference laboratory for confirmation. The likelihood of organism detection is highest in the first six days after onset of diarrhea.
Direct detection of toxin or toxin genes in the stool is more sensitive than SMAC agar and can also detect non-O157:H7 Shiga toxin-producing E. coli (STEC) strains; testing by both culture and toxin assay is recommended by the United States Centers for Disease Control and Prevention. The diagnosis of infection with E. coli O104:H4 or other non-O157 strains may be established directly (via toxin detection) or indirectly (via serologic testing).
The treatment of EHEC infection consists of supportive care and monitoring for the development of microangiopathic complications. We recommend NOT administering antibiotic therapy to patients with EHEC infection (Grade 1B). For situations in which EHEC is suspected, antibiotics should be withheld pending diagnostic information, particularly in children under the age of 10. For circumstances in which antibiotic therapy was initiated empirically, it should be discontinued if diagnostic data demonstrating EHEC become available. Antibiotics have not been observed to alter the duration of acute diarrhea, can induce the expression and release of Shiga toxin, and may increase the risk of HUS in children. Antiperistaltic agents increase the risk of systemic complications and should also be avoided.
The treatment of Enterohemorrhagic E. coli (EHEC) infection consists of supportive care and monitoring for the development of microangiopathic complications, such as hemolytic-uremic syndrome (HUS). Antiperistaltic agents increase the risk of systemic complications and should be avoided.
Role of antibiotics
Antibiotic therapy is generally not beneficial in patients with EHEC infection; in several studies it did not alter the duration of acute illnesses. Furthermore, antibiotic treatment of EHEC has been associated with development of HUS in some studies. Given these findings, we recommend not administering antibiotic therapy to patients with EHEC infection. When EHEC is clinically suspected, we favor withholding antibiotics pending diagnostic information, particularly in children under the age of 10 years. If EHEC is isolated in patients in whom antibiotic therapy was initiated empirically, we favor discontinuing it.
Several studies have shown correlation between antibiotic use and risk of HUS, although the evidence overall is mixed and of variable quality. In a meta-analysis of mainly observational studies that included over 1800 patients with EHEC infection, there was a nonsignificant trend towards a higher risk of HUS with antibiotic use (pooled odds ratio [OR] 1.33, 95% CI 0.89-1.99). The association was stronger (pooled OR 2.24, 95% CI 1.45-3.36) when analysis was limited to studies that were deemed to have a low risk of bias and that had a stringent definition of HUS. One of these was a prospective study of 259 children <10 years of age with E. coli O157:H7 infection. HUS occurred more frequently in the 25 children who received antibiotics, which included trimethoprim-sulfamethoxazole, beta-lactams, metronidazole, and azithromycin (36 compared with 12 percent in those who did not receive antibiotics). After adjustment for other variables, the absolute antibiotic-attributable risk increase for HUS incidence was 25 percent, corresponding to one case of HUS for every four children treated with antibiotics.
These clinical data are consistent with experimental studies, which have observed induction of expression and release of Shiga toxin with antibiotic therapy.
Retrospective data from the German E. coli O104:H4 outbreak in 2011 suggested that antibiotic therapy was associated with shortening of Shiga toxin-producing E. coli (STEC) fecal excretion, seizure incidence, and death, and there was no clinical evidence suggestive of antibiotic induced toxin release. However, most patients did not receive antibiotics, and the study was not randomized. Follow-up of patients infected with E. coli O104 showed a median duration of shedding of the organism of 17 to 18 days, and some patients shed the organism asymptomatically for 5 to 6 months. Receipt of antibiotics did appear to shorten subsequent excretion of this particular organism in stool.
Clin Infect Dis. 2016 May;62(10):1251-8. Epub 2016 Feb 24.
Shiga Toxin-Producing Escherichia coli Infection, Antibiotics, and Risk of Developing Hemolytic Uremic Syndrome: A Meta-analysis.
  • BACKGROUND: Antibiotic administration to individuals with Shiga toxin-producing Escherichia coli (STEC) infection remains controversial. We assessed if antibiotic administration to individuals with STEC infection is associated with development of hemolytic uremic syndrome (HUS).
  • METHODS: The analysis included studies published up to 29 April 2015, that provided data from patients (1) with STEC infection, (2) who received antibiotics, (3) who developed HUS, and (4) for whom data reported timing of antibiotic administration in relation to HUS. Risk of bias was assessed; strength of evidence was adjudicated. HUS was the primary outcome. Secondary outcomes restricted the analysis to low-risk-of-bias studies employing commonly used HUS criteria. Pooled estimates of the odds ratio (OR) were obtained using random-effects models.
  • RESULTS: Seventeen reports and 1896 patients met eligibility;8 (47%) studies were retrospective, 5 (29%) were prospective cohort, 3 (18%) were case-control, and 1 was a trial. The pooled OR, including all studies, associating antibiotic administration and development of HUS was 1.33 (95% confidence interval [CI], .89-1.99; I(2) = 42%). The repeat analysis including only studies with a low risk of bias and those employing an appropriate definition of HUS yielded an OR of 2.24 (95% CI, 1.45-3.46; I(2) = 0%).
  • CONCLUSIONS: Overall, use of antibiotics was not associated with an increased risk of developing HUS; however, after excluding studies at high risk of bias and those that did not employ an acceptable definition of HUS, there was a significant association. Consequently, the use of antibiotics in individuals with STEC infections is not recommended.
Clin Infect Dis. 2012;55(1):33.
Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis.
  • BACKGROUND: Escherichia coli O157:H7 is the leading cause of hemolytic uremic syndrome (HUS). Risk factors for development of this complication warrant identification.
  • METHODS: We enrolled children infected with E. coli O157:H7 within 1 week of the onset of diarrhea in this prospective cohort study. The study was conducted in 5 states over 9.5 years . The primary and secondary outcomes were HUS (hematocrit<30% with smear evidence of hemolysis, platelet count<150×10(3)/µL, and serum creatinine concentration>upper limit of normal for age) and oligoanuric HUS. Univariate and multivariable and ordinal multinomial regression analyses were used to test associations between factors apparent during the first week of illness and outcomes.
  • RESULTS: Of the 259 children analyzed, 36 (14%) developed HUS. Univariate analysis demonstrated that children who received antibiotics during the diarrhea phase more frequently developed HUS than those who did not (36% vs 12%; P = .001). The higher rate of HUS was observed across all antibiotic classes used. In multivariable analysis, a higher leukocyte count (adjusted odds ratios [aOR]1.10; 95% CI, 1.03-1.19), vomiting (aOR 3.05; 95% CI, 1.23-7.56), and exposure to antibiotics (aOR 3.62; 95% CI, 1.23-10.6) during the first week of onset of illness were each independently associated with development of HUS. Multinomial ordinal logistic regression confirmed that initial leukocyte count and antibiotic use were independently associated with HUS and, additionally, these variables were each associated with the development of oligoanuric HUS.
  • CONCLUSIONS: Antibiotic use during E. coli O157:H7 infections is associated with a higher rate of subsequent HUS and should be avoided.
厚 生 省  平成9年8月21日
  • O157感染症による下痢症は、細菌感染症であるので、適切な抗菌剤を使用することが基本であり、厚生科学研究事業で行われた全国調査では、抗菌剤を使用した群の中で早期投与された者ほどHUSの発症率が低かったとの結果が報告されている。
  •  一方、これまでにST合剤等を使用した場合にHUSが悪化したという症例や抗菌剤の使用の有無により臨床経過に有意な差異がなかったという研究結果が米国等で報告されていることから、欧米等には抗菌剤の使用に懐疑的な意見があり、世界保健機関(WHO)等においても検討課題として取り上げられている。また「抗菌剤が菌を破壊することによって菌からのベロ毒素放出が増加した」という試験管内での実験結果から、「患者への抗菌剤の使用は、腸管内で増殖した菌を破壊して症状を悪化させるのではないか」との理論的懸念も指摘されているが、臨床結果との関係は明確でない。
  •  したがって現時点では、抗菌剤の使用については上記の内容等を念頭に置いて、実際の臨床現場の状況を踏まえながら主治医が判断して対応すればよい。
  •  O157感染症と診断し、抗菌剤を使用する場合には、できるだけ速やかに以下に例示する抗菌剤の経口投与を行う。なお、ST合剤等は使用しない方がよい。
  • 抗菌剤の使用は経口投与を原則とする。
  • 小児 : ホスホマイシン(FOM)*、ノルフロキサシン(NFLX)**、カナマイシン(KM)
  • 成人 : ニューキノロン、ホスホマイシン*
  •   * : これまでわが国においては、ホスホマイシン(1日2~3g、小児は40~120mg/kg/日を3~4回に分服)の投与が多く実施されている
  • **: ノルフロキサシン50mg錠。5歳未満の幼児には錠剤が服用可能なことを確認して慎重に投与する。乳児等には投与しない。
  •  抗菌剤の使用期間は3~5日間とし、漫然とした長期投与は避ける。また、薬剤感受性には注意し、耐性菌と判明した場合は直ちに中止し、必要があれば他剤に変更する。(厚生科学研究事業によると、これまでに国内で分離された菌の一部にはテトラサイクリン(TC)、アミノベンジルペニシリン(ABPC)、ストレプトマイシン(SM)、ホスホマイシン(FOM)、カナマイシン(KM)、ナリジクス酸(NA)等への耐性株の存在が報告されている。)
  •  抗菌剤を使用しても消化管症状が直ちには消失することはないが、通常3~5日間程度の使用により菌は消失する。
  •  抗菌剤を使用してもHUS等の合併症が発症することがあり、また輸液・抗菌剤の使用後、症状が改善しても、その2~3日後に症状が急激に悪化することがあるので、注意を怠ってはならない。
  •  発症の早期を過ぎている場合、または激しい血便や腹痛の激しい時期に抗菌剤を使用することが適切かについては判断の材料に乏しいが、抗菌剤を使用しないか、使用する場合には静菌性抗菌剤を使用し、合併症の発症に十分に注意することが妥当と考えられる。
  •  なお、抗菌剤の使用の有無にかかわらず、乳酸菌製剤などの投与については、国内外において有効であるとの報告が行われている。
HUS guideline
JAID/JSC 感染症治療ガイドライン 2015 ―腸管感染症
腸管出血性大腸菌(EHEC または志賀毒素産生大腸菌 STEC)腸炎
腸管出血性大腸菌腸炎では下痢発症3~14日後にHUSを合併する事がある.メタ解析では抗菌薬投与によりHUS 発症リスクが高くなるという結論はないが,米国では投与による利点がなく副作用の懸念があるということ,複 数のコホート研究で,抗菌薬投与群は非投与群と比較して,HUS 発症率が高かったことの報告があることから抗 菌薬の使用については結論がでていない.
● 日本では EHEC 集団感染の際に抗菌薬,特に FOM が使用され,後方視的検討で FOM を早期に使用した群にお ける HUS 発症率が低い事が報告された.抗菌薬を投与する場合は,腸炎を発症後できるだけ早期(3 日以内)に 投与を開始する.
● EHEC 患者の家族等の保菌者に対しては,感染拡大予防を目的として手洗いの指導などを確実に行う.生活状況 や背景などを総合的に判断して,必要があれば抗菌薬投与を考慮する.
FOM 経口 1 回 10~40mg/kg・1 日 3~4 回(40~120mg/kg/日,最大 3,000mg/日)・5 日間
腸管出血性大腸菌腸炎 以前は,下痢などの症状を起こす大腸菌を病原性大腸菌と呼んでいた.しかし,その後さまざまな病原因子が明 らかになってきたことから,病原性をもつ大腸菌群全体を下痢原性大腸菌と呼ぶようになった.ヒトに下痢などの 症状をきたす下痢原性大腸菌は,大きく 5 つに分類されている. 腸管毒素原性大腸菌(enterotoxigenic Escherichia. coli:ETEC) 腸管病原性大腸菌(enteropathogenic E. coli:EPEC) 腸管出血性大腸菌(enterohemorrhagic E. coli:EHEC) 腸管侵入性大腸菌(enteroinvasive E. coli:EIEC) 腸管凝集性大腸菌(enteroaggregative E. coli:EAEC or EAggEC) このうち腸管出血性大腸菌(EHEC)では,便培養による菌分離,血清型検査を行った後に,ベロ毒素の産生に ついての検査が行われる.血清型 O157 が最も多く,その他にも O26,O111 など複数の種類の血清型がみられてい る.EHEC においては,血管障害性の志賀毒素を産生することで下痢,血便,さらに溶血性尿毒症症候群(hemolytic uremic syndrome:HUS),脳炎を合併することで重症化しやすい.全体の 5~10% の患者は HUS をきたし,HUS になった患者の約 10% は死亡または永久的な腎不全となり,なんらかの程度の腎障害になる患者は 50% におよぶ という報告もある.さらに,少数の菌量でも感染するため集団食中毒が発生しやすいことから,感染症法におい ても三類感染症として全例の届出が義務づけられている.
【抗菌薬による治療】 一般的に EHEC 以外の下痢原性大腸菌では,経過観察か補液などの対症療法のみで自然軽快することがほとんど である.しかし,EHEC の場合には小児や高齢者での重症例が多くられ,HUS や脳症を合併した場合には死亡する 危険性が高まる.止痢薬は HUS の発症リスクを高めるとの報告があるため,できる限り使用しない. EHEC に対する抗菌薬投与については,必要とする意見(抗菌薬治療にて重篤な反応は少なく,重症化を防ぎ周囲への伝播を減らす効果もあるため)と,必要ではない(抗菌薬治療により菌体から毒素が一度に排出されて重篤 化してしまうリスクがあるため)という意見の両方があり,現時点で抗菌薬治療に対しての推奨は統一されていない(C).  
欧米においては,抗菌薬使用によって菌からの毒素放出を促進され HUS 発症の危険性が増すとの報告が多く, ガイドラインでも使用は推奨されていない.一方,抗菌薬使用群と非使用群の 2 群での比較で HUS の頻度 に差を認めなかったという randomized controlled trial(RCT)研究の報告もある.また,抗菌薬の投与が HUS のリスクには影響を与えないというメタ解析もある36).さらに国内の限られた症例数ではあるが,過去のアウトブ レイクにおいてホスホマイシン(FOM)を中心として抗菌薬を使用し有効であったとの報告もある.
Clin Nephrol. 1999.
Effect of early fosfomycin treatment on prevention of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection.
  • OBJECTIVE: To clarify the effect of early fosfomycin treatment, an antimicrobial agent in common use in Japan, on children with E. coli O157 with the aim of preventing hemolytic uremic syndrome (HUS)
  • PATIENTS AND METHODS: DESIGN: Non-randomized prospective study for development of HUS among inpatients with E. coli O157.
  • SETTING: The hospitals where the 292 inpatients were treated.
  • CASES: A total of 292 inpatients aged six to eleven years with E. coli O157 infection, 36 (12.3%) of whom were HUS cases.
  • RESULTS: Most of the HUS inpatients (91.7%) developed this complication between the sixth and ninth day of illness. We therefore analyzed the effects of antimicrobial therapy, especially that of fosfomycin, on prevention of HUS within the first five days of illness, because fosfomycin was the most frequently used (88.0%). To clarify the effect of fosfomycin alone on prevention of HUS, we carried out an analysis using the data for 130 inpatients who received fosfomycin alone or did not receive any antimicrobial agents, within the first five days of illness. multivariate analysis, controlled for age, gender and presence of fever, showed that all adjusted odds ratios for the development of HUS with the use of fosfomycin within the first three days of illness were less than 1.0, with the use of fosfomycin on the second day of illness achieving statistical significance (adjusted OR, 0.09; 95% CI, 0.01-0.79). Furthermore, inpatients who took fosfomycin within the first two days of illness developed HUS significantly less often than those who did not (adjusted OR, 0.15; 95% CI, 0.03-0.78). On the other hand, fosfomycin therapy on and after the third day of illness was not associated with the prevention of HUS.
  • CONCLUSION: The early use of fosfomycin within the first two days of illness might prevent the development of HUS.
Pediatrics International 1999.
Effect of early oral fluoroquinolones in hemorrhagic colitis due to Escherichia coli O157:H7
  • Abstract During the Sakai outbreak of Escherichia coli O157:H7 infection, which was linked to contaminated cafeteria school lunches, there were several treatment modalities with regard to antimicrobial drugs. Patient outcomes among three hospitals with different modalities were compared retrospectively. Hemolytic uremic syndrome did not develop in any of the 15 patients treated with oral fluoroquinolone therapy; however, HUS did develop in three of 15 patients treated with intravenous (i.v.) fosfomycin and in two of 12 patients treated with i.v. cefotaxime and oral fosfomycin. The results indicate that oral fluoroquinolone therapy administered within 3 days of illness is effective in preventing the development of HUS; however, prospective randomized double-blind studies on early antimicrobial therapy of O157 hemorrhagic colitis are necessary. Several antibiotics, including fluoroquinolones, were reported to induce the production or release of Shiga-like toxins (STX) from E. coli O157:H7 in vitro. Although patients were examined for fecal STX, no STX were detected in the stools of patients treated with oral fluoroquinolones. In fact, treatment with fluoroquinolones for 5 days eradicated E. coli O157 in all patients.