今日の臨床サポート

腸チフス・パラチフス

著者: 氏家 無限 国立国際医療研究センター 国際感染症センター

監修: 具芳明 東京医科歯科大学大学院医歯学総合研究科 統合臨床感染症学分野

著者校正/監修レビュー済:2022/04/27
参考ガイドライン:
  1. 日本感染症学会・日本化学療法学会:JAID/JSC 感染症治療ガイドライン 2015 ―腸管感染症―
患者向け説明資料

概要・推奨   

  1. ナリジクス酸耐性菌ではキノロン系抗菌薬(オフロキサシン)で短期間の治療を行うと解熱までの期間が長く、再発率が高くなるため推奨されない(推奨度1)
  1. キノロン系抗菌薬ではセフェム系抗菌薬と比較して解熱までの時間が短く、再発率も低いため、感受性が確認できれば第1選択薬となる。
  1. セフトリアキソンと比較してシプロフロキサシンでは治療失敗例が少ないため、キノロン感受性菌では治療の変更を考慮する(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
氏家 無限 : 特に申告事項無し[2022年]
監修:具芳明 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、主に以下の点について加筆した。
  1. 2016年に報告のあった第三世代セフェム系抗菌薬に耐性の広域薬剤耐性腸チフス菌の流行及び各国への輸入症例が報告されている。
  1. アフリカ・南アジア各国で、生後9月または1歳時で対象となる腸チフスの結合体ワクチンにおいて定期接種プログラムでの使用が増加し、高い有効性が報告されている。
  1. 新型コロナウイルスのパンデミックの影響により、国内での腸チフスの報告数は2020年以降減少している。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 腸チフス、パラチフスはSalmonella entericaのいくつかの血清型で生じる全身性発熱性疾患であり、英語では“Enteric fever”と総称される。
  1. 腸チフスとパラチフスの両者に臨床的な差異はない。
  1. 一般に無症候性のキャリアまたは活動性のある患者の便中に排泄される病原体で汚染された飲食物の摂取により経口感染する。
  1. 時に性交渉による糞口感染、標準予防策が破綻した際の院内感染が起こり得る。
  1. 感染から発症までの潜伏期は最大で3~60日[1]であるが、その多くは8~14日であり[2]、渡航歴から潜伏期の整合性を検討する。
  1. 臨床症状は非特異的であり、初期(第1週)には菌血症による発熱、悪寒[3]、前頭部の鈍痛、倦怠感、食欲低下、嘔気や比較的徐脈などを認め、徐々に増悪する。
  1. 発症後2週目には腹痛のほか、体幹や腹部にバラ疹(<図表>)と呼ばれる2~4mm大で淡紅色の斑状皮疹を認めることがあり2~5日で自然消退する。
  1. 抗菌薬開始後には、バラ疹の出現頻度が30%から1.5%に低下する[4]
  1. 消化器症状は下痢となることは少なく、嘔吐は激しくない。また便秘となることもある。
  1. 肝脾腫を伴うことがある。
  1. 比較的徐脈(<図表>)、バラ疹(<図表>)、脾腫が3徴とされるが、これらの出現率は30~50%程度である[5]
  1. 無治療の場合には徐々に高熱となり40℃までの発熱が2週間程度持続する。その後徐々に解熱し、4週間程度で改善する。
  1. 無治療の場合、10%程度の症例で3カ月程度便中に排菌が持続し、1~4%程度の症例がキャリアとなり1年以上にわたって便中に排菌が持続する[6]
  1. 2010年には、低~中等度所得国で、約1190万人が腸チフスに罹患し、約12万9千人が死亡したと推計される。うち、南アジアでの症例は700万人と全体の半数以上を占める。
  1. 現在の調査体制で全数把握疾患となった1999年以降に国内で報告された腸チフス、パラチフスの症例数はそれぞれ年間約7~91症例であり、その大部分を国外からの輸入症例が占める。
  1. 2020年には新型コロナウイルス感染症パンデミックの影響から腸チフス及びパラチフスの報告数はそれぞれ21例、7例と減少した。
 
 
  1. 途上国に渡航する旅行者が腸チフスに罹患するリスクは10万人中2~20例程度と推計され、特に南アジアでのリスクが高い[7]
  1. 下水道設備がなく衛生環境が不良な地域(インド亜大陸・東南アジアなど)への渡航で罹患リスクが高い。
 
2017年における腸チフス・パラチフスの発生頻度からみた流行地域

世界中に広く流行地域を認め、特に南アジア、東南アジアでの感染リスクが高い。

出典

img1:  Typhoid fever infection - Antibiotic resistance and vaccination strategies: A narrative review.
 
 Travel Med Infect Dis. 2021 Mar-Apr;40:1・・・
 
  1. わが国における2005~08年における報告(<図表>)の78~86%の報告はアジアでの国外感染であり、そのうちインドでの感染が35~37%と最も多い。
 
腸チフス・パラチフス患者の推定感染地、2005~2008年

2005~2008年に報告のあった腸チフス・パラチフスにおいて、大多数が海外における感染が推定されており、アジア地域(特にインド)に多かった。

 
  1. わが国に承認はないが、国際的には注射の不活化多糖体ワクチンと結合体ワクチン、経口の生ワクチンが利用可能であり、海外渡航における感染のリスクに応じてワクチン接種を考慮する(国内にも未承認ワクチンを提供する医療機関はある)。
  1. 感染症法の3類感染症であり、診断後には直ちに保健所に届け出る必要がある。また、食品に直接接触する作業者に対して就業制限がある。学校保健安全法で第三種感染症に指定されており、「病状により学校医その他の医師において感染のおそれがないと認めるまで」を出席停止の期間の基準としている。
 
  1. 日本で承認された腸チフスワクチンはないが、以前から実用化されているワクチン(Ty21aワクチン、Viワクチン)はともに腸チフスの予防に有効であり、加えて2017年には、生後6月から使用が可能な結合体ワクチンが新たにWHOからpre-qualifiedワクチンとして認められた(推奨度2CS)(参考文献:[8][9][10]
  1. 腸チフスのワクチンの有効性と安全性を評価するため、2013年6月までに公表されている18の無作為対照化試験を用いて系統的レビューを行った。経口生ワクチンであるTy21aワクチンは2万人を超える評価において、接種後2年間に約1/3から半数に腸チフスに対する予防効果を認めた(1年目35% 95%CI 8-54%、2年目58% 95%CI 40-71%)が3年目には有意な予防効果を認めなかった。消化器症状の副反応との関連は認めなかったが、発熱を予防接種群より多く認めた。
  1. 不活化のVi多糖体ワクチンの腸チフスに対する予防効果は、約10万人での評価において1年目に69%(95%CI 63-74%)、約20万人での評価において2年目に59%(95%CI 45-69%)、約1万人の評価においても55%(95%CI 30-70%)であった。副反応として発熱や発疹との関連は認められなかったが、局所反応をより多く認めた。
  1. 2017年にWHOによる事前資格審査に適合した結合体ワクチンは、生後9月の小児での発生予防効果は82%(95%CI 58.8〜91.8%)と高く[11]、12か国で小児の予防接種プログラムに使用されている。実際の使用による効果も80.7%(95%CI 64.2~89.6%)と報告されている[12]
 
  1. 脾腫、比較的徐脈、バラ疹、血小板低下、AST上昇などの所見で腸チフス・パラチフスの検査前確率が高まる(推奨度2 C)
  1. 1つの後ろ向きに60例の腸チフス症例と58例の非腸チフス症例の臨床症状と検査所見を検討した対照研究[13]。腸チフスでは非腸チフスと比較して有意に、肝脾腫、比較的徐脈、バラ疹、白血球減少、血小板減少、好酸球減少、AST上昇を認めることが多かった。特に脾腫、比較的徐脈、バラ疹、血小板低下、AST上昇は診断的価値が高かった。
問診・診察のポイント  
  1. 渡航地域、渡航期間、渡航目的、飲食物への曝露、ワクチン接種歴など、詳細な海外渡航歴を聴取することが重要となる。

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文献 

Bradley A Connor, Eli Schwartz
Typhoid and paratyphoid fever in travellers.
Lancet Infect Dis. 2005 Oct;5(10):623-8. doi: 10.1016/S1473-3099(05)70239-5.
Abstract/Text Enteric fever--a more inclusive term for typhoid fever and paratyphoid fever--is a systemic infection caused by Salmonella enterica, including S enterica serotype Typhi (S typhi) and serotype Paratyphi (S paratyphi). In developed countries there have been two major changes in the pattern of the disease: a marked decline in its incidence and its characterisation as a predominantly travel-associated disease. The risk to travellers appears to vary by geographic region visited, with travel to the Indian subcontinent accounting for the greatest travel risk. Although the most common cause of enteric fever is S typhi, the incidence of disease caused by S paratyphi among travellers may be more important, since the available vaccines only protect against S typhi. Descriptions of the clinical presentation in travellers are scarce but severe complications and death are rare, probably due to rapid access to readily available medical care. Drug resistance reflects the situation in endemic countries, and shows a steady increase in multidrug-resistance patterns. Currently, the recommendation for first-line therapy is ceftriaxone and, where isolates have been found to be quinolone sensitive, fluoroquinolones can still be given. Preventive measures are educating travellers about hygiene precautions and vaccination. With an increase in multidrug-resistant strains, a more effective vaccine for S typhi and S paratyphi is urgently needed.

PMID 16183516
M K Bhan, Rajiv Bahl, Shinjini Bhatnagar
Typhoid and paratyphoid fever.
Lancet. 2005 Aug 27-Sep 2;366(9487):749-62. doi: 10.1016/S0140-6736(05)67181-4.
Abstract/Text Typhoid fever is estimated to have caused 21.6 million illnesses and 216,500 deaths globally in 2000, affecting all ages. There is also one case of paratyphoid fever for every four of typhoid. The global emergence of multidrug-resistant strains and of strains with reduced susceptibility to fluoroquinolones is of great concern. We discuss the occurrence of poor clinical response to fluoroquinolones despite disc sensitivity. Developments are being made in our understanding of the molecular pathogenesis, and genomic and proteomic studies reveal the possibility of new targets for diagnosis and treatment. Further, we review guidelines for use of diagnostic tests and for selection of antimicrobials in varying clinical situations. The importance of safe water, sanitation, and immunisation in the presence of increasing antibiotic resistance is paramount. Routine immunisation of school-age children with Vi or Ty21a vaccine is recommended for countries endemic for typhoid. Vi vaccine should be used for 2-5 year-old children in highly endemic settings.

PMID 16125594
L Ostergaard, B Huniche, P L Andersen
Relative bradycardia in infectious diseases.
J Infect. 1996 Nov;33(3):185-91.
Abstract/Text Relative bradycardia in infectious diseases is a poorly defined term. No exact and useful definition exists and the underlying mechanisms are unknown. Despite this, the term is often used in the literature and in clinical practice both as a clinical sign for an individual patient and as a characteristic feature of certain specific diseases. In this study a definition of relative bradycardia as a clinical sign in an individual patient and a definition of relative bradycardia as a characteristic feature of a specific disease were established based on a reference population comprising 673 patients with various infectious diseases. Relative bradycardia as a clinical sign in an individual patient held no predictive value regarding the likely type of infection. Relative bradycardia as a characteristic feature of specific disease was found for typhoid fever (P = 0.003), Legionnaire's disease (P = 0.005), and pneumonia caused by Chlamydia sp. (P = 0.0005), but not for mycoplasma pneumonia. It was not found for other pulmonary infections, infections caused by other Salmonella sp., other extracellular Gram-negative infections, or viral infections. Thus, relative bradycardia as a clinical sign has no predictive value for obtaining a tentative diagnosis, but relative bradycardia as a feature of specific disease is seen in typhoid fever, Legionnaire's disease, and pneumonia caused by Chlamydia sp. It seems that relative bradycardia as a feature of specific disease only occurs in diseases caused by organisms that are both Gram-negative and intracellular.

PMID 8945708
S A Klotz, J H Jorgensen, F J Buckwold, P C Craven
Typhoid fever. An epidemic with remarkably few clinical signs and symptoms.
Arch Intern Med. 1984 Mar;144(3):533-7.
Abstract/Text A major common-source, foodborne epidemic of typhoid fever occurred in San Antonio, Tex, in the fall of 1981, involving 80 verified cases. We summarize the clinical course of our 34 patients who had a nonspecific symptom complex that included at the initial examination fever (32 patients, 93%), headache (19 patients, 57%), diarrhea (11 patients, 33%), and anorexia (ten patients, 30%). The most common initial diagnoses were urinary tract and upper respiratory tract infections. The subsequent isolation of Salmonella typhi from blood cultures was usually unexpected. Physical findings were different from two previous series originating in the United States. Hepatomegaly was noted in only 7% (two patients), splenomegaly was noted in 13% (four patients), and rose spots were noted in 5% (two patients) of the patients. Liver function test results, however, were abnormal in 32 (95%) of the 34 patients (mean SGOT, 155 IU/mL). Typhoid fever, as seen in this outbreak, was notable for its nonspecific and mild manifestation and uniformly favorable outcome.

PMID 6703825
Christopher M Parry, Tran Tinh Hien, Gordon Dougan, Nicholas J White, Jeremy J Farrar
Typhoid fever.
N Engl J Med. 2002 Nov 28;347(22):1770-82. doi: 10.1056/NEJMra020201.
Abstract/Text
PMID 12456854
Robert Steffen, Ron H Behrens, David R Hill, Christina Greenaway, Karin Leder
Vaccine-preventable travel health risks: what is the evidence--what are the gaps?
J Travel Med. 2015 Jan-Feb;22(1):1-12. doi: 10.1111/jtm.12171. Epub 2014 Nov 6.
Abstract/Text BACKGROUND: Existing travel health guidelines are based on a variety of data with underpinning evidence ranging from high-quality randomized controlled trials to best estimates from expert opinion. For strategic guidance and to set overall priorities, data about average risk are useful. The World Health Organization (WHO) plans to base future editions of "International Travel and Health" on its new "Handbook for Guideline Development."
METHODS: Based on a systematic search in PubMed, the existing evidence and quality of data on vaccine-preventable disease (VPD) risks in travelers was examined and essentials of vaccine efficacy were briefly reviewed. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was used to evaluate the quality of the data.
RESULTS: Moderate-quality data to determine the risk of VPD exist on those that are frequently imported, whereas in most others the level of confidence with existing data is low or very low.
CONCLUSIONS: In order for the WHO to produce graded risk statements in the updated version of "International Travel and Health," major investment of time plus additional high-quality, generalizable risk data are needed.

© 2014 International Society of Travel Medicine.
PMID 25378212
Elspeth Anwar, Elad Goldberg, Abigail Fraser, Camilo J Acosta, Mical Paul, Leonard Leibovici
Vaccines for preventing typhoid fever.
Cochrane Database Syst Rev. 2014 Jan 2;1:CD001261. doi: 10.1002/14651858.CD001261.pub3. Epub 2014 Jan 2.
Abstract/Text BACKGROUND: Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are commercially available, Ty21a (oral) and Vi polysaccharide (parenteral), but neither is used routinely. Other vaccines, such as a new, modified, conjugated Vi vaccine called Vi-rEPA, are in development.
OBJECTIVES: To evaluate the efficacy and adverse effects of vaccines used to prevent typhoid fever.
SEARCH METHODS: In June 2013, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and mRCT. We also searched relevant conference proceedings up to 2013 and scanned the reference lists of all included trials.
SELECTION CRITERIA: Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease).
DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria and extracted data. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella typhi in blood. We calculated risk ratios (RRs) and efficacy (1-RR as a percentage) with 95% confidence intervals (CIs).
MAIN RESULTS: In total, 18 RCTs were included in this review; 12 evaluated efficacy (Ty21a: five trials; Vi polysaccharide: six trials; Vi-rEPA: one trial), and 11 reported on adverse events. Ty21a vaccine (oral vaccine, three doses) A three-dose schedule of Ty21a vaccine prevents around one-third to one-half of typhoid cases in the first two years after vaccination (Year 1: 35%, 95% CI 8% to 54%; Year 2: 58%, 95% CI 40% to 71%; one trial, 20,543 participants; moderate quality evidence; data taken from a single trial conducted in Indonesia in the 1980s). No benefit was detected in the third year after vaccination. Four additional cluster-RCTs have been conducted, but the study authors did not adjust for clustering.Compared with placebo, this vaccine was not associated with more participants with vomiting, diarrhoea, nausea or abdominal pain (four trials, 2066 participants; moderate quality evidence) headache, or rash (two trials, 1190 participants; moderate quality evidence); however, fever (four trials, 2066 participants; moderate quality evidence) was more common in the vaccine group. Vi polysaccharide vaccine (injection, one dose) A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (Year 1: 69%, 95% CI 63% to 74%; three trials, 99,979 participants; high quality evidence). In Year 2, the trial results were more variable, with the vaccine preventing between 45% and 69% of typhoid cases (Year 2: 59%, 95% CI 45% to 69%; four trials, 194,969 participants; moderate quality evidence). The three-year cumulative efficacy of the vaccine is around 55% (95% CI 30% to 70%; 11,384 participants, one trial; moderate quality evidence). These data are taken from a single trial in South Africa in the 1980s.Compared with placebo, this vaccine was not associated with more participants with fever (four trials, 133,038 participants; moderate quality evidence) or erythema (three trials, 132,261 participants; low quality evidence); however, swelling (three trials, 1767 participants; moderate quality evidence) and pain at the injection site (one trial, 667 participants; moderate quality evidence) were more common in the vaccine group. Vi-rEPA vaccine (two doses) Administration of two doses of the Vi-rEPA vaccine prevents between 50% and 96% of typhoid cases during the first two years after vaccination (Year 1: 94%, 95% CI 75% to 99%; Year 2: 87%, 95% CI 56% to 96%; one trial, 12,008 participants; moderate quality evidence). These data are taken from a single trial with children 2 to 5 years of age conducted in Vietnam.Compared with placebo, the first and second doses of this vaccine were not associated with increased risk of adverse events. The first dose of this vaccine was not associated with fever (2 studies, 12,209 participants; low quality evidence), erythema (two trials, 12,209 participants; moderate quality evidence) or swelling at the injection site (two trials, 12,209 participants; moderate quality evidence). The second dose of this vaccine was not associated with fever (two trials, 11,286 participants; low quality evidence), erythema (two trials, 11,286 participants; moderate quality evidence) and swelling at the injection site (two trials, 11,286 participants; moderate quality evidence).
AUTHORS' CONCLUSIONS: The licensed Ty21a and Vi polysaccharide vaccines are efficacious. The new and unlicensed Vi-rEPA vaccine is as efficacious and may confer longer immunity.

PMID 24385413
Celina Jin, Malick M Gibani, Maria Moore, Helene B Juel, Elizabeth Jones, James Meiring, Victoria Harris, Jonathan Gardner, Anna Nebykova, Simon A Kerridge, Jennifer Hill, Helena Thomaides-Brears, Christoph J Blohmke, Ly-Mee Yu, Brian Angus, Andrew J Pollard
Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.
Lancet. 2017 Dec 2;390(10111):2472-2480. doi: 10.1016/S0140-6736(17)32149-9. Epub 2017 Sep 28.
Abstract/Text BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi.
METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing.
FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group).
INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality.
FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 28965718
Priyanka D Patel, Pratiksha Patel, Yuanyuan Liang, James E Meiring, Theresa Misiri, Felistas Mwakiseghile, J Kathleen Tracy, Clemens Masesa, Harrison Msuku, David Banda, Maurice Mbewe, Marc Henrion, Fiyinfolu Adetunji, Kenneth Simiyu, Elizabeth Rotrosen, Megan Birkhold, Nginache Nampota, Osward M Nyirenda, Karen Kotloff, Markus Gmeiner, Queen Dube, Gift Kawalazira, Matthew B Laurens, Robert S Heyderman, Melita A Gordon, Kathleen M Neuzil, TyVAC Malawi Team
Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.
N Engl J Med. 2021 Sep 16;385(12):1104-1115. doi: 10.1056/NEJMoa2035916.
Abstract/Text BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa.
METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up.
RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination.
CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Copyright © 2021 Massachusetts Medical Society.
PMID 34525285
Ceren Kuvandik, Ilkay Karaoglan, Mustafa Namiduru, Ibrahim Baydar
Predictive value of clinical and laboratory findings in the diagnosis of the enteric fever.
New Microbiol. 2009 Jan;32(1):25-30.
Abstract/Text Although the definitive diagnosis of enteric fever requires the isolation of Salmonella enterica serotype typhi or paratyphi, the diagnosis is usually made according to clinical and laboratory findings. There is usually a diagnostic dilemma. The aim of this study was to determine the minimum required parameters that could be valuable in the diagnosis of enteric fever. A retrospective study was performed to compare the clinical and laboratory findings in 60 patients who proved to have enteric fever by cultures and 58 patients with non-enteric fever. Features independently predictive of enteric fever were assessed by multivariate logistic regression. Sensitivity, specificity and positive predictive and negative predictive values were estimated. Significant clinical features of enteric fever were hepatomegaly, splenomegaly, relative bradycardia, rose spots, leucopenia, trombocytopenia, eosinopenia and elevated AST level. Five of these features were found to be predictive for the diagnosis of enteric fever; splenomegaly, relative bradycardia, rose spots and trombocytopenia and elevated AST level. In conclusion, clinical and laboratory findings can help the clinician to diagnose enteric fever in the absence of microbiological confirmation.

PMID 19382666
S L Hoffman, N H Punjabi, R C Rockhill, A Sutomo, A R Rivai, S P Pulungsih
Duodenal string-capsule culture compared with bone-marrow, blood, and rectal-swab cultures for diagnosing typhoid and paratyphoid fever.
J Infect Dis. 1984 Feb;149(2):157-61.
Abstract/Text The sensitivity of duodenal string-capsule culture (DSCC) was compared to that of bone-marrow-aspirate culture (BMAC), single 3-ml blood culture (BC), and rectal-swab culture (RSC) for isolating Salmonella typhi and Salmonella paratyphi type A from patients with typhoid and paratyphoid fever. In 36 of 154 patients DSCC could not be used, usually because the patient was too ill to swallow the capsule. In the remaining 118 patients DSCC was positive in 57.6%, RSC in 35.6%, BC in 54.2%, and BMAC in 85.6%. The sensitivity of DSCC was improved by an additional 4.7% if subcultured daily for seven days. The DSCC has no advantage over the combination of RSC and BC and is inferior in sensitivity to the BMAC. However, when a BMAC cannot be obtained, the addition of the DSCC to BC and RSC can be expected to improve the isolation rate by greater than 17%, to at least 85%.

PMID 6421940
M H Gasem, W M Dolmans, B B Isbandrio, H Wahyono, M Keuter, R Djokomoeljanto
Culture of Salmonella typhi and Salmonella paratyphi from blood and bone marrow in suspected typhoid fever.
Trop Geogr Med. 1995;47(4):164-7.
Abstract/Text We studied the yield of blood and bone marrow (BM) cultures in 145 patients clinically suspected of typhoid fever (TF) in Indonesia. The objectives were to compare the positivity of blood culture using 3 ml versus 10 ml of blood and to examine in how far specific antibiotic treatment for TF interfered with the positivity of BM culture. Blood for culture was collected before antibiotic treatment was initiated in hospital and BM 1 to 10 days after the start of treatment. Cultures were performed with Oxgall subcultured on SS agar. Seventy-nine per cent of patients was treated for 14 days or more with oral chloramphenicol, 18% with chloramphenicol followed by ampicillin or cotrimoxazol and 3% with other antibiotics. Cultures were positive for Salmonella typhi or S-paratyphi A in 57 of the 145 patients (39.3%) when 3 ml of blood was cultured and in 58 (40%) when 10 ml of blood was cultured. BM culture was positive despite antibiotic treatment in 70 patients (48.2%); this positivity was significantly greater than that of blood cultures (p < 0.05). When we considered the positivity of BM culture in relation to the number of days on antibiotics in hospital, the yield of BM culture remained apparently unchanged during the first 5 days of treatment. This may be the consequence of slow elimination of S.typhi or S.paratyphi by the antibiotics used and could be responsible for relapses.

PMID 8560588
C W Lai, R C Chan, A F Cheng, J Y Sung, J W Leung
Common bile duct stones: a cause of chronic salmonellosis.
Am J Gastroenterol. 1992 Sep;87(9):1198-9.
Abstract/Text A chronic carrier state of Salmonella spp is present in 0.15% of the population, and is believed to be related to the presence of a diseased gallbladder. We present a patient with common bile duct (CBD) stones, whose bile cultures repeatedly indicated Salmonella typhi, despite an adequate course of antibiotic treatment. The carrier state was abolished after removal of the CBD stones 4 months later. The chronic carrier state may be related to biofilm formation on the surface of the CBD stones. The removal of the biliary stones, which are the most likely reservoir for Salmonella spp, may be a crucial step in eradication of the carrier state.

PMID 1519582
E Hofmann, J Chianale, A Rollán, J Pereira, C Ferrecio, V Sotomayor
Blood group antigen secretion and gallstone disease in the Salmonella typhi chronic carrier state.
J Infect Dis. 1993 Apr;167(4):993-4.
Abstract/Text
PMID 8450268
T E WOODWARD, J E SMADEL
Preliminary report on the beneficial effect of chloromycetin in the treatment of typhoid fever.
Ann Intern Med. 1948 Jul;29(1):131-4.
Abstract/Text
PMID 18869867
B M STUART, R L PULLEN
Typhoid; clinical analysis of 360 cases.
Arch Intern Med (Chic). 1946 Dec;78(6):629-61.
Abstract/Text
PMID 20278487
R Bitar, J Tarpley
Intestinal perforation in typhoid fever: a historical and state-of-the-art review.
Rev Infect Dis. 1985 Mar-Apr;7(2):257-71.
Abstract/Text The appropriate therapy for intestinal perforation in typhoid fever has been controversial since the late 1880s. Around the turn of the century, surgery became the established mode of therapy, with a mortality of 69% based on 166 patients in the English-language medical literature, and continued to be the preferred treatment until the advent of chloramphenicol in 1948. At this time the surgical mortality was approximately 50%. Following the recovery of a few patients with perforation treated only with antimicrobial agents (six initially, then eventually 22), nonsurgical therapy became the accepted mode of treatment. This change was never justified and this review demonstrates this. Appropriate therapy is virtually always surgical, usually consisting of simple closure and irrigation. Chloramphenicol alone is inadequate antimicrobial therapy in a patient with perforation and must be supplemented by other antimicrobials directed against enteric aerobic gram-negative bacilli and enteric anaerobes.

PMID 3890098
J P van Basten, R Stockenbrügger
Typhoid perforation. A review of the literature since 1960.
Trop Geogr Med. 1994;46(6):336-9.
Abstract/Text Typhoid fever is still a major health problem in the developing parts of the world, with an estimated annual incidence of 540 per 100,000. Probably one of the most lethal complications of typhoid fever is ileal perforation, which affects especially young men. We reviewed the literature published after 1960 on typhoid perforation in different developing countries, with special attention to the incidence and outcome of typhoid perforation. Information was obtained on a total number of 1,990 cases of typhoid perforation in 66,157 patients with typhoid fever, published in 52 reports all over the world. The overall frequency of intestinal perforation in typhoid fever was 3% with an overall mortality rate of 39.6%. In an endemic area of typhoid fever, the diagnosis of typhoid perforation should be made on physical examination. Surgery is perferable to medical treatment.

PMID 7892698
Toshiro Shirakawa, Bishnu Acharya, Shohiro Kinoshita, Shunichi Kumagai, Akinobu Gotoh, Masato Kawabata
Decreased susceptibility to fluoroquinolones and gyrA gene mutation in the Salmonella enterica serovar Typhi and Paratyphi A isolated in Katmandu, Nepal, in 2003.
Diagn Microbiol Infect Dis. 2006 Apr;54(4):299-303. doi: 10.1016/j.diagmicrobio.2005.10.016. Epub 2006 Feb 8.
Abstract/Text Typhoid fever is the most common clinical diagnosis among febrile patients presenting to hospital in Katmandu. Salmonella enterica serovar Typhi (S. enterica serovar Typhi) and Salmonella enterica serovar Paratyphi A (S. enterica serovar Paratyphi A) with decreased susceptibility to fluoroquinolones and resistance to nalidixic acid are common in recent years. In the present study, we examined the in vitro susceptibility to fluoroquinolones and the presence of gyrA gene mutations in 30 clinical strains of S. Typhi and 39 of S. Paratyphi A, all of which were isolated in Katmandu, Nepal, in 2003. In those strains, we found that 73.3% and 94.9% of S. Typhi and S. Paratyphi A strains contained gyrA gene mutation, and showed the resistance to a quinolone, nalidixic acid, and decreased susceptibility to fluoroquinolones, ciprofloxacin, and levofloxacin. Although fluoroquinolones may still be useful as antibiotics for the treatment of typhoid fever, clinicians should be aware of the possibility of treatment failures of infections with S. Typhi and S. Paratyphi A strains with decreased susceptibility to fluoroquinolones.

PMID 16466897
Mandeep Walia, Rajni Gaind, Rajesh Mehta, Premila Paul, Pushpa Aggarwal, Mani Kalaivani
Current perspectives of enteric fever: a hospital-based study from India.
Ann Trop Paediatr. 2005 Sep;25(3):161-74. doi: 10.1179/146532805X58085.
Abstract/Text UNLABELLED: The last two decades have seen a change in the pattern of enteric fever with the emergence of multidrug-resistant strains (MDRS), particularly strains resistant to nalidixic acid.
AIM: The aim of the study was to undertake a retrospective analysis of blood culture-confirmed cases of enteric fever diagnosed at Safdarjang Hospital, New Delhi, India from January 2001 to December 2003.
METHODS: The epidemiological details, clinical features, treatment outcome and antimicrobial resistance patterns were studied.
RESULTS: Of 377 blood culture-positive cases, 80.6% were Salmonella typhi and 19.4% Salmonella paratyphi A; 21.7% were children aged under 5 years and 6.1% were under 2 years. A significant decline in MDRS was observed, from 21.9% in 2001 to 12.4% in 2003 (p=0.04). There was a significant increase in nalidixic acid-resistant Salmonella (NARS) from 56.9% in 2001 to 88.9% in 2003 (p=0.0001). Complete resistance to ciprofloxacin (MIC>4 microg/ml) was detected in only two isolates, both Salmonella paratyphi A. Minimal inhibitory concentrations (MICs) of ciprofloxacin for NARS were increased (0.125-0.5 microg/ml) but were within National Committee for Clinical Laboratory Standards susceptibility ranges. NARS had a significantly longer fever defervescence time (7.7 vs 4.7 days, p<0.001) and hospital stay (12.1 vs 8.2 days, p<0.001), and higher rates of complications (55.5% vs 24.0%, p=0.014) and mortality than nalidixic acid-sensitive Salmonella (NASS). The rate of isolation of MDRS was higher in NARS than NASS (18.8% vs 7.3%, p=0.013).
CONCLUSION: The high rate of occurrence of enteric fever in children <5 years and also of infections caused by Salmonella paratyphi A in India calls for critical re-assessment of vaccination strategy. Nalidixic acid resistance and rising MICs of fluoroquinolones in Salmonella spp pose a new global threat requiring debate on the optimum treatment of enteric fever.

PMID 16156980
Christopher M Parry
The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever in Viet Nam.
Trans R Soc Trop Med Hyg. 2004 Jul;98(7):413-22. doi: 10.1016/j.trstmh.2003.10.014.
Abstract/Text Multidrug-resistant (MDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, and trimethoprim-sulphamethoxazole) and isolates with reduced susceptibility to fluoroquinolones (indicated by resistance to nalidixic acid, NaR) have caused epidemics and become endemic in southern Viet Nam during the 1990s. Short courses of ofloxacin have proved acceptable for treating MDR/NaS isolates of S. Typhi (ofloxacin MIC90 = 0.06 mg/l) causing uncomplicated disease. Ofloxacin (10-15 mg/kg/d) given for 2, 3, or 5 d cured >90% of patients with an average fever clearance time (FCT) of 4 d. Less than 3% of patients relapsed or had a positive post-treatment stool culture. In contrast, the response of NaR isolates (ofloxacin MIC90 = 0.5 mg/l) to such regimens is poor. For example, ofloxacin (20 mg/kg/d) given for 7 d cured only 75% of patients, with an FCT of 7 d, and 19% of patients had positive post-treatment faecal cultures. Currently available alternatives for NaR infections include ceftriaxone, cefixime, and azithromycin. These antimicrobials are reasonably effective but expensive. New, effective, and affordable regimens are needed to treat these NaR infections. Short courses of the new generation fluoroquinolones or combinations of the available antimicrobials are possible options.

PMID 15138078
J Wain, N T Hoa, N T Chinh, H Vinh, M J Everett, T S Diep, N P Day, T Solomon, N J White, L J Piddock, C M Parry
Quinolone-resistant Salmonella typhi in Viet Nam: molecular basis of resistance and clinical response to treatment.
Clin Infect Dis. 1997 Dec;25(6):1404-10.
Abstract/Text Nalidixic acid-resistant Salmonella typhi (NARST) was first isolated in Viet Nam in 1993. Analysis of the quinolone resistance-determining region of gyrA in 20 NARST isolates by polymerase chain reaction and single-stranded conformational polymorphism yielded two novel patterns: pattern II corresponding to a point mutation at nucleotide 87 Asp-->Gly (n = 17), and pattern III corresponding to a point mutation at nucleotide 83 Ser-->Phe (n = 3). In trials of short-course ofloxacin therapy for uncomplicated typhoid, 117 (78%) of 150 patients were infected with multidrug-resistant S. typhi, 18 (15%) of which were NARST. The median time to fever clearance was 156 hours (range, 30-366 hours) for patients infected with NARST and 84 hours (range, 12-378 hours) for those infected with nalidixic acid-susceptible strains (P < .001). Six (33.3%) of 18 NARST infections required retreatment, whereas 1 (0.8%) of 132 infections due to susceptible strains required retreatment (relative risk = 44; 95% confidence interval = 5.6-345; P < .0001). We recommend that short courses of quinolones not be used in patients infected with NARST.

PMID 9431387
M N Alam, S A Haq, K K Das, P K Baral, M N Mazid, R U Siddique, K M Rahman, Z Hasan, M A Khan, P Dutta
Efficacy of ciprofloxacin in enteric fever: comparison of treatment duration in sensitive and multidrug-resistant Salmonella.
Am J Trop Med Hyg. 1995 Sep;53(3):306-11.
Abstract/Text The efficacy of two regimens of ciprofloxacin was compared in a randomized study conducted on 69 patients with enteric fever, 52.2% of whom had infection with multidrug-resistant (MDR) strains of Salmonella typhi or S. paratyphi. Patients were randomly assigned to two regimens (10 days versus 14 days) of ciprofloxacin (500 mg twice a day). The mean +/- SD time required for defervescence was similar for both regimens (4.2 +/- 1.9 days in the 10-day group and 4.9 +/- 2.6 days in the 14-day group). A 100% cure was observed in each treatment group and no serious side effects were observed. Relapse occurred in two patients (14-day regimen). Only one patient (14-day regimen) had growth of S. typhi in stool culture at the time of the first follow-up three days after completion of therapy. Follow-up studies on available patients on two, six, and 12 months after completion of therapy revealed that all patients had negative stool cultures for S. typhi and S. paratyphi. This study indicates that ciprofloxacin may be recommended as an initial therapy for enteric fever for adult men and nonpregnant and nonlactating women in areas where MDR strains of S. typhi and S. paratyphi are prevalent, and that 500 mg twice a day of the drug given for 10 days is as effective as 14 days at the same dosage.

PMID 7573719
Surendra Karki, Prabin Shakya, Allen C Cheng, Shyam Prakash Dumre, Karin Leder
Trends of etiology and drug resistance in enteric fever in the last two decades in Nepal: a systematic review and meta-analysis.
Clin Infect Dis. 2013 Nov;57(10):e167-76. doi: 10.1093/cid/cit563. Epub 2013 Aug 28.
Abstract/Text Prospective time-trend analyses on shifting etiology and trends of drug resistance in enteric fever are scarce. Using published and unpublished datasets from Nepal, we performed a systematic review and meta-analysis to understand the trends in etiology and resistance to antimicrobials that have occurred since 1993. Thirty-two studies involving 21 067 Salmonella enterica serotype Typhi (ST) and S. enterica serotype Paratyphi A (SPA) isolates were included. There was an increasing trend in enteric fever caused by SPA during the last 2 decades (P < .01). We observed sharply increasing trends in resistance to nalidixic acid and ciprofloxacin for both ST and SPA. In contrast, multi-drug resistance (MDR), resistance to traditional first-line antibiotics such as chloramphenicol and co-trimoxazole have significantly decreased for both organisms. The resistance to ceftriaxone has remained low, suggesting it is likely to remain useful as a reserve antibiotic for treatment. Trends in decreasing resistance to traditional first-line antibiotics and decreasing MDR provide an opportunity to reconsider these first-line antimicrobials as therapeutic options.

PMID 23985342
Durrane Thaver, Anita K M Zaidi, Julia Critchley, Asma Azmatullah, Syed Ali Madni, Zulfiqar A Bhutta
A comparison of fluoroquinolones versus other antibiotics for treating enteric fever: meta-analysis.
BMJ. 2009 Jun 3;338:b1865. Epub 2009 Jun 3.
Abstract/Text OBJECTIVES: To review evidence supporting use of fluoroquinolones as first line agents over other antibiotics for treating typhoid and paratyphoid fever (enteric fever).
DESIGN: Meta-analysis of randomised controlled trials.
DATA SOURCES: Cochrane Infectious Diseases Group specialised register, CENTRAL (issue 4, 2007), Medline (1966-2007), Embase (1974-2007), LILACS (1982-2007), selected conferences, reference lists, and ongoing trial register (November 2007). Review methods Trials comparing fluoroquinolones with chloramphenicol, cephalosporins, or azithromycin in culture-proven enteric fever were included. Two reviewers extracted data and assessed methodological quality. Odds ratios with 95% confidence intervals were estimated. Trials recruiting over 60% children were analysed separately from trials on adults. Primary outcomes studied were clinical failure, microbiological failure, and relapse.
RESULTS: Twenty trials were included. Trials were small and often of limited methodological quality. Only 10 trials concealed allocation and only three were blinded. In trials on adults, fluoroquinolones were not significantly different from chloramphenicol for clinical failure (594 participants) or microbiological failure (n=378), but reduced clinical relapse (odds ratio 0.14 (95% confidence interval 0.04 to 0.50), n=467, 6 trials). Azithromycin and fluoroquinolones were comparable (n=152, 2 trials). Compared with ceftriaxone, fluoroquinolones reduced clinical failure (0.08 (0.01 to 0.45), n=120, 3 trials) but not microbiological failure or relapse. Compared with cefixime, fluoroquinolones reduced clinical failure (0.05 (0.01 to 0.24), n=238, 2 trials) and relapse (0.18 (0.03 to 0.91), n=218, 2 trials). In trials on children infected with nalidixic acid resistant strains, older fluoroquinolones (ofloxacin) produced more clinical failures than azithromycin (2.67 (1.16 to 6.11), n=125, 1 trial), but there were no differences with newer fluoroquinolones (gatifloxacin, n=285, 1 trial). Fluoroquinolones and cefixime were not significantly different (n=82, 1 trial).
CONCLUSIONS: In adults, fluoroquinolones may be better than chloramphenicol for preventing clinical relapse. Data were limited for other comparisons, particularly for children.

PMID 19493939
Christiane Dolecek, Thi Phi La Tran, Ngoc Rang Nguyen, Thi Phuong Le, Vinh Ha, Quoc Tuan Phung, Cong Du Doan, Thi Be Bay Nguyen, Thanh Long Duong, Bich Ha Luong, Trung Binh Nguyen, Thi Anh Hong Nguyen, Ngoc Dung Pham, Ngoc Lanh Mai, Van Be Bay Phan, Anh Ho Vo, Van Minh Hoang Nguyen, Thu Thi Nga Tran, Thuy Chau Tran, Constance Schultsz, Sarah J Dunstan, Kasia Stepniewska, James Ian Campbell, Song Diep To, Buddha Basnyat, Van Vinh Chau Nguyen, Van Sach Nguyen, Tran Chinh Nguyen, Tinh Hien Tran, Jeremy Farrar
A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.
PLoS One. 2008 May 21;3(5):e2188. doi: 10.1371/journal.pone.0002188. Epub 2008 May 21.
Abstract/Text BACKGROUND: Drug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing.
OBJECTIVES: We performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.
METHODS: An open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi).
PRINCIPAL FINDINGS: We enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287 patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94-118 hours for gatifloxacin versus 88-112 hours for azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.80-1.26]). Overall treatment failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43-2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were resistant to nalidixic acid and 58% (153/263) were multidrug resistant.
CONCLUSIONS: Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever particularly in regions with high rates of multidrug and nalidixic acid resistance. The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam.
TRIAL REGISTRATION: Controlled-Trials.com ISRCTN67946944.

PMID 18493312
M R Wallace, A A Yousif, G A Mahroos, T Mapes, E J Threlfall, B Rowe, K C Hyams
Ciprofloxacin versus ceftriaxone in the treatment of multiresistant typhoid fever.
Eur J Clin Microbiol Infect Dis. 1993 Dec;12(12):907-10.
Abstract/Text A randomized trial comparing ceftriaxone (3 g given parenterally per day for 7 days) to ciprofloxacin (500 mg given orally twice a day for 7 days) in the treatment of blood culture positive typhoid fever was conducted. Twenty patients were openly randomized to receive ciprofloxacin and 22 to receive ceftriaxone. The outcome was classified as clinical failure in 6 patients (27%) in the ceftriaxone group, but in none in the ciprofloxacin group (p = 0.01). The mean duration of fever was four days in the ciprofloxacin group and about five days in the ceftriaxone group (p = 0.04). In the six patients in the ceftriaxone group who experienced failure, therapy was switched to ciprofloxacin and the patients became afebrile and asymptomatic within 48 hours. Patients with resistant strains of Salmonella typhi and patients with sensitive strains responded equally well to ciprofloxacin therapy. Analysis of a subset of 12 of the multiresistant strains revealed that resistance was encoded for by a transferable 180 kilobase plasmid. Ciprofloxacin represents a useful treatment option in areas where multiresistant strains are likely to be encountered.

PMID 8187784
Anil Pandit, Amit Arjyal, Jeremy N Day, Buddhi Paudyal, Sabina Dangol, Mark D Zimmerman, Bharat Yadav, Kasia Stepniewska, James I Campbell, Christiane Dolecek, Jeremy J Farrar, Buddha Basnyat
An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever.
PLoS One. 2007 Jun 27;2(6):e542. doi: 10.1371/journal.pone.0000542. Epub 2007 Jun 27.
Abstract/Text OBJECTIVE: To assess the efficacy of gatifloxacin versus cefixime in the treatment of uncomplicated culture positive enteric fever.
DESIGN: A randomized, open-label, active control trial with two parallel arms.
SETTING: Emergency Room and Outpatient Clinics in Patan Hospital, Lagankhel, Lalitpur, Nepal.
PARTICIPANTS: Patients with clinically diagnosed uncomplicated enteric fever meeting the inclusion criteria.
INTERVENTIONS: Patients were allocated to receive one of two drugs, Gatifloxacin or Cefixime. The dosages used were Gatifloxacin 10 mg/kg, given once daily for 7 days, or Cefixime 20 mg/kg/day given in two divided doses for 7 days.
OUTCOME MEASURES: The primary outcome measure was fever clearance time. The secondary outcome measure was overall treatment failure (acute treatment failure and relapse).
RESULTS: Randomization was carried out in 390 patients before enrollment was suspended on the advice of the independent data safety monitoring board due to significant differences in both primary and secondary outcome measures in the two arms and the attainment of a priori defined endpoints. Median (95% confidence interval) fever clearance times were 92 hours (84-114 hours) for gatifloxacin recipients and 138 hours (105-164 hours) for cefixime-treated patients (Hazard Ratio[95%CI] = 2.171 [1.545-3.051], p<0.0001). 19 out of 70 (27%) patients who completed the 7 day trial had acute clinical failure in the cefixime group as compared to 1 out of 88 patients (1%) in gatifloxacin group(Odds Ratio [95%CI] = 0.031 [0.004 - 0.237], p<0.001). Overall treatment failure patients (relapsed patients plus acute treatment failure patients plus death) numbered 29. They were determined to be (95% confidence interval) 37.6 % (27.14%-50.2%) in the cefixime group and 3.5% (2.2%-11.5%) in the gatifloxacin group (HR[95%CI] = 0.084 [0.025-0.280], p<0.0001). There was one death in the cefixime group.
CONCLUSIONS: Based on this study, gatifloxacin is a better treatment for uncomplicated enteric fever as compared to cefixime.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN75784880.

PMID 17593957
N T Chinh, C M Parry, N T Ly, H D Ha, M X Thong, T S Diep, J Wain, N J White, J J Farrar
A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever.
Antimicrob Agents Chemother. 2000 Jul;44(7):1855-9.
Abstract/Text To examine the efficacy and safety of short courses of azithromycin and ofloxacin for treating multidrug-resistant (MDR, i.e., resistant to chloramphenicol, ampicillin, and cotrimoxazole) and nalidixic acid-resistant enteric fever, azithromycin (1 g once daily for 5 days at 20 mg/kg/day) and ofloxacin (200 mg orally twice a day for 5 days at 8 mg/kg/day) were compared in an open randomized study in adults admitted to a hospital with uncomplicated enteric fever. A total of 88 blood culture-confirmed patients were enrolled in the study (86 with Salmonella enterica serovar Typhi and 2 with S. enterica serovar Paratyphi A). Of these, 44 received azithromycin and 44 ofloxacin. A total of 68 of 87 (78%) isolates were MDR serovar Typhi, and 46 of 87 (53%) were nalidixic acid resistant. The MIC(90) (range) of azithromycin was 8 (4 to 16) microgram/ml for the isolates. The MIC(90) (range) of ofloxacin for the nalidixic acid-sensitive isolates was 0.03 (0.015 to 0.06) microgram/ml and for the nalidixic acid-resistant isolates it was 0.5 (0.25 to 1.0) microgram/ml. There was no significant difference in the overall clinical cure rate with ofloxacin and azithromycin (38 of 44 [86.4%] versus 42 of 44 [95.5%]; P = 0.27) or in the patients infected with nalidixic acid-resistant typhoid (17 of 21 [81.0%] versus 24 of 25 [96.0%]; P = 0.16). However, patients with nalidixic acid-resistant typhoid treated with ofloxacin had a longer fever clearance time compared with those treated with azithromycin (174 [60 to 264] versus 135 [72 to 186] h; P = 0.004) and had positive fecal cultures after the end of treatment (7 of 17 [41%] versus 0 of 19 [0%]; P = 0.002). Both antibiotics were well tolerated. A 5-day course of azithromycin was effective for the treatment of enteric fever due to MDR and nalidixic-acid-resistant serovar Typhi, whereas the ofloxacin regimen chosen was less satisfactory for these strains.

PMID 10858343
Z A Bhutta
Therapeutic aspects of typhoidal salmonellosis in childhood: the Karachi experience.
Ann Trop Paediatr. 1996 Dec;16(4):299-306.
Abstract/Text We evaluated the response to therapy in a series of 876 children consecutively admitted to The Aga Khan University Hospital with culture-proven typhoid, including 281 cases infected with multi-drug-resistant (MDR) strains. Among sensitive isolates there was no significant difference in cure rates, failure rates and time to defervescence with either ampicillin or chloramphenicol. Of the 217 children with MDR typhoid who received therapy with third-generation cephalosporins, the outcome was significantly better with intravenous ceftriaxone compared with cefotaxime. Despite comparable cure rates, the time to defervescence was significantly longer among MDR strains treated with ceftriaxone versus sensitive strains (mean (SD): 7.2 (3.4) versus 6.3 (29) days; p < 0.05). Earlier recognition and introduction of appropriate second-line therapy has allowed us to reduce the case fatality rates of typhoid to under 1%. Although a 14-day course of ceftriaxone can be used successfully to treat most children hospitalized with MDR typhoid, there is a need to evaluate the role of short-course therapy or alternative therapeutic agents.

PMID 8985527
Abstract/Text The precise duration of therapy of multidrug-resistant (MDR) typhoid with broad-spectrum cephalosporins is uncertain. We prospectively randomized 57 children with culture-proven MDR typhoid to receive treatment with intravenous ceftriaxone (CRO) (65 mg/kg of body weight/day) for 7 days (short course; n = 29) or 14 days (conventional; n = 28). The response to therapy, as evaluated by the serial monitoring of the typhoid morbidity score and bacteriological clearance, was comparable between groups. In contrast to the conventional therapy, 14% of the children receiving CRO for 7 days had a confirmed bacteriological relapse within 4 weeks of stopping therapy.

PMID 10639383
S L Hoffman, N H Punjabi, S Kumala, M A Moechtar, S P Pulungsih, A R Rivai, R C Rockhill, T E Woodward, A A Loedin
Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone.
N Engl J Med. 1984 Jan 12;310(2):82-8. doi: 10.1056/NEJM198401123100203.
Abstract/Text We compared high-dose dexamethasone (initial dose, 3 mg per kilogram of body weight) with placebo in a randomized, double-blind trial involving 38 patients with culture-positive, specifically defined severe typhoid fever. The patients in the two treatment groups ranged in age from 5 to 54 and were comparable at the outset. All patients received chloramphenicol. The case-fatality rate of 10 per cent (2 of 20 patients) in the dexamethasone group was significantly lower than the fatality rate of 55.6 per cent (10 of 18) in the placebo group (P = 0.003). There was no significant difference in the incidence of complications among the survivors in either group. Delirium, obtundation, and stupor were grave prognostic signs that were useful for predicting which patients were at high risk of dying before they became comatose or went into shock. Dexamethasone is unnecessary for most patients with typhoid but is recommended for all patients with suspected typhoid fever who are delirious, obtunded, stuporous, comatose, or in shock.

PMID 6361558
Abstract/Text 11 registered thyphoid carriers were treated by cholecystectomy combined with amoxycillin + probenecid in our department. On the basis of our observations (mean observation period was more than 1 year), all our patients can be considered recovered (cure rate = 100%).

PMID 520079
I Zavala Trujillo, C Quiroz, M A Gutierrez, J Arias, M Renteria
Fluoroquinolones in the treatment of typhoid fever and the carrier state.
Eur J Clin Microbiol Infect Dis. 1991 Apr;10(4):334-41.
Abstract/Text Typhoid fever remains an important public health problem throughout the world with a higher morbidity and mortality rate in the developing countries. Early establishment of the diagnosis and prompt initiation of treatment with chloramphenicol, ampicillin or trimethoprim-sulfamethoxazole is not necessarily followed by complete resolution of the infection. Between 1% and 6% of patients with typhoid fever become chronic biliary carriers of Salmonella typhi. These carriers are potential factors in the continued transmission of the disease. The increasing emergence worldwide of strains showing multiple resistance to the agents traditionally used in therapy has encouraged investigators to seek alternatives such as third generation cephalosporins and recently the new 4-quinolones, which have greater activity against Salmonella typhi including multi-resistant strains. The fluoroquinolones seem to be the treatment of choice in those regions where resistant strains of Salmonella typhi are prevalent.

PMID 1864294

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