Case report: failure under azithromycin treatment in a case of bacteremia due to Salmonella enterica Paratyphi A
© Kobayashi et al.; licensee BioMed Central Ltd. 2014
Received: 18 March 2014
Accepted: 3 July 2014
Published: 20 July 2014
Limited information is available regarding the clinical efficacy of azithromycin for the treatment of enteric fever due to fluoroquinolone-resistant Salmonella Typhi and Salmonella Paratyphi among travelers returning to their home countries.
We report a case of a 52-year-old Japanese man who returned from India, who developed a fever of 39°C with no accompanying symptoms 10 days after returning to Japan from a 1-month business trip to Delhi, India. His blood culture results were positive for Salmonella Paratyphi A. He was treated with 14 days of ceftriaxone, after which he remained afebrile for 18 days before his body temperature again rose to 39°C with no apparent symptoms. He was then empirically given 500 mg of azithromycin, but experienced clinical and microbiological failure of azithromycin treatment for enteric fever due to Salmonella Paratyphi A. However, the minimum inhibitory concentration (MIC) of azithromycin was not elevated (8 mg/L). He was again given ceftriaxone for 14 days with no signs of recurrence during the follow-up.
There are limited data available for the treatment of enteric fever using azithromycin in travelers from developed countries who are not immune to the disease, and thus, careful follow-up is necessary. In our case, the low azithromycin dose might have contributed the treatment failure. Additional clinical data are needed to determine the rate of success, MIC, and contributing factors for success and/or failure of azithromycin treatment for both Salmonella Typhi and Salmonella Paratyphi infections.
KeywordsSalmonella Paratyphi Enteric fever Azithromycin Treatment failure Returned traveler
Salmonella enterica Typhi and Salmonella enterica Paratyphi A, B, and C are the causative pathogens of enteric fever in tropical and subtropical countries such as southern and southeast Asia and Africa , and fluoroquinolone-resistant strains of Salmonella Typhi and Salmonella Paratyphi A have recently emerged in these countries . In developed countries, these strains cause enteric fever in travelers returning from the endemic areas . Azithromycin and the third-generation cephalosporins (e.g., ceftriaxone) are the drugs of choice for treatment of fluoroquinolone-resistant Salmonella Typhi and Salmonella Paratyphi . However, the azithromycin breakpoints for Salmonella Typhi and Salmonella Paratyphi A have not been defined by the Clinical and Laboratory Standard Institutions (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria [5, 6]. The number of studies regarding the clinical efficacy of azithromycin for the treatment of enteric fever is still limited, and to our knowledge, all of them were conducted in endemic areas [7–11]. Here, we report a case of azithromycin treatment failure in a Japanese man with Salmonella Paratyphi A infection who returned from travel.
A 52-year-old Japanese man developed a fever of 39°C with no accompanying symptoms 10 days after returning to Japan from a 1-month business trip to Delhi, India. He presented to a local clinic 5 days after the fever developed. Blood cultures grew with Gram-negative rods (GNR) after 3 days, which were subsequently identified as Salmonella Paratyphi A with unknown antibiotic susceptibility. The patient was transferred to our hospital to complete his 14-d therapy with ceftriaxone (2 g daily). He was afebrile for 18 days following the completion of the antibiotic therapy, after which his body temperature rose to 39°C with no apparent symptoms. He presented to our hospital on Day 3 of the second fever. A blood culture was performed, and the patient was empirically treated with oral azithromycin (500 mg daily) owing to a suspected relapse of enteric fever. The patient was compliant with the oral antibiotic regimen. As the blood culture results showed GNR growth in 2 days, he was readmitted to our hospital for further treatment. We continued azithromycin treatment under direct observation by the medical staff for a total of 7 days. GNR was again identified as Salmonella Paratyphi A, which was found to be susceptible to ceftriaxone (minimum inhibitory concentration [MIC], 0.12 mg/L), resistant to nalidixic acid, and showed decreased susceptibility to ciprofloxacin (MIC, 0.5 mg/L). The MIC’s for azithromycin were 8 mg/L and 16 mg/L, as determined in a reference laboratory using the E-test (Biomerieux Co. Ltd., Tokyo, Japan) and broth micro dilution (BMD), respectively.
Despite the uninterrupted 7 days of oral azithromycin treatment under direct observation, the patient remained febrile until the final day of the regimen. Another blood culture was performed, and the treatment was switched to ceftriaxone because of suspected azithromycin treatment failure. The blood culture showed GNR growth, which was again identified as Salmonella Paratyphi A with the same MICs for ceftriaxone, ciprofloxacin, and azithromycin as the initial culture results. Fluorodeoxyglucose positron emission tomography (FDG- PET) showed slightly thickened intestinal wall of the colon. However, no other inflammatory focuses suggesting deep-seeded infection, such as abscesses and aortitis, were detected. The abdominal ultrasound showed no intra-abdominal abscess on the thickened intestinal wall. The patient defervesced on Day 3 of ceftriaxone, and the result of the follow-up blood culture performed on Day 4 of ceftriaxone therapy yielded no growth. After completion of 14 days of antibiotic treatment, the patient was discharged with no signs of recurrence during the follow-up.
Enteric fever due to nalidixic acid-resistant Salmonella Typhi and/or Salmonella Paratyphi A is generally treated with ceftriaxone or azithromycin [12, 13] with previous reports demonstrating the efficacy of azithromycin in the treatment of enteric fever [7–9]. Moreover, the probability of recurrence is < 3% when treated with azithromycin compared to 3–6% when treated with ceftriaxone. Therefore, treatment with azithromycin may be preferred for quinolone-resistant Salmonella Typhi and Salmonella Paratyphi A [8, 14]. However, data are currently only available for endemic regions of enteric fever where immunity to the disease may contribute to the high success rates.
To the best of our knowledge, there has only been fewcase reports of treatment failure with azithromycin for Salmonella Paratyphi A. In one report, the MIC for azithromycin was > 64 mg/L, which was assumed to be azithromycin-resistant; however, the exact mechanism of resistance has not been defined . In another report, a case of recurrent, multifocal Salmonella enterica serotype Paratyphi A breast abscesses was presented which relapsed despite surgery and multiple courses of antibiotics, including co-trimoxazole and azithromycin . Although the bioavailability of oral azithromycin was reported to be approximately 37%, which is lower than that for fluoroquinolones, it has been suggested that the intracellular concentration of azithromycin is 50–100 times greater than that in serum and that the bactericidal effect remains stable regardless of a high MIC [17, 18]. The recent CLSI guidelines and the EUCAST criteria do not specify the MIC for azithromycin when treating Salmonella Typhi or Salmonella Paratyphi A [5, 6]. However, the EUCAST states that the wild-type isolates of Salmonella Typhi have an MIC ≤ 16 mg/L . In a study conducted in India, the MIC distributions for Salmonella Typhi and Salmonella Paratyphi A ranged from 0.0612 to 64 mg/L and from 1 to 32 mg/L, respectively, and the MIC90 values were 24 mg/L for both serovars . Recent report on MIC distribution of typhoidal Salmonella isolates of returned travelers showed that azithromycin MICs were 2–256 μg/mL among the 354 isolates, and a minority of the S. Paratyphi A isolates showed an MIC ≤ 8 mg/L .
Reported efficacy of azithromycin for treatment of Salmonella Typhi and Salmonella Paratyphi
Body weights of patients (kg)
Route of administration
MIC of isolates, g/L*
n = 36, mean age (range): 19.6 (18–30)
1 g/day on the first day, followed by 500 mg/day on the next 6 days
Clinical cure rate: 100%
BMD, MIC*90 (range): 8 (4–16)
n = 42, mean age (range): 26.2 (17–53)
500 mg/day for 7 days
Mean 52.2 (range: 40–74)
Clinical cure rate: 88% (within 8 days), 100% (within 14 days)
BMD MIC*90 (range): 16 (4–32)
n = 44, mean age (range): 26.6 (15–68)
1 g/day for 5 days
Mean 47.3 (range: 34–60)
Clinical cure rate: 95.5%
E-test, MIC90 (range): 8 (4–16)
n = 62, mean age (range): 10.5 (4–42)
10 mg/kg/day for 7 days
Mean 24 (range: 12–58)
Clinical cure rate: 82%
E-test MIC90 (range): 16 (4–32)
n = 142, median age 11 yrs, (range 1–41)
20 mg/kg/day for 7 days
Median 24.5 (9.5–57)
Treatement failure: 9.3%
E-test, MIC90 (range): 12 (4–16)
In this case, no infectious focus such as arteritis or abscesses was detected by the PET-CT scan and abdominal sonography. We suspected that the thickening of intestinal wall of the colon might be due to the hypertrophy of Peyer’s patches; one of the classic presentations observed in cases of enteric fever due to Salmonella Typhi or Salmonella Paratyphi .
There are limited data available for the treatment of enteric fever using azithromycin in travelers from developed countries who are not immune to the disease, and thus, careful follow-up is necessary. Additional clinical data are needed to determine the rate of success, MIC, and contributing factors for success and/or failure of azithromycin treatment for both Salmonella Typhi and Salmonella Paratyphi.
Written informed consent was obtained from the patient for the publication of this case report. A copy of the written consent is available for review by the Editor of this journal.
This work was partly supported by funding from the Research on Emerging and Re-emerging Infectious Diseases by the Ministry of Health, Labor, and Welfare, Japan (H24-shinkou-ippan-013).
- Crump JA, Luby SP, Mintz ED: The global burden of typhoid fever. Bull World Health Organ. 2004, 82: 346-353.PubMed CentralPubMed
- Humphries RM, Fang FC, Aarestrup FM, Hindler JA: In vitro susceptibility testing of fluoroquinolone activity against Salmonella: recent changes to CLSI standards. Clin Infect Dis. 2012, 55: 1107-1113.View ArticlePubMed
- Leder K, Torresi J, Libman MD, Cramer JP, Castelli F, Schlagenhauf P, Wilder-Smith A, Wilson ME, Keystone JS, Schwartz E, Barnett ED, von Sonnenburg F, Brownstein JS, Cheng AC, Sotir MJ, Esposito DH, Freedman DO, GeoSentinel Surveillance Network: GeoSentinel surveillance of illness in returned travelers, 2007–2011. Ann Intern Med. 2013, 158: 456-468.PubMed CentralView ArticlePubMed
- Threlfall EJ, de Pinna E, Day M, Lawrence J, Jones J: Alternatives to ciprofloxacin use for enteric fever, United Kingdom. Emerg Infect Dis. 2008, 14: 860-861.PubMed CentralView ArticlePubMed
- Clinical and Laboratory Standards Institute: M100-23 Performance Standards for Antimicrobial Susceptibility Testing. 2013, Wayne, PA, , Twenty-Third Informational Supplement
- The European Committee on Antimicrobial Susceptibility Testing (EUCAST): Breakpoint Tables for Interpretation of MICs and Zone Diameters Version 3.1. 2013, Available at: [http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_3.1.pdf]. Accessed February 12, 2014
- Butler T, Sridhar CB, Daga MK, Pathak K, Pandit RB, Khakhria R, Potkar CN, Zelasky MT, Johnson RB: Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India. J Antimicrob Chemother. 1999, 44: 243-250.View ArticlePubMed
- Parry CM, Ho VA, le Phuong T, Bay PV, Lanh MN, le Tung T, Tham NT, Wain J, Hien TT, Farrar JJ: Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother. 2007, 51: 819-825.PubMed CentralView ArticlePubMed
- Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM, Tribble D, Khakhria R: Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrob Agents Chemother. 1999, 43: 1441-1444.PubMed CentralPubMed
- Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, Wain J, White NJ, Farrar JJ: A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrob Agents Chemother. 2000, 44 (7): 1855-1859.PubMed CentralView ArticlePubMed
- Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, Doan CD, Nguyen TB, Duong TL, Luong BH, Nguyen TB, Nguyen TA, Pham ND, Mai NL, Phan VB, Vo AH, Nguyen VM, Tran TT, Tran TC, Schultsz C, Dunstan SJ, Stepniewska K, Campbell JI, To SD, Basnyat B, Nguyen VV, Nguyen VS, Nguyen TC, Tran TH, Farrar J: 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, 3 (5): e2188-PubMed CentralView ArticlePubMed
- Bhan MK, Bahl R, Bhatnagar S: Typhoid and paratyphoid fever. Lancet. 2005, 366: 749-762.View ArticlePubMed
- Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J: Harrison’s principles of internal medicine. Enteric (Typhoid) Fever. Volume 2. 2011, New York: McGraw Hill, 1277-18
- Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA: Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2011, doi:10.1002/14651858.CD004530.pub4, 10View Article
- Molloy A, Nair S, Cooke FJ, Wain J, Farrington M, Lehner PJ, Torok ME: First report of Salmonella enterica serotype paratyphi A azithromycin resistance leading to treatment failure. J Clin Microbiol. 2010, 48: 4655-4657.PubMed CentralView ArticlePubMed
- Fernando S, Molland JG, Gottlieb T: Failure of oral antibiotic therapy, including azithromycin, in the treatment of a recurrent breast abscess caused by Salmonella enterica serotype Paratyphi A. Pathog Glob Health. 2012, 106 (6): 366-369.PubMed CentralView ArticlePubMed
- Foulds G, Luke DR, Teng R, Willavize SA, Friedman H, Curatolo WJ: The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chemother. 1996, 37: 37-44.View ArticlePubMed
- Panteix G, Guillaumond B, Harf R, Desbos A, Sapin V, Leclercq M, Perrin-Fayolle M: In-vitro concentration of azithromycin in human phagocytic cells. J Antimicrob Chemother. 1993, 31: 1-4.View ArticlePubMed
- Capoor MR, Rawat D, Nair D, Hasan AS, Deb M, Aggarwal P, Pillai P: In vitro activity of azithromycin, newer quinolones and cephalosporins in ciprofloxacin-resistant Salmonella causing enteric fever. J Med Microbiol. 2007, 56: 1490-1494.View ArticlePubMed
- Hassing RJ, Goessens WH, van Pelt W, Mevius DJ, Stricker BH, Molhoek N, Verbon A, van Genderen PJ: Salmonella subtypes with increased MICs for azithromycin in travelers returned to The Netherlands. Emerg Infect Dis. 2014, 20 (4): 705-708.PubMed CentralView ArticlePubMed
- Kraus MD, Amatya B, Kimula Y: Histopathology of typhoid enteritis: morphologic and immunophenotypic findings. Mod Pathol. 1999, 12 (10): 949-955.PubMed
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/404/prepub
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