Antimicrobial susceptibility was analyzed for 354 typhoidal Salmonella isolates collected during 1999–2012 in the Netherlands. In 16.1% of all isolates and in 23.8% of all isolates that showed increased MICs for ciprofloxacin, the MIC for azithromycin was increased. This resistance may complicate empirical treatment of enteric fever

Annelies Verbon

Booker

Bruno H. Stricker

Butler

Capoor

Chinh

Dik J. Mevius

Dolecek

Girgis

Gordillo

Hassing

Leclercq

Molloy

Nicky Molhoek

Parry

Perry J.J. van Genderen

Robert-Jan Hassing

Sjölund-Karlsson

Wil H.F. Goessens

Wilfrid van Pelt

Emerging Infectious Diseases

PubMed

Antimicrobial susceptibility was analyzed for 354 typhoidal Salmonella isolates collected during 1999-2012 in the Netherlands. In 16.1% of all isolates and in 23.8% of all isolates that showed increased MICs for ciprofloxacin, the MIC for azithromycin was increased. This resistance may complicate empirical treatment of enteric fever

Hassing, R.J.

Goessens, W.H.

Pelt, W., van

Mevius, D.J.

Stricker, B.H.

Molhoek, W.M.L.

Verbon, A.

Genderen, P.J.

Name not available

Salmonella subtypes with increased MICs for Azithromycin in travelers returned to the Netherlands.

Hassing, Robert-Jan

Goessens, Wil

van Pelt, W (Wilfred)

Mevius, DJ

Stricker, Bruno

Molhoek, N

Verbon, Annelies

van Genderen, Perry

EUR Research Repository

Salmonella Subtypes with Increased MICs for Azithromycin in Travelers Returned to the NetherlandsRobert-Jan Hassing, Wil H.F. Goessens,  Wilfrid van Pelt, Dik J. Mevius,  Bruno H. Stricker, Nicky Molhoek,  Annelies Verbon, and Perry J.J. van GenderenAntimicrobial susceptibility was analyzed for 354 typhoidal Salmonella	 isolates	 collected	during	1999–2012	in the Netherlands. In 16.1% of all isolates and in 23.8% of all	 isolates	 that	 showed	 increased	MICs	 for	 ciprofloxacin,	the MIC for azithromycin was increased. This resistance may complicate empirical treatment of enteric fever.Enteric fever caused by Salmonella enterica serotypes Typhi and Paratyphi A, B, and C is mainly a disease of the developing world, and it is occasionally diagnosed as an imported disease in countries where the disease is not endemic (1). Its empirical treatment has been ham-pered by resistance to ampicillin, chloramphenicol, and trimethoprim and by decreased ciprofloxacin susceptibil-ity (MIC for ciprofloxacin 0.125–1.0 µg/mL), and cipro-floxacin resistance (MIC for ciprofloxacin >1.0 µg/mL) (2,3). As a consequence, third-generation cephalosporins are used as first-line drugs for intravenous treatment, and azithromycin is frequently used for empirical treatment of uncomplicated enteric fever.Although no clinical breakpoints are available to define azithromycin susceptibility or resistance, several clinical studies have demonstrated good efficacy of azithromycin for the treatment of uncomplicated enteric fever in clinical and in vitro studies (4–10). Regarding MIC breakpoints, the European Committee on Antimicrobial Susceptibility Testing states that isolates with an MIC <16 µg/mL for azithromycin should be considered as wild-type organisms that are responsive to treatment (3). The Clinical and Labo-ratory Standards Institute (www.clsi.org/) does not provide clinical breakpoints for macrolides for the group of Entero-bacteriaceae. In previous studies of typhoidal Salmonella isolates, MICs for azithromycin ranged from 4 µg/mL to 64 µg/mL (8–13). The first clinical case for which treatment of illness caused by typhoidal Salmonella spp. with azithromycin (MIC 256 µg/mL) failed was reported during 2010, evi-denced by testing a S. enterica Paratyphi A isolate from Pakistan (14). Further, in a study of isolates from blood samples collected in India during 2005–2008, MICs >16 µg/mL for azithromycin were observed in 34.7% (35/101 isolates) of the typhoidal Salmonella isolates; clinical non-response was reported in 19 of 36 patients treated with azithromycin (13). Whether this problem of increasing MICs for azithromycin is limited to India or is emerging globally is not clear. The objective of our study was to in-vestigate azithromycin susceptibility and trends in antibac-terial drug resistance over time in isolates collected during 1999–2012 in the Netherlands.The StudyEnteric fever is a notifiable disease in the Netherlands. During January 1999–December 2012, a total of 354 iso-lates were submitted by microbiology laboratories to the Salmonella National and Community Reference Labora-tory (www.eurlsalmonella.eu/): 177 (50%) S. enterica Ty-phi isolates, 98 (27.7%) S. enterica  Paratyphi A isolates, 78 (22.0%) S. enterica  Paratyphi B isolates, and 1 (0.3%) S. enterica Paratyphi C isolate. There was no statistically significant difference in sex among patients whose tests showed S. enterica  Typhi isolates (56.3% male, 43.7% fe-male, p = 0.18) and S. enterica  Paratyphi isolates (51.6% male, 48.4% female, p = 0.18). Patients ranged in age from 0 to 92 years. The median ages, 28.4 and 29.5 years, re-spectively (p = 0.60), did not differ between patients in whose samples S. enterica Typhi and Paratyphi were iso-lated. Trends in cumulative 1-year incidence were deter-mined by linear regression analysis; data were weighted on the number of isolates collected each year. The cumulative 1-year incidence of enteric fever was relatively stable dur-ing 1999–2012, with an average of 25 isolates (4–39/year) for that period (p = 0.42).All MICs were determined by using the broth micro-dilution method with Mueller-Hinton II cation–adjusted broth (Difco, Franklin Lakes, NJ, USA). We applied Eu-ropean Committee for Antimicrobial Susceptibility Test-ing guidelines for category interpretation for different 	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	20,	No.	4,	April	2014	 705Author	 affiliations:	 Erasmus	 Medical	 Centre,	 Rotterdam,	 the	 Netherlands (R.-J. Hassing, W.H.F. Goessens, B.H. Stricker, A. Verbon);	Inspectorate	of	Health	Care,	The	Hague,	the	Netherlands	(R.-J. Hassing, B.H. Stricker); National Institute for Public Health and	the	Environment	(RIVM),	Bilthoven,	 the	Netherlands	(W.	van	Pelt);	 Utrecht	 University,	 Utrecht,	 the	Netherlands	 (D.J.	Mevius);	Central	 Veterinary	 Institute	 of	 Wageningen	 UR,	 Lelystad,	 the	 Netherlands (D.J. Mevius); Travel Clinic Havenziekenhuis, Rotterdam (N. Molhoek, P.J.J. van Genderen); and Institute for Trop-ical Diseases, Havenziekenhuis, Rotterdam (P.J.J. van Genderen)DOI:	http://dx.doi.org/10.3201/eid2004.131536antibacterial drugs (3). Azithromycin MICs were 2–256 µg/mL among the 354 isolates and were increased in 57 (16.1%) of the isolates (Figure 1). The distribution of azithromycin MICs of S. enterica Typhi and Paratyphi A and B peaked at 8, 16, and 8 µg/mL, respectively (Figure 1). Trend analysis showed no increased MIC over time for all isolates (p = 0.21) or for S. enterica Typhi (p = 0.35) or Paratyphi (p = 0.70). One Paratyphi A isolate, from a sample acquired in Malaysia in 2007, required an MIC of 256 µg/mL. Decreased susceptibility to ciprofloxacin was observed in 116 (32.8%) and ciprofloxacin resistance in 6 (1.7%) of the 354 isolates. Cumulative 1-year incidence of isolates with decreased susceptibility or resistance to cip-rofloxacin increased significantly from 0% (0/12 isolates) in 1999 to 64.3% (18/28 isolates) in 2012 (p<0.001) (on-line Technical Appendix Figure, wwwnc.cdc.gov/EID/article/20/4/13-1536-Techapp1.pdf). Among isolates with decreased susceptibility or resistance to ciprofloxacin, 23.8% (29/122 isolates) showed an increased MIC for azithromycin; MIC increased for 12.1% (28/232 isolates) of the ciprofloxacin-susceptible isolates (p = 0.004) (Figure 2). No significant increase in amoxicillin, trimethoprim, or chloramphenicol resistance was observed (amoxicillin, p = 0.97; trimethoprim, p = 0.95; and chloramphenicol, p = 0.99) (online Technical Appendix Figure). For all isolates, the MICs for erythromycin ranged from 64 to ≥512 µg/mL. Resistance to third-generation cephalosporins was not ob-served in the isolates.The origins of isolates for which the country of ac-quisition was known (205 of 354 strains) were distrib-uted among geographic regions by using the United Na-tions geoscheme (http://unstats.un.org/unsd/methods/m49/m49regin.htm). Besides imported cases from countries in which enteric fever is highly endemic, such as India, Indonesia, and Pakistan, rates of importation were high for travelers from Turkey and Morocco (Table).Percentages of elevated MICs for azithromycin were highest for isolates acquired in regions that had concurrent high proportions of isolates with decreased susceptibility or resistance to ciprofloxacin (Table). In isolates acquired in countries from Southern Asia, increased MICs for cip-rofloxacin and increased MICs for azithromycin  were ob-served in 21.4% (18/84 isolates) of the isolates.DISPATCHES706	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	20,	No.	4,	April	2014Figure 1. MICs of azithromycin of 354 Salmonella enterica serotypes Typhi and Paratyphi A, B, and C isolates from samples collected from ill returned travelers in the Netherlands, 1999–2012.	 For	 wild	 type	 isolates,	MIC<16 µg/mL.Figure	 2.	 MICs	 of	 azithromycin	 in	 relation	 to	 ciprofloxacin	susceptibility of 354 Salmonella enterica serotypes Typhi and Paratyphi isolates. Increased MICs for azithromycin (MIC >16 µg/mL)	 in	 isolates	 with	 decreased	 ciprofloxacin susceptibility or ciprofloxacin	resistance	(MIC	>0.125 µg/mL)	versus	ciprofloxacin-susceptible isolates (MIC <0.125 µg/mL)	(p	=	0.004).Increased MICs for Azithromycin, the NetherlandsConclusionsWe found high percentages of elevated azithromy-cin MICs in typhoidal Salmonella isolates collected in the Netherlands during 1999–2012. MICs >16 µg/mL for azithromycin were found in 16.1% of all isolates and in 23.8% of isolates with elevated MICs for ciprofloxacin. This observation may be explained by increased use of azithromycin in countries from which samples yielded high rates of typhoidal Salmonella isolates with decreased susceptibility or resistance to ciprofloxacin. Moreover, our findings are aligned with an alarming report from India on increasing MICs for azithromycin (13). Our study shows higher MICs than anticipated based on another Western case series (11), implying that these potentially resistant strains are not confined to India.Besides treatment with third-generation cephalospo-rins, empirical treatment options may be scarce for patients with potential azithromycin-resistant Salmonella serotypes. Reuse of antibacterial drugs, such as ampicillin, chloram-phenicol, or trimethoprim may be a valuable treatment op-tion upon proven susceptibility, but widespread use of these antibacterial drugs as first-line treatment will likely result in rapid reemergence of multidrug resistance and associ-ated drug-related adverse effects. Further, increasing the dose of ciprofloxacin or using alternative fluoroquinolones has been suggested as an effective treatment in some cases (15). This option will not be feasible for empirical treatment because it applies only in a minority of cases and may be associated with drug toxicity. The danger of losing azithro-mycin to antimicrobial resistance could be detrimental in countries faced with endemic or epidemic enteric fever and complicated by poverty; therefore, azithromycin should be used with care. The results of this study also implicate the importance of developing more effective vaccines as con-trol measures for enteric fever. Future research is needed to evaluate clinically relevant breakpoints of azithromycin by analyzing the treatment outcome of azithromycin in rela-tion to their MICs.In conclusion, typhoidal Salmonella isolates in ill re-turned travelers from the Netherlands already show a high percentage of increased MICs for azithromycin. Because the highest proportions of increased MICs for azithromycin are found in isolates with increased MICs for ciprofloxacin and in regions where decreased susceptibility or resistance to ciprofloxacin is already widely prevalent among S. enterica Typhi and Paratyphi isolates, this resistance may further limit future treatment options for enteric fever.AcknowledgementsWe thank Marian ten Kate and Aart van der Meijden for performing susceptibility testing and Kees Veldman for sending the isolates.Dr Hassing is a PhD candidate and an infectious diseases specialist at the Erasmus Medical Centre, Rotterdam, the Neth-erlands, and a pharmacovigilance inspector at the Health Care Inspectorate, The Hague, the Netherlands. His research interests include antimicrobial resistance in Enterobacteriaceae.References  1. Parry CM. Typhoid fever. Curr Infect Dis Rep. 2004;6:27–33. http://dx.doi.org/10.1007/s11908-004-0021-6  2. Booker BM, Smith PF, Forrest A, Bullock J, Kelchlin P, Bhavnani SM, et al. Application of an in vitro infection model and simulation for reevaluation of fluoroquinolone breakpoints for Salmonella enterica serotype typhi. Antimicrob Agents Chemother. 2005;49:1775–81. http://dx.doi.org/10.1128/AAC.49.5.1775-1781.2005  3. Leclercq R, Cantón R, Brown DF, Giske CG, Heisiq P, MacGowan AP, et al. EUCAST expert rules in antimicrobial susceptibility testing. Clin Microbiol Infect. 2013;19:141–60. http://dx.doi.org/10.1111/j.1469-0691.2011.03703.x  4. Gordillo ME, Singh KV, Murray BE. In vitro activity of azithro-mycin against bacterial enteric pathogens. Antimicrob Agents Che-mother. 1993;37:1203–5. http://dx.doi.org/10.1128/AAC.37.5.1203	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	20,	No.	4,	April	2014	 707Table. Isolates with	elevated	MICs	for	ciprofloxacin and isolates with an MIC for azithromycin above that for wild	type	(>16	mg/L)	in	Salmonella enterica serotype Typhi and Paratyphi isolates collected in travelers returning	to	the	Netherlands,	1999–2012 Region No. (%) isolates  No. (%) isolates with elevated MICs  Azithromycin Ciprofloxacin Azithromycin and ciprofloxacin All 205 36 (17.6) 83 (40.5) 20	(9.8)  Asia 161 (78.5) 31	(19.3) 80	(49.7) 20 (12.4)   Southern Asia* 84 (40.0) 21 (25) 69	(82.1) 18 (21.4)   South-Eastern Asia† 44 (21.5) 5 (12.2) 3 (6.8) 1 (2.3)   Western Asia‡ 27 (13.2) 1 (3.7) 6 (22.2) 1 (3.7)   Eastern Asia§ 5 (2.4) 1 (20) 2 (40) 0  Unknown 1 (0.5) 0 0 0  Africa¶ 35 (17.1) 5 (14.3) 1	(2.9) 0  Europe** 4 (2.0) 0 2 (50) 0  Latin	America†† 5 (2.4) 0 0 0 *India,	Pakistan,	Bangladesh,	Nepal,	Afghanistan,	Nepal,	Sri	Lanka. †Indonesia, Cambodia, Malaysia, Thailand. ‡Turkey, Iraq, Syria. §China. ¶Morocco, Ghana, Nigeria, Senegal, Tunisia, Malawi, Tanzania. **Gibraltar (Great Britain), Greece, Italy, Romania. ††Peru,	Mexico,	unknown.    5. Metchock B. In-vitro activity of azithromycin compared with other macrolides and oral antibiotics against Salmonella typhi. J Antimi-crob Chemother. 1990;25 Suppl A:29–31.  6. Butler T, Sridhar CB, Daga MK, Pathak K, Pandit RB, Khakhria R, et al. Treatment of typhoid fever with azithromycin versus chlor-amphenicol in a randomized multicentre trial in India. J Antimicrob Chemother. 1999;44:243–50. http://dx.doi.org/10.1093/jac/44.2.243  7. Parry CM, Ho VA, Phuong LT, Truong NT, Bay PVB, Lahn MN, et al. Randomized controlled comparison of ofloxacin, azithro-mycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother. 2007;51:819–25. http://dx.doi.org/10.1128/AAC.00447-06  8. Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM, Tribble D, et al. Azithromycin versus ciprofloxacin for treatment of uncom-plicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrob Agents Chemother. 1999;43:1441–4.  9. Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, et al. A randomized controlled comparison of azithromycin and ofloxa-cin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrob Agents Chemother. 2000;44:1855–9. http://dx.doi.org/10.1128/AAC.44.7.1855-1859.200010. Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, et al. 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:e2188. http://dx.doi.org/10.1371/journal.pone.000218811. Sjölund-Karlsson M, Joyce K, Blickenstaff K, Ball T, Haro J, Medalla FM, et al. Antimicrobial susceptibility to azithromycin among Salmonella enterica isolates from the United States. Antimi-crob Agents Chemother. 2011;55:3985–9. http://dx.doi.org/10.1128/AAC.00590-1112. Capoor MR, Rawat D, Nair D, Hasan AS, Deb M, Aggarwal P, et al. In vitro activity of azithromycin, newer quinolones and cepha-losporins in ciprofloxacin-resistant Salmonella causing enteric fever. J Med Microbiol. 2007;56:1490–4. http://dx.doi.org/10.1099/jmm.0.47353-013. Rai S, Jain S, Prasad KN, Ghoshal U, Dhole TN. Rationale of azithro-mycin prescribing practices for enteric fever in India. Indian J Med Microbiol. 2012;30:30–3. http://dx.doi.org/10.4103/0255-0857.9301714. Molloy A, Nair S, Cooke FJ, Wain J, Farrington M, Lehner PJ, et al. First report of Salmonella enterica serotype paratyphi A azithromycin resistance leading to treatment failure. J Clin Microbiol. 2010;48:4655–7. http://dx.doi.org/10.1128/JCM.00648-1015. Hassing RJ, Goessens WH, Mevius DJ, van Pelt W, Mouton JW, Verbon A, et al. Decreased ciprofloxacin susceptibility in Salmo-nella Typhi and Paratyphi infections in ill-returned travellers: the impact on clinical outcome and future treatment options. Eur J Clin Microbiol Infect Dis. 2013;32:1295–301. http://dx.doi.org/10.1007/s10096-013-1878-9Address for correspondence: Robert-Jan Hassing, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, the Netherlands; email: r.hassing@erasmusmc.nlDISPATCHES708	 Emerging	Infectious	Diseases	•	www.cdc.gov/eid	•	Vol.	20,	No.	4,	April	2014Search past issues of EID at wwwnc.cdc.gov/eid

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Salmonella Subtypes with Increased MICs for Azithromycin in Travelers Returned to the Netherlands

Hassing, R.J. (Robert)

Goessens, W.H.F. (Wil)

Pelt, W. (Wilfred) van

Mevius, D.J. (D.)

Stricker, B.H.Ch. (Bruno)

Molhoek, N. (Nicky)

Verbon, A. (Annelies)

Genderen, P.J.J. (Perry) van

Erasmus University Digital Repository

Salmonella subtypes with increased MICs for azithromycin in travelers returned to the Netherlands

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<i>Salmonella</i>Subtypes with Increased MICs for Azithromycin in Travelers Returned to the Netherlands

van Pelt, W.

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