Reply to Godbole et al

To the Editor—We have read with interest Godbole et al’s brief report about isolation of an extended-spectrum beta-lactamase (ESBL)–producing and quinolone-resistant Salmonella enterica subspecies enterica, serovar Typhi (S.Typhi).

Both of our reports have shown that ESBL-producing S.Typhi is an emerging pathogen. Given the low prevalence of ESBL enzymes in S. Typhi isolates in Europe, finding different ESBL types might be seen as a surprise. Extended-spectrum beta-lactamases in Enterobacteriaceae have spread globally, and CTX-M-15 is one of the predominant ESBLs. Recently, an S. Typhi strain producing CTX-M-15 ESBL from the Democratic Republic of Congo was subjected to whole-genome sequencing [1]. The authors concluded that the plasmid carrying the bla_CTX-M-15 gene originated in other Enterobacteriaceae species. Given the ease with which plasmids can be exchanged between bacteria in this family, one might assume different ESBL enzymes in S. Typhi strains occur because of repetitive events of plasmid acquisition.

The spread of ESBLs in S. Paratyphi in the past years is regarded to be established even in nonendemic countries [2]. We now may be witnessing the catch-up of S. Typhi. Extended-spectrum beta-lactamase–producing strains have been reported from different countries (eg, Bangladesh, India, Pakistan, Philippines, Iran, Iraq, and Egypt) [3]. The current proportion of ESBL-producing strains among S. Typhi in endemic countries is, to our knowledge, not known exactly but should be determined. A survey from 2013 in New Delhi identified 2% of S. Typhi isolates producing ESBLs [4]. Increased usage of certain antibiotics, such as third-generation cephalosporins, acts as a selection factor, speeding up the distribution of ESBL producers. We’d like to emphasize that a high proportion of colonization with ESBL-producing Enterobacteriaceae has been recently described in a study on Finnish travelers. The proportion of colonization was even more increased when travelers were subjected to antimicrobial chemotherapies [5].

Prior studies have shown that the pattern of antibiotic resistance in countries with imported cases of typhoid fever has changed in parallel to the changes that have taken place in endemic regions during the last years [6]. Meanwhile, ESBL-producing S. Typhi have rarely been found in travelers in Europe; returning travelers from Guatemala [7] and Iraq [8] have been documented to be infected with S. Typhi with CTX-M-15 production. Moreover, in 2007 2 unrelated S. Typhi isolates with SHV-12 from the Philippines were described, the same ESBL as in our case report. It is noteworthy that the latter cases remained sensitive to quinolones and azithromycin [9].

The limited response to meropenem in both cases is particularly worrisome. The increase of S. Typhi strains with ESBL production has to be taken into account in therapy of typhoid fever. We feel a strong need for studies on the potential advantage of combination antimicrobial therapy regimes for both empiric and targeted treatment. We agree that a combination therapy should be considered in severe cases and in immunosuppressed patients, particularly if defervescence does not occur timely. Although a number of studies failed to demonstrate advantages of combination antimicrobial therapy over monotherapy [10], the clinical course of the patients described in our case report and that of Godbole et al demonstrates that combination antimicrobial chemotherapy may be the key to clinical success in selected patients.

Note

Potential conflicts of interest. All authors except Y. P. are employees of the University Hospital of Bonn. G. T. R. H. has received payments for lectures, including service on speakers’ bureaus from Pfizer Pharma GmbH, Heraeus Medical GmbH, and Curetis AG. E. M. has received payments for lectures, including service on speakers’ bureaus from Roche, Pfizer, and MSD. U. S. has consulted for AbbVie and has received a royalty from UpToDate. S. S. has received accommodations from Janssen. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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