In The Literature

Enteric Fever in Travelers and Antibiotic Resistance

Hagmann SHF, Angelo KM, Huits R, et al. Epidemiological and clinical characteristics of international travelers with enteric fever and antibiotic resistance profiles of their isolates: a GeoSentinel analysis. Antimicrob Agents Chemother [published online ahead of print, 2020 Aug 17]. 2020; AAC.01084-20. doi:10.1128/AAC.01084-20.

Ever since the introduction of chloramphenicol as treatment of typhoid fever more than 7 decades ago, there has been a progression of antibiotics that have met the same fate as chloramphenicol— the emergence of resistance. In addition to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, and others, this has affected a saga of serial antibiotic-busting. The resistance picture for Salmonella enterica serovar Typhi and, to a lesser extent, S. enterica serotypes Paratyphi A, Paratyphi B, and Paratyphi C is only getting worse. Furthermore, because of widespread travel, this resistance is being encountered globally.

Hagmann and colleagues reviewed all culture-confirmed cases of enteric fever (typhoid and paratyphoid) reported by GeoSentinel sites from 2007 through 2018. GeoSentinel is a surveillance system that involves 68 travel and tropical medicine sites in 28 countries that monitor travel-related illnesses in international travelers as well as migrants.

Enteric fever was diagnosed in 889 individuals (17 of whom were migrants), including 474 infected with S. Typhi, 414 with S. Paratyphi, and 1 with both. The patients ranged from age 0 to 79 years (median, 28); 58% were male. Only 35% of travelers for whom the information was available had undergone a pretravel consultation, and this was true of 80% of those who developed typhoid fever; only 7 (10%) of 70 of whom had been vaccinated. Only 1 of 114 children was reported to have been vaccinated, and that child was a teenager.

The majority (71%) acquired their infection in South Asia, including India (41%), Nepal (12%), Bangladesh (9%), and Pakistan (9%). Southeast Asia accounted for 12% of cases, followed by Central and South America (7%) and sub-Saharan Africa (5%), with the remaining regions accounting for ≤2%. Sixteen infections were acquired in Mexico and 9 in Bolivia. The duration of travel ranged from 18 to 61 days (median, 31), with the duration being <7 days in 7% and <2 weeks in almost one-half. The reason for travel in 41% of cases was to visit friends and relatives, including 53% of those who developed S. Typhi infection and 28% who became infected with S. Paratyphi.

Antimicrobial susceptibility data were available for 143 and 75 S. Typhi and S. Paratyphi isolates, respectively. Among the former, 65% were nonsusceptible to ciprofloxacin, 50% to ampicillin, 13% to trimethoprim-sulfamethoxazole, 8% to macrolides, and 1.5% (representing 2 isolates) to third-generation cephalosporins; all were susceptible to carbapenems. South Asia and sub-Saharan Africa had the highest prevalence of fluoroquinolone nonsusceptibility among S. Typhi at 78% and 60%, respectively. Of the S. Paratyphi isolates, nonsusceptibility was seen to fluoroquinolones (56%), macrolides (16%), and to both isolates tested against ampicillin. All S. Paratyphi isolates tested were susceptible to trimethoprim-sulfamethoxazole, third-generation cephalosporins, and carbapenems.

The emergence of extensively drug-resistant (XDR) S. Typhi isolates in Pakistan several years ago was a wake-up call, and its ongoing transmission should serve as a red flag warning. While none of the isolates reported by Hagmann and colleagues were considered to be XDR, as defined by resistance to ceftriaxone, ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole, such isolates have been acquired by international travelers. Since 2016, 10 cases of XDR S. enterica serovar Typhi, 9 with positive blood cultures, have been identified in Ontario, Canada, among individuals who had traveled to Pakistan [1]. This resulted in an alert recommending initiation of treatment with carbapenems or azithromycin in suspect cases. The Centers for Disease Control and Prevention (CDC) identified 30 (31%) XDR infections among 96 Typhi infections in US travelers to or from Pakistan from 1 January 2016 to 31 August 2019 [2].

Additional strains, genetically unrelated to those that caused the ongoing XDR S. Typhi XDR outbreak centered in Pakistan but resistant to a key antibiotic, ceftriaxone, have emerged. As an example, in 2018 the CDC identified a ceftriaxone-resistant S. Typhi that had intermediate susceptibility to ciprofloxacin and remained fully susceptible to other tested antibiotics, including chloramphenicol and trimethoprim-sulfamethoxazole, and they subsequently identified 9 similar isolates [3]. None of the 10 patients had traveled to Pakistan, but 8 had traveled to Iraq, 1 to Iran, and the grandfather of a nontraveling infant had traveled to Iraq. The isolates were all genetically unrelated to the Pakistan XDR strain.

These observations bring us to the question of the optimal empiric therapy for a traveler to the United States who presents with possible enteric fever due to S. Typhi. In part, the most precise answer depends, at least to some extent, on the country or region of origin of the infection, with the greatest concern about resistance being in patients traveling from South Asia. In such cases, a carbapenem or azithromycin should be initiated, although azithromycin resistance has been reported. In addition, carbapenemases have been detected in S. Paratyphi and non-typhoidal Salmonella.

Prevention is the optimal approach to this problem, with the most important aspect being the implementation of strategies designed to limit the emergence of antibiotic resistance at its source and elsewhere. In the meantime, in the United States, we need to improve our ability to ensure the availability of pretravel consultation and typhoid vaccination.

References

Neonatal Ocular Spiroplasma Infection

Matet A, Le Flèche-Matéos A, Doz F, Dureau P, Cassoux N. Ocular Spiroplasma ixodetis in newborns, France. Emerg Infect Dis. 2020; 26(2):340–344. https://dx.doi.org/10.3201/eid2602.191097

After an uncomplicated full-term delivery, an otherwise healthy 26-day-old female was examined in Paris because her parents noted her to have leukocoria (“white pupil”; coria derives from the Greek word “kore” meaning pupil), a finding suggestive at that age of retinoblastoma. Retinoblastoma was not, however, present, but she was found to have bilateral anterior uveitis, with keratitic precipitates, iris nodules, posterior synechia, cyclitic membrane, and cataracts. Serologic examinations for potential infectious pathogens were negative. Macrophages were detected in the anterior humor, and she was given topical dexamethasone and atropine as well as oral josamycin. Josamycin is a macrolide antibiotic that is not available in the United States, but other drugs of this class are likely suitable as may be other antibiotics active against Mycoplasma. She sequentially underwent cataract removal and lens implantation in each eye. There was no recurrence after 4 years of follow-up.

Culture of the lens and vitreous aspirates from the right eye were negative, but polymerase chain reaction (PCR) amplified a complete rrs gene sequence that had 98% similarity to that of type strains of Spiroplasma ixodetis. No evidence of potential laboratory contamination was detected nor was the organism detected in lenses removed from 5 control infants who underwent cataract surgery.

Two additional very similar cases were encountered by the authors, one 4 years later and one 5 years later. In addition, a case had previously been reported by Lorenz and colleagues in Germany in 2002 [1]. That case was also caused by S. ixodetis, which received its species name by virtue of having been first identified in Ixodes pacificus, the western black-legged tick, a vector of Borrelia burgdorferi. Of note is that a different Spiroplasma that is phylogenetically related to S. ixodetis, Spiroplasma mirum, is also called the suckling mouse cataract agent.

Spiroplasma have twice been reported to cause a systemic infection—1 in an adult with agammaglobulinemia and 1 with rheumatoid arthritis receiving biological disease-modifying agents [2, 3]. Spiroplasma belong to the Class Mollicutes, which also contains Mycoplasma as well as the Acholeplasma, all of which lack a cell wall—a characteristic that the very class name indicates: the Latin word “mollis” means soft or pliable while “cutis,” of course, refers to skin. The genus name, Spiroplasma, refers to its spiral shape and its corkscrew motility.

Matet and colleagues suggest that the described Spiroplasma ocular infections may have resulted from either intrauterine or early postnatal infection. They recommend that intraocular fluid and lens material removed from neonates with cataracts and uveitis be examined using 16S-rRNA PCR to detect bacterial nucleic acid.

References