Correspondence when this drug was combined with fluconazole. This combination could be of interest in those cases where the isolates of this species show high MICs of fluconazole. In spite of the predominance of indifferent interactions, which agrees with the results provided by other authors,2,9 the lack of antagonism and the percentages of synergism obtained against C. albicans and C. tropicalis are interesting issues. Although scarce in vivo data on the activity of this combination are available, it has been demonstrated that it was able to prolong survival and to reduce tissue burden in murine models of C. glabrata infection and in trichosporonosis.10,11 Therefore, combination of these agents may warrant future clinical evaluation in Candida infections.
Acknowledgements This work was supported by a grant from Fondo de Investigaciones Sanitarias from the Ministerio de Sanidad y Consumo of Spain (PI 050031).
Transparency declarations None to declare.
1. Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J et al. International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed and refractory candidemia. Eur J Clin Microbiol Infect Dis 2005; 24: 654–61. 2. Roling EE, Klepser ME, Wasson A et al. Antifungal activities of fluconazole, caspofungin (MK0991), and anidulafungin (LY 303366) alone and in combination against Candida spp. and Cryptococcus neoformans via time–kill methods. Diagn Microbiol Infect Dis 2002; 43: 13 –7. 3. Serena C, Ferna´ndez-Torres B, Pastor FJ et al. In vitro interactions of micafungin with other antifungal drugs against clinical isolates of four species of Cryptococcus. Antimicrob Agents Chemother 2005; 49: 2994–6. 4. Serena C, Marine M, Pastor FJ et al. In vitro interaction of micafungin with conventional and new antifungals against clinical isolates of Trichosporon, Sporobolomyces and Rhodotorula. J Antimicrob Chemother 2005; 55: 1020– 3. 5. National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts-Second Edition: Approved Standard M27-A2. NCCLS, Wayne, PA, USA, 2002. 6. Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003; 52: 1. 7. Laverdiere M, Hoban D, Restieri C et al. In vitro activity of three new triazoles and one echinocandin against Candida bloodstream isolates from cancer patients. J Antimicrob Chemother 2002; 50: 119 –23. 8. Espinel-Ingroff A. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature. Rev Iberoam Micol 2003; 20: 121–36. 9. Karlowsky JA, Hoban DJ, Zhanel GG et al. In vitro interactions of anidulafungin with azole antifungals, amphotericin B and 5fluorocytosine against Candida species. Int J Antimicrob Agents 2006; 27: 174–7. 10. Marine M, Serena C, Pastor FJ et al. Combined antifungal therapy in a murine infection by Candida glabrata. J Antimicrob Chemother 2006; 58: 1295– 8.
Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dkm114 Advance Access publication 21 April 2007
Travel-acquired salmonellosis due to Salmonella Kentucky resistant to ciprofloxacin, ceftriaxone and co-trimoxazole and associated with treatment failure Jean-Marc Collard1, Sammy Place2, Olivier Denis2, Hector Rodriguez-Villalobos2, Martine Vrints1, Franc¸ois-Xavier Weill3, Sylvie Baucheron4, Axel Cloeckaert4, Marc Struelens2 and Sophie Bertrand1* 1
National Reference Centre for Salmonella and Shigella, Bacteriology Division, Scientific Institute of Public Health, 14 Wytsman Street, B-1050 Brussels, Belgium; 2Hoˆpital Erasme, Microbiologie, Lennickstreet, 808 B-1070 Brussels, Belgium; 3Centre National de Re´fe´rence des Salmonella, Unite´ de Biodiversite´ des Bacte´ries Pathoge`nes Emergentes, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France and 4Unite´ Infectiologie Animale et Sante´ Publique, Institut National de la Recherche Agronomique, 37380 Nouzilly, France Keywords: extended-spectrum cephalosporins, Clostridium difficile, gastroenteritis *Corresponding author. Tel: þ32-26425281; Fax: þ3226425240; E-mail:
[email protected] Sir, In Belgium, the vast majority of salmonellosis is caused by the serovars Enteritidis and Typhimurium, which represent together more than 80% of the isolates. Salmonella enterica serovar Kentucky is a very uncommon serovar that represented 0.02% to 0.5% of the total isolates during the last decade, but 0.8% in 2006. Indeed, this serovar showed a usual increase in Europe during the third quarter of 2006 with several of them acquired during travels to Northeast Africa and Turkey.1 We report here the first Belgian case of a travel-acquired multidrug-resistant Salmonella Kentucky resulting in a treatment failure because of a high resistance level to ciprofloxacin and secondarily acquired resistances to extended-spectrum cephalosporins (ESCs) and trimethoprimþsulfamethoxazole (co-trimoxazole). In September 2005, a 77-year-old healthy man on a cruise along the North Africa coast developed febrile diarrhoea a few hours after a meal (chicken couscous and dates) in a small restaurant on the Libyan coast. Consequently, he was admitted for 48 h in a hospital in Cairo (Egypt) and treated with intravenous (iv) mezlocillin followed by co-trimoxazole given orally for a few more days whereby he slowly recovered. Two weeks after his return to Belgium, he presented again with febrile diarrhoea and arthritis of the wrist. After examination of his stool, the Clostridium difficile stool toxin test was positive and Salmonella Kentucky was isolated. The Salmonella isolate
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References
11. Serena C, Pastor FJ, Gilgado F et al. Efficacy of micafungin in combination with other drugs in a murine model of disseminated trichosporonosis. Antimicrob Agents Chemother 2005; 49: 497–502.
Correspondence
Figure 1. Dendrogram generated by BioNumerics showing the results of cluster analysis on the basis of XbaI PFGE of Salmonella enterica serovar Kentucky isolates. Similarity analysis was performed using the Dice coefficient. The different PFGE profiles and the phenotypes of resistance to the three classes of antibiotic recommended to treat salmonellosis (R-type) are indicated. CIP, ciprofloxacin; SXT, co-trimoxazole; CRO, ceftriaxone.
analysis of the PCR product revealed 100% identity with the blaCTX-M-1 sequence (GenBank accession number X92506). To determine the genetic relatedness between the two consecutive Salmonella Kentucky isolates, an XbaI PFGE analysis was performed (Figure 1). Two very similar profiles were observed differing only by one additional band of 100 kb in the cephalosporin-resistant strain. To the best of our knowledge, this is the first isolation of a Salmonella resistant to the three antibiotic classes recommended to treat invasive salmonellosis (fluoroquinolones, ESCs and co-trimoxazole) and associated with a treatment failure. The existence of ciprofloxacin-resistant but ESC-susceptible Salmonella Kentucky was also recently reported after their isolation from French patients having travelled in Northeast and Eastern Africa.3 Previously, Salmonella Kentucky was considered as an unsuccessful pathogen because it was rarely associated with human illness, although this serovar was widespread in the food supply (http://msc.tigr.org/ salmonella/salmonella_enterica_subsp_enterica_serovar_kentucky_ strain_cdc191/index.shtml). However, the spread of an Egyptianimported Salmonella Kentucky case in two hospitals in the Slovac Republic highlights the pathogenicity and the dissemination and establishment features of this serovar.6 An increased surveillance of such strains should be recommended as it was proven that they could disseminate on a large scale and finally could jeopardize classical antibiotic therapy in patients at risk.
Acknowledgements We are very grateful to L. Willems, D. Baeyens, H. Steenhout, F. De Cooman and D. Delbecq for their technical help. Parts of this work were financed by the Federal Public Service Health, Food Chain Safety and Environment and the Flemish and French Communities.
Transparency declarations None to declare.
References 1. Enter-net. Quarterly Salmonella Report July –Sept 2006/3. http:// www.hpa.org.uk/hpa/inter/enter-net/06q3summ2.pdf (21 December 2006, date last accessed). 2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Testing—
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was susceptible to co-trimoxazole, but resistant to ampicillin, tetracycline, streptomycin, sulphonamide, nalidixic acid and ciprofloxacin (full resistance) by the standard disc diffusion susceptibility method according to CLSI (formerly NCCLS) guidelines.2 MICs of nalidixic acid and ciprofloxacin determined by standard agar doubling dilution were .1024 and 4 mg/L, respectively. In order to identify the mechanisms responsible for ciprofloxacin resistance, the quinolone resistance-determining regions of gyrA, gyrB, parC and parE were amplified and sequenced as described previously.3 Two mutations leading to substitutions Ser-83!Phe (TCC!TTC) and Asp-87!Asn (GAC!AAC) were identified in gyrA. An additional substitution was observed in parC resulting in Ser-80!Ile (AGC!ATC). In the presence of the efflux pump inhibitor Phe-Arg-b-naphthylamide, the MIC of ciprofloxacin was reduced 4-fold, suggesting that an active efflux mechanism was also present. The involvement of the AcrAB-TolC efflux system was determined by measuring AcrA expression with a method described previously.4 However, the expression of the AcrA protein was equivalent to the baseline production in a susceptible reference strain. As ambulatory treatment, the patient received a prescription for co-trimoxazole (160 mg of trimethoprim/800 mg of sulfamethoxazole, twice a day) and metronidazole (500 mg, three times a day) given orally for 10 days. One week after drug discontinuation, diarrhoea and arthritis reappeared. A new stool culture was again positive for Salmonella Kentucky. In addition to the profile observed in the first isolate, this strain presented additional resistances to co-trimoxazole (MIC . 256 mg/L) and ESCs [cefotaxime MIC . 256 mg/L, ceftriaxone MIC . 256 mg/L, cefepime MIC ¼ 16 mg/L and showed increased MIC of ceftazidime (4 mg/L)]. The strain was susceptible to meropenem (MIC ¼ 0.5 mg/L). The C. difficile toxin test was again positive for the second stool culture. As diarrhoea persisted, the patient was this time admitted for iv treatment with meropenem (1 g three times a day for 5 days) combined with oral vancomycin (250 mg three times a day for 10 days). Although the stool cultures performed during the hospitalization remained positive for the C. difficile toxin, the diarrhoea disappeared but abdominal pain persisted. Therefore, a colonoscopy was performed and showed non-specific rectal ulcerations. Abdominal pain was resolved with mesalazine enema treatment. To determine the nature of produced b-lactamases provoking the cephalosporin resistance, PCR amplifications specific for b-lactamase genes of the TEM, SHV and CTX-M families were performed as described previously.5 Only the CTX-M consensus PCR assay gave the expected PCR fragment (545 bp). Sequence
Correspondence Twelfth International Supplement: Approved Standard MS100-S12. NCCLS, Villanova, PA, USA, 2001. 3. Weill FX, Bertrand S, Guesnier F et al. Ciprofloxacinresistant Salmonella Kentucky in travelers. Emerg Infect Dis 2006; 12: 1611–2. 4. Baucheron S, Imberechts H, Chaslus-Dancla E et al. The AcrB multidrug transporter plays a major role in high-level fluoroquinolone resistance in Salmonella enterica serovar Typhimurium phage type DT204. Microb Drug Resist 2002; 8: 281 –9. 5. Bertrand S, Weill F-X, Cloeckaert A et al. Clonal emergence of extended-spectrum b-lactamase (CTX-M-2)-producing Salmonella enterica serovar Virchow isolates with reduced susceptibilities to ciprofloxacin among poultry and humans in Belgium and France (2000 to 2003). J Clin Microbiol 2006; 44: 2897–903. 6. Majtan V, Majtan T, Matjan J et al. Salmonella enterica serovar Kentucky: antimicrobial resistance and molecular analysis of clinical isolates from the Slovac Republic. Jpn J Infect Dis 2006; 59: 358–62.
Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dkm148 Advance Access publication 12 May 2007
Marco Bongiovanni1*, Roberto Ranieri1, Daris Ferrari2, Carla Codeca`2, Tiziana Tartaro2 and Lilj Uziel2 1
Clinic of Infectious and Tropical Diseases, San Paolo Hospital, University of Milan, via di Rudinı` 8, 20142 Milan, Italy and 2Oncology Unit, San Paolo Hospital, University of Milan, via di Rudinı` 8, 20142 Milan, Italy Keywords: liposomal amphotericin B, Mucor, haematological malignancies *Corresponding author. Tel: þ39-0281843061; Fax: þ390281843054; E-mail:
[email protected] Sir, Mucormycoses are invasive infections due to non-septate, filamentous fungi. Infections by these pathogens, although uncommon, are usually observed in immune-compromised subjects with diabetes, haematological diseases, advanced HIV infection or in persons receiving immunosuppressive treatment.1 Cerebral mucormycosis may present with three different patterns: (i) as a rhinocerebral infection, usually following involvement of the sinuses; (ii) as part of a systemic disease originating from the lungs; (iii) as an isolated form without involvement of other organs.2 The typical neurological symptoms of rhinocerebral mucormycosis are those of space-occupying lesions with ringenhancement featuring focal signs; however, a case with features of thrombotic stroke has been reported.3 All the clinical patterns of mucormycosis are rapidly fatal. A large study of 59 subjects with haematological malignancies with a proven or probable diagnosis of mucormycosis showed a mortality .80% within 3 months of the diagnosis and, in most patients, the cause of death was mucormycosis itself rather than the progression of the underlying disease; the only predictor of
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Prolonged survival of an HIV-infected subject with severe lymphoproliferative disease and rhinocerebral mucormycosis
survival was the use of liposomal amphotericin B treatment.4 Additionally, mucormycosis is usually reported as an unexpected finding during autopsy in subjects with advanced HIV infection.5 We report the case of a 45-year-old man who in September 2002 was admitted to our hospital because of fever, latero-cervical lymphadenopathy and rhinolalia. During the admission, he was found to be HIV-infected with moderate immune-depression (HIV plasma RNA load: 230 000 copies/mL; CD4: 270 cells/mm3). A latero-cervical lymph node biopsy showed a diffuse, large, CD20þ, CD10þ, B cell non-Hodgkin lymphoma. Antiretroviral treatment with zidovudine, lamivudine and lopinavir/ritonavir was initiated with rapid virological suppression and immunological recovery (after 1 month HIV plasma RNA load: ,400 copies/mL; CD4: 350 cells/mm3). Fifteen days after the diagnosis of lymphoma, the patient started six cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, etoposide and intrathecal prophylaxis with methotrexate and cytosine arabinoside,6 with complete remission of disease until November 2004, when routine tests revealed circulating blasts, with a 65% bone marrow infiltration of pre-B cells CD19þ CD19/DRþ, Ph-negative, CD202, CD102; acute lymphoblastic leukaemia (ALL) was diagnosed. Chemotherapy consisted of an induction phase with cyclophosphamide, asparaginase, vincristine and idarubicin, followed by a seven-cycle consolidation phase with cyclophosphamide, vincristine, idarubicin, prednisone and intrathecal prophylaxis with methotrexate and cytosine arabinoside. At the end of the induction phase, the patient had grade IV pancytopenia associated with fever, right orbital pain with omolateral exophthalmos, impaired vision and paralysis of the third cranial nerve. Magnetic resonance imaging (MRI) of the brain showed ringenhancing lesions surrounded by oedema in the left cerebellum and in the right frontal cortical lobe; the latter lesion involved the white matter, the ocular nerve and the optical chiasm (Figure 1a). Additionally, features of right sphenoidal sinus inflammation were observed. A lumbar puncture was negative for infections and abnormal cells. A culture of the sinus aspirate showed colonies of Mucor. Antimycogram showed sensitivity to all antifungal drugs; a treatment with liposomal amphotericin B (dose of 3 mg/kg daily) was initiated and, after 2 months, both of the lesions appeared reduced in size and less oedematous. We repeated a culture of the sinus aspirate, which was negative. The consolidation treatment for ALL was continued and was followed by a complete remission; HIV infection continued to be well controlled (CD4: 450 cells/mm3; HIV plasma RNA load: ,50 copies/ mL). The maintenance treatment with cyclophosphamide, purinethol and methotrexate was discontinued due to grade IV pancytopenia. In December 2005 and June 2006, ALL relapsed again so that a rescue therapy with vincristine, daunorubicin and steroids was started. From April 2005, owing to partial but not complete resolution of MRI lesions (Figure 1b), liposomal amphotericin B was empirically reduced to a dose of 5 mg/kg twice weekly and from August 2005 until February 2007 to 5 mg/kg weekly. This treatment is still ongoing, and, to date, no clinical or radiological relapse of mucormycosis has been observed. No drug-related toxicities have been observed throughout the follow-up. Rhinocerebral mucormycosis is an uncommon disease associated with a high rate of mortality; few cases have been reported in HIV-infected patients, probably because AIDS patients primarily have a deficiency of T cell-dependent cellular immunity and only rarely have a bone marrow suppression leading to a severe neutropenia as observed in persons with haematological
