Severe sepsis from a Ciprofloxacin resistant salmonellosis in a kidney transplant recipient

A diarreia é comum entre receptores de transplante renal (RTR). Muitas são suas possíveis etiologias e os casos podem variar de discretos e limitados a crônicos e incapacitantes.1-3 A prevalência de bactérias gram-negativas multirresistentes pode variar de 20% a 50% entre receptores de transplante de órgãos sólidos, dependendo da população estudada.4,5 A enterite causada por Salmonella sp. é uma forma rara de infecção que não pode ser clinicamente diferenciada da enterite aguda comum; geralmente, responde bem a tratamento com fluoroquinolonas.6-8 Em pacientes imunossuprimidos, contudo, pode se associar mais facilmente a bacteremia e, consequentemente, a um prognóstico muito pior.9-11 Sepse grave por salmonelose Ciprofloxacino-resistente em paciente transplantado renal


IntRoductIon
Diarrhea is common among kidney transplant recipients (KTR).2][3] Prevalence of multidrug resistant gram-negative bacteria may reach 20 to 50% among solid-organ transplant recipients, depending on the studied population. 4,5[11] In this paper, we present a rare case of invasive diarrhea with severe sepsis caused by ciprofloxacin resistant Salmonella sp. in a KTR, and a brief literature review.

cAse RepoRt
A 73 year-old, male KTR with a previously well-functioning graft (serum creatinine 1.2 mg/dL), receiving prednisone (5 mg PO every other day), sirolimus (2 mg PO daily) and mofetil mycophenolate (750 mg PO twice a day), was admitted with a 5-day history of asthenia, diffuse abdominal pain and watery non-inflammatory diarrhea, with over 10 evacuations per day.He denied the use of antibiotics for the last 2 years.
At physical examination, the patient was dehydrated, tachycardic (105 bpm), with orthostatic hypotension (90x50 mmHg), and afebrile.The abdomen was flaccid, with slightly enhanced peristalsis, and no palpable masses.He had been hospitalized for 7 days, six months before, for investigation of a thyroid benign nodule.
In the second day, the patient experienced an episode of bloody diarrhea.Kidney function (creatinine 6.6 mg/dL) and metabolic acidosis (pH 7.10, HCO3 -4 mEq/L) worsened and hemodialysis was then started.An exploratory laparotomy was first indicated after an abundant drainage of fecaloid material through a nasogastric tube, but it was later contraindicated based on the very poor clinical condition.
The patient showed an apparent clinical improvement after dialysis, but presented hemodynamic deterioration and cardiac arrest 54 hours after the antibiotic treatment was first initiated.The stool culture, grown in Mac Conkey agar, and conventional blood culture, manually incubated in chocolate agar medium, were available only 24 hours after death, and were both positive for a strain of Salmonella sp, susceptible only to chloramphenicol and antipseudomonal third and fourth-generation cephalosporins, such as ceftazidime and cefepime, but not to ciprofloxacin, ampicillin and cotrimoxazole.An overview of laboratorial data from this case is displayed in Table 1.

dIscussIon
We described an atypical case of a 73 year-old KTR, who presented acute invasive diarrhea, and developed a severe sepsis caused by a ciprofloxacin resistant strain of Salmonella sp. that could not be effectively treated with standard antibiotic therapy.
Diarrhea is a relatively common complication among KTR, with an incidence of over 20% per year. 1,2It is usually mild, self-limited or indolent, and often related to a viral or bacterial infection, use of medications, or to specific immunosuppressant gastro-intestinal toxicity, markedly due to mycophenolic acid preparations. 3An enteritis caused by Salmonella sp.cannot be clinically distinguished from those caused by other bacteria, as in both cases the classical symptoms are acute-onset fever, diarrhea and abdominal pain. 6,7he incidence of salmonellosis in KTR is lower than 2% per year. 6,8This clinical condition has a broad spectrum of gravity, but in immunocompetent hosts, bacteremia can be seen in less than 5 to 10%.][11] Bacteremia from Salmonella sp. is known to bear a high risk of mortality, as described in a series of  cases from the Massachusetts General Hospital, in which an outbreak registered in 1990 caused the death of 18% of patients. 7Overall, the duration of the infection tends to be longer in KTR, with relapse rates of 43 to 45%, and mortality rates of 5 to 6%. 6,10 A literature review with 37 cases of salmonellosis in KTR identified the species of Salmonella sp. in 35 patients, with predominance of S. typhimurium in 24 cases, S. panama in 3 cases, and S. johannesburg and S. enteritidis in 2 cases each. 6In southeastern Brazil, the region where this case was registered, most common serotype is S. enteritidis (67.4%), followed by S. typhimurium. 11nfections caused by Salmonella sp. must be treated with empiric venous antibiotics, preferentially a 14-day scheme consisting of a fluoroquinolone or a third generation cephalosporin, to be initiated after collection of standard blood and stool cultures, which can be grown in chocolate agar, sheep blood agar or Mac Conkey agar media, as appropriate. 3,7,12n cases of Salmonella sp-related bacteremia, the same classes of antibiotics are indicated, but the length of antibiotic therapy must be individualized, as a longer course of antibiotics or a surgical intervention may be needed, due to a higher incidence of relapses observed in immunocompromised hosts, and to the possibility of a source of persistent infection, such as an abscess. 3,7,12he case we described has the peculiarity of presenting a very dramatic form of salmonellosis, caused by a string of Salmonella sp, presenting a broad spectrum of resistance, including ciprofloxacin resistance, which is not common in the literature and could not be timely diagnosed based on cultures, reason for which the initial antibiotic treatment was not changed from ciprofloxacin. 13 Moreover, the patient did not present any specific risk factors for a ciprofloxacin resistant bacterial infection, such as previous treatment with broadspectrum antibiotics, prolonged use of any medical device, or a recent prolonged hospital stay, and had been in good clinical condition for a long period, prior to the beginning of the enteritis. 14Lack of clinical response could not be thoroughly judged, since a period no longer than 48 hours from admission and from the start of antibiotic treatment had passed until the patient showed further clinical deterioration.
The global prevalence of resistant infections caused by Gram-negative bacteria has been increasing in the last years.The same pattern has also been reported in transplant recipients.The most clinically important drug-resistant bacteria reported in transplant patients include non-lactose fermenters such as Pseudomonas species, Burkholderia species and Stenotrophomonas species, carbapenem-resistant Acinetobacter species, and multidrug-resistant (MDR) Enterobacteriaceae, with carbapenem-resistant Enterobacteriaceae being of particular concern.It is worth noting that Salmonella species are not included in the group of major concern. 14articularly regarding this case, the isolated bacteria, despite a rather broad pattern of resistance, which included ciprofloxacin, retained susceptibility to some antibiotics, such as chloramphenicol, and therefore could not be classified as MDR. 15iprofloxacin-resistant salmonellosis is rather uncommon, though increasingly reported in the literature, and has been suggested to be related to previous use of antibiotics, contactants, or agricultural use of quinolones.The patient, we described here, did not report previous exposure to ciprofloxacin. 15n conclusion, this ciprofloxacin-resistant pattern rendered the treatment ineffective, and the patient developed an invasive and rapidly lethal form of infection.This case illustrates that rather common manifestations such as diarrhea can correspond to potential life-threatening and rare forms of infection in KTR, and suggests that, in addition to other forms of resistant bacteria, the possibility of ciprofloxacinresistant salmonellosis should be considered, when initial evidence-based antibiotic therapy does not lead to a clinical improvement within 48 hours of treatment.