Enterobacter sakazakii Infections among Neonates, Infants, Children, and Adults

Introduction Enterobacter sakazakii was originally designated as yellow-pigmented variant of Enterobacter cloacae until 1980 when it was introduced as a new species based on differences between E. sakazakii and E. cloacae in DNA-DNA hybridization, biochemical reactions, the production of yellow-pigmented colonies, and antibiotic susceptibility (12). It is a motile peritrichous, Gram-negative rod and its normal habitat is unclear. Muytjens and Kollee (26) could not isolate E. sakazakii from environmental sources such as surface water, soil, mud, rotting wood, grain, bird dung, rodents, domestic animals, cattle, and raw cow’s milk. Most of the E. sakazakii strains described in the literature have been isolated from clinical sources. Although its epidemiology and reservoir are unknown, intrinsically and extrinsically contaminated dried infant formula has been implicated as the source of outbreaks and sporadic cases of E. sakazakii infections and colonization among neonates (4,9,26,28,31). E. sakazakii is a rare cause of infections but has been known to cause sepsis and meningitis, particularly among neonates and infants (1,3,4,6,9,15,19,20,22,25,28,29,30,31,36–38,40). The first 2 known cases of E. sakazakii neonatal meningitis were reported by Urmenyi and Franklin (38) in 1961; it was then still classified as the pigmented strain of E. cloacae. The case-fatality rate of neonatal E. sakazakii infections has been reported to be as high as 50%, with half of the previously reported patients dying within 1 week of diagnosis. Neonatal meningitis caused by E. sakazakii has a propensity to result in cerebral abscess or infarction with cyst formation with severe neurologic impairment. There were only 4 reported cases of E. sakazakii infections among adults: 3 bacteremias of which 2 were due to urosepsis, and 1 osteomyelitis (10,16,18,32). To better delineate the clinical characteristics and outcomes of E. sakazakii infection, we report 5 cases of E. sakazakii infections in 1 child and 4 adults, and review the literature on this subject. Methods We reviewed all cultures positive for E. sakazakii from January 1995 to December 1996. The charts of patients with E. sakazakii infections at the University of Massachusetts Medical Center were abstracted for demographic data, underlying diseases, surgical procedures, type of infections, presence of ventilators and central lines, susceptibility testings, antimicrobial therapy, and outcome. We then reviewed the English-language literature from 1960 to 1999 with the use of MEDLINE (National Library of Medicine, Bethesda, MD). To broaden the search for E. sakazakii infections, the key words Enterobacteriaceae, Enterobacter, Enterobacter sakazakii infection, and Enterobacter infection were used. Available data regarding the clinical manifestations, treatment, and outcome are summarized. Abstracts of foreign-language literature with English translation were perused for cases of E. sakazakii infections through the same period. E. sakazakii was identified by the Vitek System and also by conventional biochemicals for Enterobacteriaceae (11). Susceptibility testings were determined by broth microdilution procedures. Epidemiology Review of the microbiology data showed that from 1994 through 1999, 3.6% (range, 2.2%-4.3%) of the blood stream infections at our institution were related to Enterobacter species. E. sakazakii was the etiologic agent only in fiscal year 1996 and accounted for 0.4% of all blood stream infection. With the exception of isolation of E. sakazakii in the sputa and blood of the patients in this report from January 1995 through December 1996, E. sakazakii has not been isolated from other clinical specimens at our institution. There was no clustering noted in this period. The 5 E. sakazakii infections reported were scattered throughout the 2-year period. Case Reports From January 1995 to December 1996, 5 cases of nosocomial E. sakazakii infections involving 1 child and 4 adults were observed. The infections included 3 bloodstream and 2 respiratory infections. The bloodstream infections were due to a central line, biliary source, and abdominal infection. Three patients had malignancies: embryonic rhabdomyosarcoma, tonsillar carcinoma, and Klatskin tumor. Two of these patients underwent chemotherapy and 1 was neutropenic when bacteremic with E. sakazakii. Two patients recovered and 3 died;E. sakazakii bacteremia contributed to 2 of the deaths. Case 1 A 3-year-old boy with embryonic rhabdomyosarcoma of the prostate metastatic to the temporal lobe underwent radiation therapy and 6 cycles of chemotherapy through a Broviac catheter for a period of 4 months. The patient was admitted for fever and neutropenia with an absolute neutrophil count of 100/mm3. On admission, blood cultures were positive for E. sakazakii and Serratia marcescens. The line was removed. E. sakazakii was resistant to cefazolin, intermediately sensitive to ampicillin, but sensitive to cefotaxime, gentamicin, and trimethoprim-sulfamethoxazole. The patient was begun on nafcillin and ceftazidime, which were changed to gentamicin and cefotaxime, and upon discharge he was given gentamicin and ceftriaxone for a total of 15 days. He became afebrile on day 5 and subsequent blood cultures were negative. Case 2 A 39-year-old man underwent resection of tonsillar carcinoma a year ago and received chemotherapy for metastatic disease. He was admitted for placement of gastrostomy tube and subsequently required emergent tracheostomy. His chest X-ray showed bibasilar bronchopneumonia consistent with aspiration pneumonitis. His sputum was purulent and grew E. sakazakii and Staphylococcus aureus. E. sakazakii was resistant to cefazolin and ampicillin and sensitive to cefotaxime, ceftazidime, genta-micin, and trimethoprim-sulfamethoxazole. He was given ceftazidime and clindamycin for 5 days followed by cefuroxime axetil and clindamycin via the gastrostomy tube for another 2 days. He recovered and his follow-up chest X-ray was free of infiltrates. Case 3 A 73-year-old woman was admitted for evaluation of painless jaundice. Endoscopic retrograde cholangiographic pancreatogram revealed stricture of hepatic duct that was relieved by stent placement. She had an exploratory laparotomy with resection of the common bile duct and hepatojejunostomy. The common bile duct revealed a Klatskin tumor. Her postoperative course was complicated by hypotension, hypoxemia, and renal failure. Cholangiogram showed occlusion of the left hepatic duct, with bile drainage growing E. sakazakii, Serratia marcescens, and enterococci. Blood cultures were positive for E. sakazakii. E. sakazakii was resistant to cefazolin, ampicillin, cefotaxime, ceftazidime, piperacillin-tazobactam, gentamicin, and ofloxacin, and was sensitive to amikacin, imipenem-cilastatin, and trimethoprim-sulfamethoxazole. She was given piperacillin-tazobactam for 3 days and 1 dose of gentamicin and switched to imipenem on the fourth day when she died from biliary sepsis. Case 4 An 82-year-old woman underwent emergent abdominal aortic aneurysmal repair. Her course was complicated by abdominal compartment syndrome with massively swollen viscera, acute respiratory distress syndrome, fever, metabolic acidosis, and oliguria. Nine days postoperatively her blood cultures were positive for E. sakazakii, which was resistant to cefazolin, cefuroxime, and ampicillin, and was sensitive to cefotaxime, piperacillin/tazobactam, gentamicin, ofloxacin, and trimethoprim-sulfamethoxazole. She was treated with ofloxacin and on the second day piperacillin/tazobactam was added, but she died on the sixth day. Case 5 A 76-year-old woman was found unresponsive and was intubated before being brought to the emergency room. She underwent emergent surgery for cecal volvulus with resection of the cecum. She remained intubated and developed Candida albicans bloodstream infection for which she was given amphotericin B. Three weeks postoperatively her chest X-ray showed an infiltrate and her purulent sputum grew E. sakazakii and S. aureus. There were 2 strains of E. sakazakii: the first strain was sensitive only to the aminoglycosides, quinolones, and trimethoprimsulfamethoxazole, while the second strain was susceptible only to the aminoglycosides and trimethoprim-sulfamethoxazole. She was initially treated with tobramycin and ceftazidime, and on the second day ceftazidime was discontinued and ofloxacin was added for a total of 10 days. Her course was complicated by hypotension requiring pressors and development of intraabdominal abscess requiring drainage. She expired 1 month after surgery. Comment: Cases 2 and 5 were patients with evidence of pneumonia with isolation of S. aureus and E. sakazakii. E. sakazakii might not be the causative agent for their infections. Susceptibility Testing These E. sakazakii isolates were uniformly resistant to ampicillin, cefazolin, and extended spectrum penicillins, and were not uniformly susceptible to the third-generation cephalosporins or the quinolones. They were uniformly susceptible to the aminoglycosides and trimethoprim-sulfamethoxazole. Literature Review Findings in the literature and our own cases of infections due to E. sakazakii in neonates, infants, children, and adults are summarized in Tables 1 and 2. Cases of colonization with E. sakazakii described in the outbreaks in neonates by Arseni’s group (3) are excluded. In addition, we excluded 1 case of E. sakazakii meningitis mentioned by Lecour et al (22), 2 cases of bacteremia from the M. D. Anderson Cancer Center reported by Bodey et al (5), and 2 cases of E. sakazakii bacteremia reported by Ansari et al (2), since no clinical details were given. One case of bacteremia in an infant who later developed a brain abscess was reported twice (14,15) and therefore was counted once. One case of E. sakazakii bacteremia reported by Chow et al (8) was excluded since there was no clinical information. Emery and Weymouth (10) mentioned 6 patients with clinical isolates of E. sakazakii but did not describe the types of infection with the exception of 1 patient with extended spectrum betalactamase producing E. sakazakii. This patient was included as 1 of the adult cases. Varaldo and colleagues (39) reported on the distribution and antibiotic susceptibility of extraintestinal clinical isolates of Enterobacteriaceae. Twelve of these isolates were E. sakazakii, of which 8 were from urine, 1 from genital secretion, 2 from respiratory secretion, and 1 from spinal fluid; however, there was no clinical information and therefore these were excluded.TABLE 1: Enterobacter sakazakii infections in neonates, infants, and childrenTABLE 1: ContinuedTABLE 1: ContinuedTABLE 1: ContinuedTABLE 2: Enterobacter sakazakii infections in adultsE. sakazakii infections among neonates, infants, and children In the literature there were 31 cases of E. sakazakii infections affecting neonates, infants, and children with sufficient clinical information to be included. Almost all cases were nosocomial and quite a few cases were associated with contaminated powdered milk or infant formula. The ages of these neonates, infants, and children with E. sakazakii infections ranged from 3 days to 4 years with half of them ≤1 week of age, and close to three-quarters being <1 month of age. Twenty-one patients presented with meningitis, 12 of whom also had concomitant E. sakazakii bacteremia, 7 with bacteremia alone, 1 with urinary tract infection, 1 with diarrheal illness, and 1 with infected dermoid cyst. Fifty-five percent of the neonates with birth weight available had weights ≤2,500 g. Seventy-five percent were either premature infants or had peripartum complications. Seizures were described in 9 of the 21 patients (43%) with meningitis. Pneumoencephalogram was performed on Patient 3 (see Table 1) and showed cysts in the ventricles; craniectomy revealed abscess. Computerized tomography (CT) of the head was first mentioned in a report from Kleiman et al (20). All CTs revealed abnormalities: cystic changes were most common, followed by abscesses or fluid collections, dilated ventricles, and infarctions. Persistently positive cerebral spinal fluid (CSF) cultures on treatment were noted in 5 of the patients with meningitis as late as day 40 of illness. Three of the 7 patients with bacteremia had diarrhea or bloody diarrhea, and necrotizing enterocolitis was mentioned in 2 of the patients with concomitant meningitis and bacteremia. These were the patients whose infection might be related to contaminated infant formulas. Susceptibility testing when available showed that E. sakazakii was usually sensitive to ampicillin, the aminoglycosides, chloramphenicol, and the third-generation cephalosporins. The neonates and infants were treated with a variety of antibiotics. Before 1985, patients with E. sakazakii infections were frequently treated with ampicillin, gentamicin and/or chloramphenicol. After 1985, the third-generation cephalosporins were commonly used in conjunction with ampicillin and gentamicin. The overall case-fatality rate for E. sakazakii infections among neonates and infants was 33%. Patients with meningitis had a case-fatality rate of 45%, and there was 1 death among patients with bacteremia without meningitis. E. sakazakii infections caused a higher case-fatality rate among premature or low-birth weight infants than full-term or infants with birth weight ≥2,500 g (50% versus 30%). The case-fatality rate among patients with meningitis before the use of third-generation cephalosporins was 62%; with the introduction of third-generation cephalosporins, it was 14%. Nine of the 11 patients with meningitis who survived the infection had follow-ups, all had hydrocephalus, some form of developmental delay, and neurologic sequelae. Autopsy reports were mentioned in 5 patients with meningitis. Pathologic findings showed evidence of meningoencephalitis or cerebral necrotic hemorrhage inflammation caused by massive invasion by Gram-negative bacilli. As mentioned previously, a few patients developed E. sakazakii bacteremia in the setting of contaminated infant formula. Bacteremia tended to affect low-birth weight and premature infants. Only 1 of the 7 patients with E. sakazakii bacteremia died. E. sakazakii infections among adults In contrast to the 31 cases of infection in neonates, infants, and children, there were only 4 reported cases of E. sakazakii infections in adults: 3 with bacteremia, 2 of which were secondary to urosepsis, and 1 with osteomyelitis of the foot, which was also coinfected with Staphylococcus epidermidis and Enterococcus species (10,16,18,32). Two of our patients presented with pneumonia and 2 with bacteremia. All patients were in their sixth decade of life with the exception of 1 of our patients (Case 2) who was 39 years of age. Two of the 4 patients from the literature and 2 of our patients with E. sakazakii infections had neoplasm. The other patients had serious underlying conditions that are ultimately fatal. Most adult cases were nosocomial. Among the adult patients, third-generation cephalosporins and the quinolones were frequently used for treatment of E. sakazakii infections. Three patients reported in the literature survived their infections, 3 of our patients died. Susceptibility testing Antibiotic susceptibility testing results were available for some of the isolates reported in the literature. E. sakazakii was susceptible to ampicillin, tetracycline, chloramphenicol, gentamicin, and the third-generation cephalosporins, which is in contrast to our strains with uniform resistance to ampicillin and variable resistance to the other beta-lactams including the third-generation cephalosporins. Discussion E. sakazakii infections continue to be rare but are more common among neonates and infants than adults. Among neonates and infants, E. sakazakii has a propensity to cause meningitis resulting in ventriculitis, brain abscess or cyst formation, and late development of hydrocephalus requiring ventricular-peritoneal (VP) shunt. Other Gram-negative bacilli with a propensity to cause neonatal brain abscess are Citrobacter diversus and Escherichia coli(13,21). Using DNA-DNA hybridization techniques, strains of E. sakazakii have shown a 50% relationship to C. diversus(12). Mortality and morbidity of E. sakazakii meningitis is high with virtually all patients recovering from central nervous system infections suffering from developmental delay mentally and/or physically. The majority of the adults with E. sakazakii infections had underlying diseases and notably 4 out of 8 adults had malignancies. However there has not been a known case of meningitis. Muytjens and van de Repe (27) performed comparative in vitro susceptibilities of 8 Enterobacter species including E. sakazakii. Their results showed that resistance to ampicillin or inhibition by a high concentration of cephalothin was likely to exclude E. sakazakii, and they further suggested that this could be used to eliminate additional steps in the identification of E. sakazakii. Indeed the isolates gleaned from the literature were uniformly sensitive to ampicillin. However, in contrast, our isolates were all resistant to ampicillin and some of the broad-spectrum beta-lactams as well. Burwen and colleagues (7) tested 3,992 Enterobacter isolates and found that 36% were resistant to ceftazidime. Resistance increased significantly during the 1987–1991 period and was more common among isolates from patients in intensive care units, urinary tract or bloodstream infection sites, and teaching hospitals. The prevalence of resistance among isolates of Enterobacter to beta-lactams, trimethoprim-sulfamethoxazole, and quinolones, in general, increases with the size of the hospital, reflecting possible selective antibiotic pressure on the development of resistance among the Enterobacter. Although the authors did not specify what proportion of the Enterobacter tested was E. sakazakii, the overall increasing trend of antibiotic resistance among all Enterobacter species may well explain the increased antibiotic resistance that was observed among our clinical E. sakazakii isolates. Before the introduction of the third-generation cephalosporins, E. sakazakii meningitis was treated with ampicillin and gentamicin or ampicillin and chlor-amphenicol. Of the 13 cases treated before the availability of third-generation cephalosporins, 8 patients (62%) died. Seven cases were treated with a third-generation cephalosporin in combination with ampicillin plus or minus gentamicin, all survived with 1 person dead within hours and there was no outcome information on another patient (Patient 29). It would seem that the outcome of E. sakazakii meningitis improved with the availability of the third-generation cephalosporins. Enterobacter species are among those Gram-negative bacteria most likely to produce beta-lactamases capable of inactivating broad-spectrum penicillins and cephalosporins (8,10). With increasing antibiotics resistance being observed among Enterobacter species, the use of carbapenems, or the newer cephalosporins, such as cefepime, in combination with a second agent should be considered and susceptibility testing done. Sanders and colleagues (35) did not note emergence of resistance to cefepime when they treated a variety of infections caused by multiply-resistant species with this and of the infections were However of the infections the central nervous emergence of resistance to cefepime during treatment of bacteremia and hepatic abscess due to E. in a patient who underwent has been reported The this report the use of cefepime in patients with infections such as pneumonia or abscess caused by strains of Enterobacter species. The further suggested that of susceptibility testing should be when Enterobacter infections due to strains with This would to the emergence of with resistance to ceftazidime and a higher concentration to cefepime still within the of this is the to to should be susceptibility data that Enterobacter species sensitive to the aminoglycosides and and these may be as a second agent the of aminoglycosides the central nervous system may their use to or and colleagues reported their own for the treatment of Enterobacter meningitis and reviewed the literature. They found that all patients treated with were to of those who received resistance to cephalosporins developed in for which these were days the of the antibiotics. E. sakazakii has a propensity to the central nervous system of neonates and infants and frequently the development of cysts or head should be considered on in the of patients with isolation of E. sakazakii from the blood or Although some authors reported from fluid from the cysts or abscesses the aspiration after weeks of antibiotic and isolated E. sakazakii from fluid from the abscess on the day of after than a week of antibiotics and a at 2 weeks A follow-up should be the first not cystic since new findings such as hydrocephalus may and/or of fluid may be in when there was no fluid in the The findings of this are by the that the literature search was to in The Enterobacteriaceae and Enterobacter species were in that describe Enterobacter, of these did not additional cases of E. sakazakii infection. English from foreign-language literature were perused for E. sakazakii infections from through 1999, at 5 cases were Two of these were in premature and there was no of the ages for the other One infant had meningitis with cerebral and and the a premature had Of the 3 patients, 2 had E. sakazakii isolated from and a from an Enterobacter sakazakii cause serious infections among the and the It to be more common among neonates and infants than adults. for the central nervous system in neonates and infants a Among neonates and infants, E. sakazakii has a propensity to cause meningitis resulting in ventriculitis, brain abscess or cyst formation, and development of hydrocephalus requiring ventricular-peritoneal shunt. tomography of the head is therefore in patients with E. sakazakii meningitis. Mortality and morbidity of E. sakazakii meningitis is and virtually all patients recovering from the central nervous system infection and developmental The case-fatality rate among patients with meningitis treated with the third-generation cephalosporins. Most adults with E. sakazakii infection had serious underlying diseases and 50% of the adults with the infection had malignancies. However there has been a known case of meningitis. antibiotic resistance among Enterobacter species should to the or the newer cephalosporins in combination with a second agent such as an data that may be a agent in the treatment of infections caused by the Enterobacter species, in of the production of capable of inactivating the cephalosporins and The and for the cases.