Community-acquired CTX-M-15-type ESBL-producing .
Case ReportCommunity-acquired CTX-M-15-type ESBL-producing Escherichia colimeningitis: a case report and literature reviewNazif Elaldi1, Mustafa G. Gozel 1, Fetiye Kolayli2, Aynur Engin1, Cem Celik3, Mustafa Z. Bakici3,Haluk Vahaboglu41Department of Infectious Diseases and Clinical Bacteriology, Cumhuriyet University, Sivas, TurkeyDepartment of Clinical Microbiology, Kocaeli University, Izmit, Turkey3Department of Clinical Microbiology, Cumhuriyet University, Sivas, Turkey4Department of Infectious Diseases and Clinical Microbiology, Kocaeli University, Izmit, Turkey2AbstractIn this report, a case of community-acquired acute bacterial meningitis (CA-ABM) caused by CTX-M-15-producing Escherichia coli in anelderly male patient was presented in the light of literature. Cultures of cerebrospinal fluid, blood, ear discharge, and stool samples yieldedCTX-M-15-producing E. coli in-vitro, which was resistant to the extended-spectrum cephalosporins and ciprofloxacin and susceptible toimipenem, meropenem and amikacin. Meningitis was treated with parenteral meropenem plus parenteral and intraventricular amikacinadministration. Since bacterial meningitis is a life-threatening infection, empiric antibiotic therapy with carbapenem can be started before theculture results are obtained, mainly in areas where the ESBL epidemiology is well known.Key words: Escherichia coli; CTX-M-15; meningitisJ Infect Dev Ctries 2013; 7(5):424-431. doi:10.3855/jidc.2820(Received 29 June 2012 – Accepted 30 October 2012)Copyright 2013 Elaldi et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.IntroductionBacterial meningitis is a medical emergency whichis associated with high mortality, neurological sequela,and community-acquired acute bacterial meningitis(CA-ABM) causing Escherichia coli is a rare entity.The most important prognostic factor is theappropriate choice of pathogen-specific antibacterialtherapy [1,2]. For Gram-negative bacillary meningitis,current guidelines recommend the use of a thirdgeneration cephalosporin guided by in-vitrosusceptibility test results [3]. Extended-spectrum betalactamase (ESBL)-producing Gram-negative bacillicause a significant therapeutic challenge since theyhydrolyze all β-lactams except carbapenems andcephamycins. E. coli remains one of the main ESBLproducing microorganisms isolated worldwide.Among the ESBLs, the cefotaximases (CTX-M)constitute a rapidly growing cluster of enzymes, andCTX-M-producing E. coli has emerged anddisseminated worldwide as an important cause of bothnosocomial and community-acquired infections [4,5].Recent studies from Turkey show that CTX-M-15 isthe most prevalent ESBL among the CTX-M in E. colistrains [6-8]. Herein, we report a case of CA-ABMsecondary to chronic otitis media and cerebrospinalfluid (CSF) fistula caused by CTX-M-15 type ESBLproducing E. coli in an elderly male patient. A reviewof the English-language medical literature isemphasized on the ESBL-type, origin, patientcharacteristics, treatment, and outcome of E. colimeningitis.Case reportAn 84-year-old man was admitted to theemergency department with a one-day history ofaphasia and confusion. His relatives reported that hehad a history of chronic intermittent purulent right eardischarge over the course of a few months, for whichhe refused medical care. They also noted that he hadhad complaints of fever, chills, vomiting, andheadaches prior to the development of aphasia andconfusion. His past medical history revealed a righttympanoplasty operation for chronic otitis media threeyears ago. Before his admission, he had also receivedoral ciprofloxacin (1 gram daily in two divided doses)treatment for three weeks for chronic prostatitis andbut he had stopped taking this medication five dayspreviously. On physical examination, he was
Elaldi et al. – ESBL-producing Escherichia coli meningitisunconscious with a body temperature of 37.8 C, pulserate was regular with a rate of 90 beats per minute,blood pressure was 110/60 mmHg, and respiratory ratewas 20 breaths per minute. The respiratory system,cardiovascular system, and abdomen were normal.Otoscopic examination showed purulent discharge,tympanic membrane perforation, and a moderatehyperemia in the right ear. Neurological examinationshowed nuchal rigidity and ptosis of the left eyelid.Laboratory analysis revealed a white blood cell(WBC) count of 13.700/mm3, a serum C-reactiveprotein (CRP) level of 201 mg/l, and an erythrocytesedimentation rate of 127 mm/h. Lumbar puncture wasimmediately performed and analysis of the CSFshowed 2.200 leukocytes/mm3 (90% polymorphnuclear), increased protein (495 mg/dl), decreasedglucose (4 mg/dl with a concurrent blood glucose levelof 121 mg/dl), and Gram-negative rods. A Gram stainfrom the ear discharge revealed the presence ofmultiple leukocytes and Gram-negative rods. Empiricintravenous ceftriaxone treatment (4 gr/day in 2divided doses) was started immediately after thecultures were performed. An enhanced computerizedtomography (CT) scan of the brain demonstratedventricular dilatation (communicating hydrocephalus)and a defect in the right mastoid bone (secondary toprevious ear surgery) as a cause of CSF leakage andacute purulent meningitis. The patient underwentexternal ventricular drainage for the management ofCSF leakage from the ear.However, his clinical situation worsened on thesecond day of admission and ceftriaxone treatmentwas switched to intravenous meropenem (3 gr per dayin three divided doses) for the possibility of resistance.On the third day, cultures from CSF and ear dischargesamples grew ESBL-producing E. coli which wasresistant to extended-spectrum cephalosporins (ESCs)and ciprofloxacin, but susceptible to amikacin andcarbapenem (imipenem and meropenem) antibiotics(Table 1). Throat culture was evaluated as normalflora. Stool culture was performed for the possiblesource of meningitis, and a fecal carriage of ESBLproducing E. coli yielded an ESBL-producing E. colistrain having the same antimicrobial susceptibilitypattern with the previous E. coli strains.CSF examination, which was repeated on the thirdday of meropenem treatment, showed minimalimprovement in CSF findings: 1.800 leucocytes/mm3,a protein level of 150 mg/dL, and a glucose level of 9mg/dL . Therefore, intravenous and intraventricularamikacin 1.5 gr per day in three divided doses and 30mg per day were added to the regimen, respectively.J Infect Dev Ctries 2013; 7(5):424-431.CSF examination on the sixth day of meropenem andthe third day of intraventricular amikacin treatmentrevealed 2.700 leucocytes/mm3, protein level of 390mg/dL and glucose level of 4 mg/dL. Cultures fromthe second CSF sample and blood grew ESBLproducing E. coli with the same antimicrobialsusceptibility pattern as in the previous E. coli isolates,suggesting the same microorganism. All four E. colistrains were sent to the Kocaeli University,Microbiology Lab, Turkey, for the determination ofESBL-type. On the seventh day of admission, revisionmastoidectomy operation was performed due to thepersistent right ear discharge. The stool culture on the14th day of meropenem treatment and the CSF cultureon the 17th day of the antibiotic regimen were stillpositive for the presence of ESBL-producing E. coli.CSF examination on the 28th and the 30th days ofmeropenem treatment showed 200 and 48leucocytes/mm3, 120 and 45 mg/dL of protein levelsand 41 and 54 mg/dL of glucose levels, respectively.CSF culture was negative for the first time on the 28thday of meropenem treatment; therefore, antibioticswere discontinued on the 30th day. The results of threesequential CSF cultures with two-day intervals werenegative and the patient’s condition was stable after 30days in the ICU.MethodologySampling, identification procedure of microorganismsand antimicrobial testsBlood samples were inoculated into blood culturebottles (BD BACTEC plus Aerobic/F, Shannon,County Clare, Ireland). CSF and ear discharge sampleswere inoculated onto sheep blood agar, chocolate agar,and EMB agar plates. One droplet of the positivegrowth blood cultures (BD BACTEC 9240 BloodCulture System, Franklin Lakes, NJ, USA) was placedon sheep blood agar, chocolate blood agar, and EMBagar plates and pricked by a sterile needle. Sheep andchocolate blood agar plates were incubated inmicroaerobic conditions and EMB agar plates wereincubated in aerobic conditions at 37ºC for 24 to 48hours. Stool samples were inoculated onto an EMBagar plate containing 2 μg/mL of cefotaxime forselection of ESBL-producing strain. The isolates wereidentified to the species level and tested forsusceptibility to various antimicrobial agents and forESBL-production by Phoenix 100 (BD DiagnosticInstrument Systems, Towson, Md.) automatic int/ID Panels (BD Phoenix NMIC/ID-82).425
Elaldi et al. – ESBL-producing Escherichia coli meningitisJ Infect Dev Ctries 2013; 7(5):424-431.Table 1. Antimicrobial susceptibility pattern of Escherichia coli isolatedfrom the cerebrospinal fluid (CSF)AntibioticMICInterpretation(μg/mL)AmikacinS 8Amoxicillin/clavulanate16/8RAmpicillin 16RAztreonam 16RCefazolin 16RCefepime 16RCefotaxime 32RCefoxitinS 4Ceftazidime 16RChloramphenicol8SCiprofloxacin 2RGentamicin 8RImipenemS 1Levofloxacin 4RMeropenemS 1Piperacillin 64RPiperacillin/tazobactam16/4STetracycline 8RTrimethoprim/sulfamethoxazol1/190.5/9.5SMIC minimum inhibitory concentration, S susceptible, R resistantESBL typing and sequence analysis of E. coli strainsFragment length patterns obtained by RandomAmplified DNA (RAPD) PCR of the four E. coli wereidentical, indicating the clonality among isolates [9](Figure 1). Isoelectric focusing revealed the existenceof a single beta-lactamase at (approx.) pI 8.5 whilePCR and sequencing of an 876 bp fragment amplifiedby CTX-M primers (CTXoF5'ATG GTT AAA AAATCA CTG CGC-3' & CTXoR5'TTA CAA ACC GTCGGT GAC GAT-3') confirmed the existence of blaCTXM-15 in all four isolates. Sequencing was performed onboth strands by the aid of four primers; two primerswere used for amplification and the other two wereinner primers (5'-ATG TGC AGC ACC AGT AAAGT-3' and reverse primer: 5' CCC CCA CAA CCCAGG AAG CA-3'), as described elsewhere [10].DiscussionA review of the current English-language medicalliterature revealed a total of 8 cases of ESBLproducing E. coli meningitis, including the presentcase [1,11-15] (Table 2). Four were nosocomial andthe other three were CA-ABM cases. Molecular typingand the ESBL-type of E. coli strains were determinedin six strains and four of them were CTX-M-15, onewas CTX-M-2, and the other was TEM-52-producingE. coli. It has been reported that all the nosocomial E.coli meningitis cases occurred during the outbreaks ininfants in neonatal wards [1,11,12,14]. Two CA-ABMcaused by ESBL-producing E. coli occurred in adults(Table 2).In the presented case, PCR and sequence analysisshowed that the intestinal colonization of the ESBLproducing E. coli was the source of bacterialmeningitis. We postulate that the route of CSFinfection in this case was due to the CSF fistulafollowed by ear contamination via the patient’s hands.There is a relationship between the fecal carriage ofESBL-producing microorganisms and urinary tractinfection in the community. The prevalence of fecalcarriage of ESBL-producing microorganisms in thesepatients is reported to be 67.9% [16]. Whilehospitalization is a risk factor for intestinalcolonization of ESBL-producing microorganisms, it isnot a risk factor for CTX-M-type ESBL-producing E.coli colonization, suggesting that the colonization isacquired in the community. Detection of CTX-Mproducing E. coli strains in the samples from livestockshows that animals might act as an important reservoir[4]. However, these strains may colonize in thegastrointestinal system of infants and may also causean outbreak in the newborn units [1,11,12]. It has beenpreviously demonstrated that fluoroquinolone use,advanced age, and severe underlying disease are426
Elaldi et al. – ESBL-producing Escherichia coli meningitisJ Infect Dev Ctries 2013; 7(5):424-431.Figure 1. RAPD-PCR for Escherichia coli isolatesM, DNA marker (1 kb); ESBL strains from ear discharge (lane 1);blood (lane 2); CSF (lane 3); and stool (lane 4) of the patientindependent risk factors for the acquisition of ESBLproducing isolates in the community setting,particularly CTX-M-type enzymes [7]. Our patient hadall of these risk factors. Despite a 14-day course ofintravenous meropenem and amikacin treatment,persistent fecal colonization of the ESBL-producing E.coli still continued and we decided that potentparenteral antibiotics did not have any effects on thefecal colonization of such resistant bacteria. A clinicalstudy demonstrated that parenteral meropenem,despite being successful in treating the systemicillness, failed to protect the digestive tract fromcolonization of ESBL-producing K. pneumoniae [17].The main risk factors for CA-ABM with E. coliare alcoholism, cirrhosis, malignancies, diabetes, andimmunosuppressive therapy. Nosocomial E. colimeningitis occurs frequently after neurosurgery and itis usually associated with multi-drug resistant strains[15]. Our patient had a CSF fistula secondary to a righttympanoplasty operation three years ago. Theliterature review reveals clear data regarding the coexisting factors in four of the seven ESBL-producingE. coli meningitis cases; very low birth weight infantsin two cases, infected cephalhematoma in one case,and alcoholism and aortic mycotic aneurisms in onecase. The neonatal age is considered to be a significantrisk factor for Gram-negative bacillary meningitis[18]. It has been observed that all the nosocomialESBL-producing E. coli meningitis cases were withinthe neonatal age accordingly (Table 2).Current therapy of Gram-negative bacillarymeningitis is third-generation cephalosporin andgentamicin may be added to the therapeutic regimen ifthe causative agent is susceptible. imethoprim-sulfamethoxazole are the second-lineantibiotics [3]. Fluoroquinolones are widely added tothe therapeutic regimen because of their excellent CSFpenetration and bactericidal activity in the neonatalperiod. However, resistance is frequently found inCTX-M-15-positive isolates, as seen in our E. coliisolates [1,8]. Nevertheless, meropenem, was given tothe patient one day later and intraventricular amikacin427
428J Infect Dev Ctries 2013; 7(5):424-431.Elaldi et al. – ESBL-producing Escherichia coli meningitisTable 2. Previous reports of meningitis in the English literature caused by extended spectrum beta-lactamase (ESBL)-producing Escherichia coliAuthors [Ref. no.]YearCountryAgeOriginof eatmentRamdani-Bouguessa N, et al.[11]2006AlgeriaOutcomeChildNosocomialNo informationCTX-M-15No informationCuredChildCommunityNo informationCTX-M-15No informationCuredDiedBoyer-Mariotte S, et al. [1]2008FranceChildNosocomialVery low birthweight infantCTX-M-15NotreatmentspecificMoissenet D, et al. [12]2010FranceChildNosocomialVery low birthweight infantTEM-52CuredAndrade LN, et al. [13]2010BrazilChildNo informationCTX-M-2Nakwan N, et al. edcephalhematomaNotdeterminedImipenem Gentamicin CiprofloxacinNospecifictreatmentMeropenemWeyrich P, et al. [15]2012FranceAdultCommunityAlcoholism, Aorticmycotic aneurismsNotdeterminedMeropenem CiprofloxacinPresent nialsurgery,Cerebrospinal fluidfistulaCTX-M-15Meropenem DiedCured
Elaldi et al. – ESBL-producing Escherichia coli meningitiswas also added to the regimen five days later.Although any antimicrobial agents have beenapproved by the Food and Drug Administration (FDA)in the United States for intraventricular or intratechaluse, amikacin and gentamicin are the most usedaminoglycosides [19]. When faced with ESBLproducing microorganisms, delay in initiating anappropriate antibiotic is significantly associated withdeath. The literature review reveals that treatment datais available in six of the eight ESBL-producing E. colimeningitis cases and two of them were fatal becauseof the inefficiency of the empiric antibiotic therapy.Although the emergence of resistance duringcarbapenem therapy has been reported, a relativelyhigh rate of clinical success with carbapenem isdemonstrated in patients infected with ESBLproducers [4,20]. The literature review also revealedthat half of the cases were treated with a carbapenem(Table 2). The mortality rate among patients infectedwith ESBL-producing E. coli is threefold greater thanthat of patients infected with non-ESBL strains [21].The overall mortality rate in Gram-negative bacillarymeningitis varied from 25% to 100% [18,22] anddeath occurred in three (38%) of eight ESBLproducing E. coli meningitis cases (Table 2).ConclusionPhysicians should be aware of the presence ofESBL production when they encounter a Gramnegative bacterium associated CA-ABM case,especially when there is a history of prior antibioticuse. Since bacterial meningitis is a life-threateninginfection, empiric antibiotic therapy with carbapenemcan be started before the culture results are obtained,mainly in areas where the ESBL epidemiology is wellknown.References1.2.3.4.Boyer-Mariotte S, Duboc P, Bonacorsi S, Lemeland JF,Bingen E, Pinquier D (2008) CTX-M-15-producingEscherichia coli in fatal neonatal meningitis: failure ofempirical chemotherapy. J Antimicrob Chemother 62: 14721474.Pitout JD, Nordmann P, Laupland KB, Poirel L (2005)Emergence of Enterobacteriaceae producing extendedspectrum beta-lactamases (ESBLs) in the community. JAntimicrob Chemother 56: 52-59.Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL,Scheld WM, Whitley RJ (2004) Practice guidelines for themanagement of bacterial meningitis. Clin Infect Dis 39: 12671284.Rossolini GM, D'Andrea MM, Mugnaioli C (2008) Thespread of CTX-M-type extended-spectrum beta-lactamases.Clin Microbiol Infect 14 Suppl 1: 33-41.J Infect Dev Ctries 2013; key PM and Jones AM (2009) The changingepidemiology of resistance. J Antimicrob Chemother 64 suppl1: i3-i10.Gonullu N, Aktas Z, Kayacan CB, Salcioglu M, Carattoli A,Yong DE, Walsh TR (2008) Dissemination of CTX-M-15 blactamase genes carried on Inc FI and II plasmids amongclinical isolates of Escherichia coli in a University Hospital inIstanbul, Turkey. J Clin Microbiol 46: 1110-1112.Yumuk Z, Afacan G, Nicolas-Chanoine MH, Sotto A,Lavigne JP (2008) Turkey: a further country concerned bycommunity-acquired Escherichia coli clone O25-ST131producing CTX-M-15. J Antimicrob Chemother 62: 284-288.Azap OK, Arslan H, Serefhanoğlu K, Colakoğlu S, ErdoğanH, Timurkaynak F, Senger SS (2010) Risk factors forextended-spectrum beta-lactamase positivity in uropathogenicEscherichia coli isolated from community-acquired urinarytract infections. Clin Microbiol Infect 16: 147-151.Sechi LA, Karadenizli A, Deriu A, Zanetti S, Kolayli F,Balikci E, Vahaboglu H (2004) PER-1 type beta-lactamaseproduction in Acinetobacter baumannii is related to celladhesion. Med Sci Monit 10: BR180-184.Celik AD, Yulugkural Z, Kuloglu F, Eroglu C, Torol S,Vahaboğlu H, Akata F (2010) CTX-M type extendedspectrum beta-lactamases in Escherichia coli isolates fromcommunity acquired upper urinary tract infections at auniversity in the European part of Turkey. J MicrobiolImmunol Infect 43: 163-167.Ramdani-Bouguessa N, Mendonc N, Leitao, Ferreira E, TazirM, Caniça M (2006) CTX-M-3 and CTX-M-15 extendedspectrum b-lactamases in isolates of Escherichia coli from ahospital in Algiers, Algeria. J Clin Microbiol 44: 4584-4586.Moissenet D, Salauze B, Clermont O, Bingen E, Arlet G,Denamur E, Mérens A, Mi
fluid (CSF) fistula caused by CTX-M-15 type ESBL-producing E. coli in an elderly male patient. A review of the English-language medical literature is emphasized on the ESBL-type, origin, patient characteristics, treatment, and outcome of E. coli menin
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