Citrobacter is a genus of Gram-negative bacteria that is commonly found in soil, water, and the intestinal tract of humans and animals. While usually harmless, some Citrobacter species can cause opportunistic infections, especially in immunocompromised patients. Citrobacter freundii is one of the most clinically significant species, known to cause infections of the urinary tract, respiratory tract, blood, and central nervous system. It has developed resistance to many antibiotics. Citrobacter infections in neonates can be serious, with meningitis being particularly dangerous. Diagnosis involves blood and CSF cultures, while treatment requires a combination of antibiotics and sometimes surgery.

1. Contents Main Topic Citrobacter
1. Citrobacter ………………………………………………………………………
2. Scientific classification ………………………………………………………
3. Descriptionandsignificance……………………………………………….
4. Genome structure……………………………………………………………..
5. Ecology……………………………………………………………………………..
6. Pathology………………………………………………………………………….
7. ApplicationtoBiotechnology……………………………………………..
8. Antibiotic resistance…………………………………………………………..
9. Clinical significance…………………………………………………………….
10.The Role of Citrobacter inClinical Disease of Children………..
11.Diagnosis…………………………………………………………………………..
12.Treatment…………………………………………………………………………
13.Citrobacter Disease inNeonates………………………………………..
14.BacteremiaDue toCitrobacter Species………………………………
PreparedBy Amjad Khan
SubmittedtoDear sir , Dr Muhammmad Riaz
Date 18/10/2015

2.  Citrobacter:
 Citrobacter is a genusof Gram-negative coliformbacteriainthe Enterobacteriaceaefamily.
 The species C.amalonaticus, C.koseri,andC. freundiican use citrate as a sole carbonsource.
 Citrobacterspeciesare differentiatedbytheirabilitytoconvert tryptophan toindole,
fermentlactose,anduse malonate.
 Citrobactershowsthe abilitytoaccumulate uraniumbybuildingphosphate complexes.
 These are acidophilic.
 These can alsosurvivesinacidicenvironmrnts
 These alsocause UTI.
Scientificname:Citrobacter
Higher classification:Enterobacteriaceae
Lower classifications:Citrobacterkoseri
Rank: Genu
Scientific classification
Kingdom: Bacteria
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Enterobacteriales
Family: Enterobacteriaceae
Genus: Citrobacter
Werkman and Gillen,1932

3.  Description and significance:
The Citrobacterspecies,includingCitrobacterfreundii,are aerobicgram-negativebacilli.Citrobacter
freundii are longrod-shapedbacteriatypically1-5μm inlength.Most C. freundii cellsare surrounded
by manyflagellausedtomove about,buta few are non-motile.Itshabitatincludesthe environment
(soil,water,sewage),food,andthe intestinal tractsof animalsandhumans. It belongstothe familyof
Enterobacteriaceae.
As an opportunisticpathogen,C.freundii isresponsibleforanumberof significantopportunistic
infections.Itisknowntobe the cause of a varietyof nosocomial infectionsof the respiratorytract,
urinarytract, bloodand several othernormallysterile sitesinpatients.C.freundiirepresents
approximately29%of all opportunisticinfections.Therefore,one of the chief reasonsmanydifferent
strainsand plasmidsof the C.freundii genome are beingsequencedisinordertofindantibioticsthat
can fightthese opportunisticinfections.
Surprisingly,thisinfectiousmicrobe inhumansplaysapositiverole inthe environment.C.freundii is
responsible forreducingnitrate tonitrite inthe environment.Thiscrucial conversionisanimportant
stage in the nitrogencycle.Andrecyclingnitrogenis veryessentialbecause the earth'satmosphere is
about85% nitrogen.Therefore,due toitsimportantcontributiontothe environmentisanother
motivationforsequencingthe genomeof C.freundii.
 Genome structure:
The cell structure of C.freundi islongandrod-shapedusually1-5μm inlength.The outside of the cell
containsmanyflagellausedformotality.Since C.freundiiisgram-negative bacteria,itcontainstwo
membranes(innerandouter).The periplasmicspace liesinbetweenthe twomembranes. The outer
membrane doesnotcontainanenergysource;butit doescontainmanyporinsembeddedwithinthat
helpthe organismacquire importantions.Unlike gram-positive bacteria,C.freundii cellsdonotcontain
a thick cell wall made upof peptidoglycan.
For metabolism, C.freundiihasanamazingabilitytogrow on glycerol asthe sole carbon and energy
source.In thisprocess,glycerol isfermentedbyadismutationprocess.Thisprocessrequirestwo
pathways. Inthe firstpathway,glycerol isdehydrogenatedbya NAD1-linkedglycerol dehydrogenase to
dihydroxyacetone.The dihydroxyacetoneisthenphosphorylatedandfunneledtoglycolysisby
dihydroxyacetone kinase .Inthe secondpathway,glycerol isdehydratedbythe coenzymeB12-
dependentglycerol dehydratasetoform3-hydroxypropionaldehyde .Thisproductisreducedtothe
majorfermentationproduct1,3-propanediolbythe NADH-linked1,3-propanediol dehydrogenase,
whichregeneratesNAD1.The dharegulonencodesthe fouressential enzymesof thesetwopathways.
Amazingly,the expressionof the dharegulonisonlyinducedwhenglycerol ispresent.
Cellsof C.freundii are alsoable tometabolize lactoseorcitrate as a carbon source
 Ecology:

4. Citrobacterfreundii are commonlyfoundinthe environment,mainlyinsoil,water,andsewages.They
are an indicatorof potential contaminationof water.Theyare alsofoundondifferentorgansof diseased
animals,includingmammals,birds,reptiles,andamphibians.Theyare not knowntointeractwithother
organims.
In the environment,C.freundii canconvertnitrate orthe ammoniumion(whichisa nitrogenatom
combinedwithfourhydrogenatoms) tonitrite;thisreactionoccursinthe environmentaswell aswithin
the digestive tractof humansand otheranimals.Afteritconvertsnitrate tonitrite inthe environment,
the nitrite isconvertedtonitrogen,andthisfinal stepcompletesthe nitrogencycle inthe earth's
atmosphere,whichismade upof 85% nitrogen.Thisorganism'secological role notonlyincludesits
importantrole inthe nitrogencycle,because itcanalsoaccumulate uranium(whichisthe basicmaterial
for nucleartechnology)bybuildingphosphate complexes.
Citrobacterfreundii hasalsobeeninvestigatedforbiodegradationof tannicacidusedin tannerys
 Pathology:
As an opportunisticpathogen,Citrobacterfreundiiisoftenthe cause of significantopportunistic
infections,meaningthatitdoesnot generallycause diseaseinhealthyhumanhosts.Theyonlyaffect
patientswithaweakimmune system,signifyingthattheyneedan"opportunity"toinfectthe person.
Therefore,inpatientswithasuppressedimmune system, Citrobacterspeciesare knowntocause a wide
varietyof nosocomial infectionsof the respiratorytract,urinarytract, andthe blood.Hepatic,biliary
and pancreaticdisease are alsocommondiseasesthatare causedby C. freundii.The biliarytractisthe
mostcommon site of infectionbythe C.freundii bacilli.
One fatal disease thatC.freundii hasbeenassociatedwithisneonatal meningitis.Neonatal meningitisis
the inflammationof the meninges(thesystemof membraneswhichsurroundthe CNS) due tobacterial
invasion .The mortalityrate of Citrobactermeningitisisunacceptablyhigh,withdeathratesof patients
rangingfrom25 to 50 %.Moreover,seriousneurological problemsstillpersistin75% of survivors.Inthis
disease,Citrobacterfreundii isable topenetrate the blood-brainbarrierthatconsistsof the choroid
plexusepitheliumandthe braincapillaryendothelium.
TestsperformedbyBadgeret.al inthe article “Citrobacterfreundii InvadesandReplicatesinHuman
Brain MicrovascularEndothelialCells”suggestthatbacterial proliferationof C.freundii takesplace atthe
intracellularlevel,whichhadbeencontraryto the general scientificthought.The findingsindicate that
C. freundii traversesvacuoles,replicatesandisreleasedintothe basolateral side of the humanbrain
microvascularendothelial cells(HBMEC) inorderto cross the blood-brainbarrier.Furtheranalysismay
potentiallyallow fortherapeuticstrategiestotreatinfections.There isstill notherapeutictreatment
available .
 Application to Biotechnology:
In the Biotechindustry,Citrobacterfreundii producesmanyimportantenzymes.The firstenzymesit
producesisphosphatase.Phosphatase activityof C.freundii hasbeenpostulatedtobe involvedinlead

5. accumulation,whichcanhave playan importantrole inthe Biotechindustry.The phosphataseactivity
of C.freundii hasbeenalsodiscoveredtohave resistance tosome diagnosticreagents.
The purificationandcharacterizationof bacterial selenocysteine beta-lyase,anenzyme which
specificallycatalyzesthe cleavage of L-selenocysteine toL-alanine,hasbeenpurifiedfromCitrobacter
freundii.The enzyme ismonomericwithamolecularweightof ca.64,000 and contains1 mol of
pyridoxal 5'-phosphateasa cofactor permol of enzyme.The enzymealsocatalyzesthe alpha,beta
eliminationof beta-chloro-L-alanine toformNH3,pyruvate .
C. Freundii strainsalsocarrya plasmidthatencodesclass1 AmpCcephalosporinase.Theseenzymescan
hydrolzye inactivatenewcephamycinsandcephalosporins
 Antibiotic resistance:
Citrobacterspeciesare acommoncause of nosocomial infectionsassociatedwithpatientsthatare
undergoingprolongedhospital treatments.C.freundii hasrecentlybeenreportedtoexpressresistance
to broad-spectrumantibiotincsincludingpiperacillin,piperacillintazobactam, vancomycinand
cephalosporins.Isolationof ceftriaxone-resistantCitrobacterfreundii (CRCF) hasbeenassociatedwith
the overprescribedbroadspectrumantibiotics.
The emergingnewCRCFstrainscouldsuggestinductionordepressionof resistance genesaswell as
eliminationof competingorganisms.CRCFhasbeenmostly isolatedfrompatientswithsignificant
comorbiditiesincludingAIDS,peripheral vasculardisease,andcerebrovasculardisease.The usage of
fluoroquinolone hasalsobeenreportedtohave noaffectagainstthe isolationof CRCF.
Clinical significance:
These bacteriacan be foundalmosteverywhere in soil, water,wastewater,etc.Theycanalso be found
inthe humanintestine.Theyare rarelythe source of illnesses,exceptforinfectionsof the urinary
tract and infantmeningitis andsepsis.
C. freundiistrainshave inducible ampCgenesencodingresistance to ampicillinandfirst-
generation cephalosporins.Inaddition,isolatesof Citrobactermaybe resistanttomanyother antibiotics
as a resultof plasmid-encodedresistance genes.
 The Role of Citrobacter inClinical Disease of Children:
Variousspeciesof Citrobactermaycause infectionsinneonatesandimmunocompromisedhosts.
Citrobacterkoseri (formerlyCitrobacterdiversus) isbestknownasthe cause of sepsisandmeningitis
leadingtocentral nervoussystem(CNS) abscessesinneonatesandyounginfants.Earlyonsetandlate-
onsetinfectionsoccurasfor otherneonatal bacterial infections.
The majorityof cases are sporadic,withno clearsource of infection.A few have beenconfirmedtobe
verticallytransmitted,andnosocomial outbreakshave occurredinneonatal care units.The
pathophysiologyisnotwell understood,butasurface proteinhasbeenidentifiedasapossible virulence

6. factor amongstrainsthat cause citrobacterbrain abscesses inneonates.Despite improvementsin
diagnosticimagingtechniques,surgery,andantibiotictherapy,approximatelyone-thirdof infantswith
abscessesdie,andone-half sustainCNSdamage.Inthisarticle,the taxonomy,epidemiology,
pathogenesis,diagnosis,treatment,andoutcome of citrobacterdisease inchildrenare reviewed.
 Diagnosis:
Classicsignsandsymptomsof sepsisandmeningitisthatoccurin otherneonatal infectionsapplyto
citrobacterdisease -creasedoral intake,seizures,jaundice, vomiting,lethargy,hy- potonia,abnormal
sighingrespirations,seizures,andabulgingfontanelle.Infantswithsuchsignsandsymptomsshould
have a complete evaluation,includingbloodculture,urineculture lumbarpuncture forCSFchemistries,
cytology,gramstaining,andculture.
 Treatment:
Neonatal citrobacterinfectionsof the CNShave beentreatedbyavarietyof methods,the resultsof
whichhave beengenerallydisappointing.Antibioticsremainthe mainstayof therapythoughadjunctive
surgical drainage hasalsobeenwidelybutnotuniversallyappliedinsuchcases.Nostandardtherapeutic
regimenhasbeenestablishedassuperior.Antibioticsandsurgeryare usuallyusedincombination.
 Citrobacter Disease inNeonates:
Age at diagnosis.In1981, Graham and Band summarized74cases of neonatal meningitisdue to
Citrobacterspecies[73],includingafewpreviouslyreportedbythe SecondNeonatal Meningitis
Cooperative StudyGroup[74].Amongthe 56 additional casesreviewedforthe currentarticle,there
were 54 infantswithclinical disease.Fifty-one hadmeningitis,one hadbacteremia,andtwohadsepsis,
but itwas not clearwhethermeningitiswasalsopresent.Twowere onlycolonizedbutare included
since theyare among the small numberof reports verifyingvertical transmissionof Citrobacter.
 BacteremiaDue toCitrobacter Species:
Citrobacterspeciesare aerobic,gram-negativebacilli commonlyfoundinwater,soil,food,andthe
intestinal tractsof animalsandhumans.These organismscause awide spectrumofinfectionsinthe
urinarytract, respiratorytract,wounds,bone,peritoneum, endocardium, meninges,andintestines.
Citrobacterbacteremiaisarare infection;we are aware of onlytworeportedseriesinthe English-
language literature [2,3].
Therefore,little isknownaboutcitrobacterbacteremiaintermsof incidence,associatedunderlying
diseases,primarysitesof infection,andoutcome.AlthoughdifferencesbetweenCitrobacterfreundii and
Citrobacterdiversusintermsof antimicrobial susceptibilityhave beencited[3-6],thatthese differences
existwhenthese organismsare the cause of bacteremiaisunclear.Citrobacterhasbeenreportedtobe
frequentlyassociatedwithpolymicrobial bacteremia],butthere are nodata that explainthis
phenomenon.

7. Afterthe the third-generationcephalosporinswere introduced,multidrugresistantstrainsof
Enterobacteremergedasa cause of bacteremia butno data are available onCitrobacterspecies.
References:
1. LipskyBA, HookIII EW, SmithAA, et al.:Citrobacter infections inhumans:Experience at the Seattle Veterans
Administration MedicalCenter anda review of the literature. RevInfect Dis1980;2:746-760.
2. Jump up^ L. E. Macaskie, R. M. Empson, A. K. Cheetham, C. P. Grey, A. J. Skarnulis (1992). "Uranium bioaccumulation
by a Citrobacter sp. as a result of enzymicallymediated growth of polycrystalline HUO2PO4". Science 257 (5071): 782–
784.Bibcode:1992Sci...257..782M. doi:10.1126/science.1496397. PMID 1496397.
3. Jump up^ V. Drelichman;J. D. Band (1985). "Bacteremias due to Citrobacter diversus and Citrobacter freundii.
Incidence, risk factors, and clinical outcome". Archives of Internal Medicine 145 (10): 1808–
1810. doi:10.1001/archinte.145.10.1808.PMID 3899035.
PreparedBy Amjad Khan Afridi
Submittedto Dear sir, Doctor
19/10/2015