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Antibiotics and Neonatal Sepsis Workup

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Brief review of commonly used antibiotics in the NICU …

Brief review of commonly used antibiotics in the NICU
followed by clinical applications and sepsis workup

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  • The widespread use of antibiotics in neonates may contribute to abnormal gut colonization.Antibiotic exposure also may delay beneficial colonization with normal gastrointestinal flora, and promote proliferation of pathogenic and antibiotic-resistant organisms. The increase in potentially pathogenic organisms and decrease in normal gut flora coupled with impairment in the intestinal epithelial barrier may predispose preterm neonates to NEC.There were several limitations with this study, they did not collect data on the use of H2-blockers (a known independent risk factor for NEC). Also, it is possible that duration of antibiotic exposure was a marker of illness severity, and the inclusion of an illness severity score may have been helpful in differentiating this from the true effect of antimicrobial exposure. Lastly, inclusion of a larger population (more than one hundred twenty four cases) would have likely improved validity of their results.
  • Prolonged initial empirical antibiotic therapy is associated with a 2-fold higher incidence of LOS, NEC, or death, and with a 3-fold higher incidence of LOS alone. Importantly, these associations persisted after adjusting for proxy severity of illness indicators previously identified as predictors for mortality.
  • Transcript

    • 1. Prepared ByM A G E D Z A K A R I ANeonatologistAntibiotics2013
    • 2. Bacterial pathogens of humanare classified as Gram-positive or Gram-negative, some notableexceptions being themycoplasmas, chlamydiae, spirochetes and themycobacteria.Medically Important Bacteria
    • 3. CocciGram POS BacteriaAerobic Anaerobic Aerobic AnaerobicStaphylococciStreptococciEnterococciListeria ClostridiumRodsMedically Important Bacteria
    • 4. CocciGram NEG BacteriaAerobic(Facultative Anaerobic)Anaerobic AnaerobicNeisseriaRodsAerobic(Facultative Anaerobic)Enterobacteriaceae(Lactose Fermenters)E coliKlebsiella(Non-Lactose Fermenters)SalmonellaShigellaBacteroidesPseudomonasVibrioHemophilusMedically Important Bacteria
    • 5. Intracellular BacteriaChlamydiaRickettsiaMiscellaneous / PoorlyStaining SpeciesAcid Fast StainMycobacteriaPoorly StainingMycoplasmaLegionellaMedically Important Bacteria
    • 6. Mechanism of Action of Antibiotics
    • 7. Mechanism of Action of AntibioticsAntibacterial agents are directedagainst specific targets notpresent in human cells to limittoxicity to the host and maximizechemotherapeutic activityaffecting invading microbes only.
    • 8. • Bactericidal drugs KILL the bacteria that are within theirspectrum of activity; bacteriostatic drugs only INHIBITbacterial growth.• Bactericidal activity is necessary for patients with alteredimmune systems (e.g., neutropenia), protected infectious foci(e.g., endocarditis or meningitis), or specific infections(e.g., complicated Staphylococcus aureus bacteremia).Mechanism of Action of Antibiotics
    • 9. Inhibition of Cell-wall SynthesisOne major difference betweenbacterial and human cells is thepresence of a rigid CELL WALLexternal to the cell membrane inbacteria protecting the usuallyhyperosmolar bacterial cells (relativeto the host environment) fromosmotic rupture.
    • 10. • Antibiotics act at any step of the synthesis of cell wall units(peptidoglycans) lead to inhibition of bacterial cell growth and, in mostcases, to CELL DEATH (bactericidal).• Antibacterial agents act to inhibit cell-wall synthesis are:o β-Lactam antibiotics acting on penicillin-binding proteins (PBPs) (penicillins,cephalosporins, and carbapenems).o Glycopeptides (vancomycin and teicoplanin).o Bacitracin.Inhibition of Cell-wall Synthesis
    • 11. Inhibition of Protein Synthesis• Most of protein synthesis inhibitors selectively interact with bacterialribosomes that are different in composition between bacterial and humancells.o Aminoglycosides (gentamicin, tobramycin, and amikacin).o Macrolide antibiotics (erythromycin, clarithromycin, and azithromycin).o Lincosamides (clindamycin).o Linezolid.
    • 12. Inhibition of Bacterial MetabolismoSulfonamides (sulfisoxazole, sulfadiazine, andsulfamethoxazole).oTrimethoprim.For infants > 6 wks of age
    • 13. Inhibition of Nucleic Acid SynthesisoQuinolones (nalidixic acid and its fluorinated derivatives(ciprofloxacin, and levofloxacin).oRifampin.oMetronidazole (active only against anaerobic bacteria andprotozoa).
    • 14. CHEMOTHERAPEUTICS MONOGRAPH
    • 15. Penicillins• BACTERICIDAL cell wall synthesis inhibitors.• Poorly penetrate into CSF UNLESS meninges are inflamed.• Destroyed by β-lactamase enzyme produced by manybacteria including Staph., E. coli and H. influenzae.• β-lactamase is overcomed by adding a β-lactamaseinhibitor (sulbactam, clavulanate or tazobactam).
    • 16. Ampicillin+SulbactamAmoxycillin+ClavulanatePiperacillin+Tazobactam
    • 17. Broad Spectrum Penicillino AMPICILLIN is the preferred penicillin forinitial EMPIRICAL THERAPY for neonatalsepticemia and meningitis because it providesbroader antimicrobial activity with good safety.o Side effects include nonspecific rashes, transaminases,  creatinine, alteration ofintestinal flora, and diarrhea.UNASYN
    • 18. Broad Spectrum Penicillino For therapy for bacterial meningitis, a doseof at least 200 mg/kg/day should beused, although some consultants usedosages as high as 300 mg/kg/day.o CSF concentrations is inhibitory to group Bstreptococci (GBS) and L. monocytogenesbut not E. coli.UNASYNAmpicillin + Sulbactam
    • 19. AugmentinAmoxacillin + ClavulanateBroad Spectrum Penicillin
    • 20. Broad Spectrum Penicillino Amoxicillin has similar properties to ampicillin, and there is little to choosebetween the two antibiotics when given IV, although amoxicillin is said to bemore rapidly “bactericidal”.o Clavulanic acid has no antibiotic properties of its own but inhibits many b-lactamase enzymes.o Administration to women in preterm labor is associated with a higher riskof neonatal NEC.o Amoxicillin shows better bioavailability than ampicillin when taken by mouthGras-Le Guen C, Boscher C, Godon N, et al. Therapeutic amoxicillin levels achieved with oraladministration in term neonates. Eur J Clin Pharmacol 2007;63:657–62.
    • 21. Piperacillin / TazobactamUSESNon-CNS infections, caused bysusceptible β-lactamase producingbacteria (e.g. E. coli, Enterobacter,Klebsiella, H. Influenzae, Proteus,Pseudomonas and Staph. as well as GBS.Na content is 2.35 mEq per gram of piperacillin
    • 22. Advantages and Disadvantages of the AminoglycosidesAdvantages DisadvantagesFamiliarity among physicians Relatively narrow therapeutic ratioBroad spectrum of activityToxicities: nephrotoxicity, ototoxicity,neuromuscular blockade (rare)Rapid bactericidal actionPoor penetration into certain bodyfluids such as CSF and bileRelatively low cost Lack of enteral absorptionChemical stability Inactivity against anaerobes reactionsRare association with allergic reactionsSynergism with b-lactam antibiotics andvancomycinAminoglycosides• Include gentamycin, tobramycin and amikacin.
    • 23. Aminoglycosides Ototoxicity• Ototoxicity can be cochlear and/or vestibular damage.• Gentamicin causes more vestibular damage while amikacin causesmore auditory damage.• Reports on hearing loss in children who received gentamicin asneonates are scanty. Aminoglycoside induced hearing loss contributesto only a small proportion of the deafness in the community.• Individuals with certain mutations in mitochondrial DNA (seen inup to 50% of cases and are exclusively maternally inherited), havehigher susceptibility to aminoglycoside induced hearing loss.
    • 24. • Approximately 8-26% of patients who receive aminoglycosides for>7-10 days develop mild renal impairment which is almost alwaysreversible.• It usually presents as gradually worsening non-oliguric renal failure.• Severe acute tubular necrosis may occur rarely.• Toxicity is increased by use of other nephrotoxic drugs e.g. lasixand vancomycin, hypokalemia, hypovolemia and hypomagnesemia.Aminoglycosides Nephrotoxicity
    • 25. Gentamicin AmikacinAmikacin has almost similar spectrum to gentamicin and is safe in children. It may beeffective against some gentamicin-resistant bacteria and so is more suitable whengentamicin resistance rates are high.Comparative Information on Aminoglycoside Toxicity (AustralianMedicines Handbook)Vestibular Cochlear NephrotoxicityAmikacin + ++ ++Gentamicin ++ ++ ++
    • 26. Neither ototoxicity nornephrotoxicity were notedin a Cochrane review doneto assess safety andefficacy of once dailydosing of gentamicin,based on 11 studies (n=574) in neonates withsepsis2006
    • 27. • Serum-aminoglycoside concentration should be measured in allchildren receiving parenteral aminoglycosides and must bedetermined in neonates or if there is renal impairment.• Blood samples should be taken just before the next dose isadministered (‘trough’ concentration). If the trough concentration ishigh, the interval between doses must be increased.• Blood samples should also be taken ~1 hour after IM or IVadministration (‘peak’ concentration). If the peak concentration ishigh, the dose must be decreased.
    • 28. • Urea and creatinine should be monitored prior totreatment with aminoglycosides and twice weeklythereafter in stable patients (more often if renalimpairment is present at baseline or develops duringtherapy).• The dose interval is determined by the serum gentamicintrough level measured at 22 hours from commencement ofthe dose.
    • 29. Third Generation CephalosporinsCephalosporinsThe third generation cephalosporins have excellent activity against Gram–ve organismsCephalosporins are not effective against Listeria and Enterococci.Theoretical advantages of third-generation cephalosporins1. Low toxicity2. Unnecessary measurement of serum level
    • 30. Cefoperazone / SulbactamClaforanCefotaximeFortumCeftazidimeThird Generation Cephalosporins
    • 31. • Cefotaxime is typically not used alone for initialtherapy in suspected sepsis because of its pooractivity against L. monocytogenes and enterococci.• The addition of ampicillin provides antibacterialcoverage against these organisms.• One potential problem associated with the routine useof this drug is the possible emergence ofcefotaxime-resistant gram-negative bacteria in theNICU.ClaforanCefotaxime
    • 32. • There’s a higher neonatal mortality rate with theuse of cefotaxime compared with gentamicin.• Resistance develops rapidly when cefotaxime isused for empiric therapy.• So, it seems wise to restrict its use to infantswith meningitis due to susceptible organisms.Clark RE, Bloom BT, Spitzer AR, Gerstmann DR: empiric use of ampicillin andcefotaxime compared to ampicillin and gentamicin is associated with an increased risk ofClaforanCefotaxime
    • 33. CeftriaxoneNeonatal sepsis and meningitis by G-ve organisms (e.g. E. coli,Pseudomonas, Klebsiella and H.influenza).Gonococcal infections.Not recommended for use withhyperbilirubinemia, hypoalbuminemia, acidosisand impaired bilirubin binding; it displacesbilirubin from albumin binding sites.Concurrent use of Ca-Containing solutions innot recommended within 48h of the lastadministration of ceftriaxone.
    • 34. Fourth Generation CephalosporinsUSESG-ve organisms (e.g. E.coli, H.influenza,Enterobacter, Klebsiella, Morganella, Neisseria,Serratia and Proteus species), esp. Pseudomonasaeruginosa that is resistant to 3rd generationcephalosporins.G+ve organisms (e.g. Strep pneumonia, Streppyogenes, Strep agalactiae and Staph aureus).ADVERSE EFFECTSRash, EosinophiliaDiarrhea,  ALT, AST.Positive Coombs’ test
    • 35. Carbapenems (Imipenem and Meropenem)• Carbapenems are structurally related toβ-lactam antibiotics but resistant to β-lactamases. They are effective againststreptococci, enterococci, pneumococci, methicillin-sensitive S aureus, gram-negativerods except stenotrophomonas.• They treat both aerobic and anaerobicbacteria.• MRSA is not susceptible.
    • 36. • Both Tienam and Meronempenetrate well into the CSF.• Tienam treatment in infantswith bacterial meningitis waspossibly associated with drug-related seizure activity, that isnot seen with Meronem.• Lastly, they can increase the riskof superficial or invasive fungaldisease because of their broadspectrum of activity.
    • 37. Glycopeptides• Include Vancomycin and Teicoplanin.• BACTERICIDAL.• Synergistic bacterial killing has beendemonstrated with aminoglycosides.
    • 38. VancomycinMONITOR Renal function during treatment.ADVERSE EFFECTSNephrotoxicity and ototoxicity.Rash and hypotension (red man syndrome),resolves within minutes to hours  slow therate of infusion.Neutropenia (if administrated > 3 wks).Vancomycin does not readily penetrate the CSFunless the meninges are inflamed.Excreted unchanged in the urine.Bactericidal
    • 39. TeicoplaninUSESActive against1. Many G+ve anaerobes (particularly Clostridium)2. Most Listeria, enterococci and staphylococci (including MRSA)Rifampicin may sometimes be synergistic in the management ofstaphylococcal infection.Vancomycin resistant organisms are sometimes sensitive to teicoplanin.ADVERSE EFFECTSLeucopenia and thrombocytopenia.Disturbances of liver function.
    • 40. LinezolidOnly used to treat VRSA, and VREThrombocytopenia occurs in 2% of patientswho were on the drug for > 2 wksCBC should be obtained weekly while on linezolidLinezolid is a last resort drug and its use is limitedto prevent development of resistanceBacteriostaticRapid and nearly completeabsorption after oraldosing.
    • 41. Macrolides• Include erythromycin, clarithromycin and azithromycin.• Effective in atypical pneumonia caused by mycoplasma,chlamydia and legionella.
    • 42. AzithromycinADVERSE EFFECTS / PRECAUTIONSDiarrhea and/or vomiting (5-12%).Irritability, rash and blood in stool.Pyloric stenosis ?!Pertussis: 10 mg/kg/dose PO Q24h (5 d)Chlamydia trachomatis Conjunctivitis and Pneumonitis: 20 mg/kg/dose PO Q24h(3 d)IV Dose: 5 mg/kg/dose Q24h over 60 min.
    • 43. ClindamycinPseudomembranous colitis is rare in pediatric practiceNo significant activity against gram –ve bacteriaEffective against gram +ve aerobes andanaerobes.Should NOT be used in ttt of meningitis (poor CSF penetration)Eliminated primarily by the liverWidely distributed throughout the bodyincluding pleural fluid, ascites, bone, and bile
    • 44. MetronidazoleUSESMeningitis, ventriculitis and endocarditis causedby Bacteroides fragilis and other anaerobesresistant to penicillin.Serious intra-abdominal infections and C. difficilecolitis.T. vaginalis infections.ADVERSE EFFECTS PRECAUTIONSCarcinogenic?!!Seizures, sensory polyneuropathy.Brownish discoloration of urine.
    • 45. RifampinADVERSE EFFECTS / PRECAUTIONSOrange/red discoloration of body secretions.Potent CP450 enzyme inducer;  Effect of aminophylline, fluconazole,morphine, phenobarbital, phenytoin, propranolol.Used in combination with vancomycin oraminoglycosides for ttt of persistent systemicstaphylococcal bacteremia or ventriculitis in highrisk neonates.Eliminated in bileBacteriocidal
    • 46. CiprofloxacinMost anaerobes are not susceptible.Avoid use with MRSA (resistant).
    • 47. ADVERSE EFFECTS PRECAUTIONSFluoroquinolones may damage growing cartilage causingarthropathy thus not routinely recommended for patientsunder 18 years of age.However, the arthropathy is reversible and there is a growingagreement that fluoroquinolones may be used in children insome cases (eg, for treatment of pseudomonal infections inpatients with cystic fibrosis).Ciprofloxacin
    • 48. PRINCIPLES OF ANTIBACTERIAL CHEMOTHERAPY
    • 49. Although both ampicillin and gentamicin are stillused frequently for treating sepsis, antibioticsshould be prescribed according to the bacterialprevalence and resistance patterns of each unit.It is more important to know the antibioticsresistance patterns of ones own NICU.Information on resistance pattern can usually beobtained from hospital microbiology laboratories.
    • 50. GET SMART principles can be applied toempiric use (when infection is suspectedbut cultures are pending), definitive use(when an organism has been identified), orfor prophylaxis (e.g. prevention ofpostoperative infections).
    • 51. Principles and Strategies of AntimicrobialStewardship in the Neonatal Intensive Care UnitSemin Perinatol 36:431-436 © 2012 Elsevier Inc.
    • 52. Get Smart for Health Care Campaign for the NICUGet Smart Principles ExamplesAccurately identify patients whoneed antibiotic therapyObtain 2 blood cultures for evaluation of LOSbefore starting antibioticsUse local and regionalantibiogramsAvoid use of meropenem for empiric treatment ofsuspected LOS if rates of multidrug-resistantgram-negative bacilli are lowAvoid therapy with overlappingactivityAvoid simultaneous use of metronidazole andmeropenem to treat NECGive the right dose and intervalof drugTarget vancomycin trough to 15-20 mg/L to treatpneumonia caused by MRSA
    • 53. Get Smart for Health Care Campaign for the NICUGet Smart Principles ExamplesReview culture results and adjustantibioticsReview microbiology results at transitions ofcare (eg, sign out, weekend crosscoverage) andnarrow antibiotic coverage promptlyMonitor for toxicity and adjusttherapy accordinglyAdjust antibiotic dose for patients withdeteriorating renal functionStop therapy promptly if indicatedby culture resultsDiscontinue antibiotics after 48 hours if bloodcultures are negative and ongoing infection isnot suspected
    • 54. • We first must do everything possible to ascertain whether theinfant truly has an infection that requires antibiotictherapy.• Culture of blood is performed routinely, but 2 blood cultures ofat least 0.5 mL each should be obtained before antibioticinitiation. A larger volume of blood (1-2 mL) may furtherincrease organism recovery and reduce the likelihood oftreating contaminants.Before StartingAntibiotics—Diagnostic Strategies
    • 55. • The need for a lumbar puncture is often debated becausemeningitis is a rare occurrence among otherwise stable preterminfants with RDS.• However, meningitis can be present at birth, and when sepsis isstrongly suspected, a lumbar puncture should be performed. Asthe incidence of early-onset E coli infection increases in preterminfants, performance of a lumbar puncture is even more importantto help guide antibiotic therapy.• Knowing that the CSF culture is sterile before initiation ofantibiotic therapy can help shorten the duration of treatment.Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP, et al. Early onset neonatal sepsis: theburden of group B Streptococcal and E coli disease continues. Pediatrics 2011;127:817-26.Weiss MG, Ionides SP and Anderson CL (1991): Meningitis in premature infants with respiratory distress: role ofadmission lumbar puncture. J Pediatr ;119:973-5.
    • 56. • Sterile blood culture results should beinterpreted as no active infection at that site,and antibiotics should be stopped by 36 and 48hours in suspected early and late-onsetinfections, respectively. Pneumonia, however, isoften a reason for prolonged use of antibiotictherapy because it occurs despite sterile bloodand CSF cultures.Finally, one does need to trust the culture results
    • 57. Before StartingAntibiotics—Diagnostic Strategies• Obtaining urine for culture is notrecommended at birth because urinary tractinfections do not occur so early.However, with a lumbar puncture, a urineculture is a necessary part of the evaluationfor possible late-onset sepsis.
    • 58. Evaluation of asymptomatic infants <37 weeks’gestation with risk factors for sepsisAAP 2012
    • 59. Evaluation of asymptomatic infants ≥37 weeks’gestation with risk factors for sepsisAAP 2012
    • 60. Evaluation of asymptomatic infants ≥37 weeks’gestation with risk factors for sepsisInadequate treatment is defined as the use ofan antibiotic other than penicillin, ampicillin,or cefazolin or if the duration of antibioticsbefore delivery was <4 h.AAP 2012
    • 61. • Antibiotics are disposed of by hepatic elimination(metabolism or biliary elimination), by renal excretion of theunchanged or metabolized form, or by a combination of thetwo processes.• The most practical application of the mode of excretion of anantibiotic is in adjusting dosage when elimination capability isimpaired.Pharmacokinetics of Antibiotics
    • 62. Antibiotics Dose Adjustments In Renal ImpairmentAntibiotic Major route of excretion Dose adjustment with renal impairmentAminoglycosides Renal YesAzithromycin Biliary NoCefepime Renal YesCeftazidime Renal YesCeftriaxone Renal/Biliary Modest reduction in severe renal impairmentCiprofloxacin Renal/Biliary Only in severe renal impairmentClarithromycin Renal/Biliary Only in severe renal impairmentLinezolid Metabolism NoMetronidazole Biliary NoPiperacillin Renal Only with ClCr of < 40 mL/minTMP-SMX Renal/biliary Only in severe renal InsufficiencyVancomycin Renal Yes
    • 63. Dose in Renal ImpairmentCr Cl 26-50 mL/min/1.73m2  use normal dose Q12hCr Cl 10-25 mL/min/1.73m2  use half normal dose Q12hCr Cl <10 mL/min/1.73m2  use half normal dose Q24hDOSE IN SEPSIS:20 mg/kg/dose IVI Q12hAn empirically derived formula to estimate CrCl:In Preterm neonates =In Term neonates =Antibiotics Dose Adjustments In Renal Impairment
    • 64. Early-onset Sepsis (GBS - E.coli - Listeria)• Unasyn + Amikin ± 3rd generation cephalosporin (Claforan orFortum; if patient is critically ill).Late-onset Sepsis• CONS - MRSA: Vancomycin – Targocid – Zyvox.• Enterococci (associated with indwelling catheters, meningitis,NEC): are usually resistant to cephalosporins, penicillins.Treatment requires the synergistic effect of an aminoglycosidewith ampicillin or vancomycin. Zyvox is also effective.Choosing the Right Antibiotics
    • 65. • Pseudomonas: treatment requires thecombination of 2 agents active againstpseudomonas; Fortum – Tazocin – Gentamicin– Tobramycin (best aminoglycoside activity).• Enterobacter: Maxipime or Meronem andGentamicin.• Klebsiella: Claforan – Meronem – Gentamicin.Choosing the Right Antibiotics
    • 66. • When adding a second antibacterial agent, it should beacting through a different mechanism of action from that ofthe first is added to prevent the emergence of these resistantmutants (e.g., imipenem plus an aminoglycoside or afluoroquinolone for systemic Pseudomonas infections).• However, since resistant mutants have emerged aftercombination chemotherapy, this approach clearly is notuniformly successful.Antibiotic Combinations
    • 67. • Antibiotics may be combined to extendtheir antimicrobial spectrum:1. Penicillin + Third generation Cephalosporin2. Meronem + Vancomycin3. Penicillin + Aminoglycoside + Flagyl or Dalacin-CAntibiotic Combinations
    • 68. Drugs Not Routinely Used in NeonatesDrug Potential Adverse EffectTetracycline Depressed bone growth and teeth abnormalitiesChloramphenicolCirculatory collapse, impaired mitochondrial proteinsynthesis, bone marrow aplasia; gray baby SyndromeSulfonamideBilirubin displacement with rare but possible kernicterus;increased risk of hemolysis in G6PD-deficient infantsTrimethoprim/sulfamethoxazoleSame as sulfonamide; bilirubin displacement with rare butpossible kernicterus; increased risk of hemolysis in G6PD-deficient infantsCeftriaxoneHighly protein bound, potential to displace bilirubin;cannot be co-administered with calcium containing fluids
    • 69. Duration of Therapy• Duration of antibiotics therapy differs according to the siteof infection and the causative organism.• For bacteremia, most organisms require treatment withantibiotics for at least 7 days (e.g. for CONS) up to 14 days(e.g. for Pseudomonas).• For Meningitis, the usual treatment course is 14-21 days.• Duration of therapy is 3-4 weeks for osteomyelitis.
    • 70. Biomarkers as a Guide For Antimicrobial Therapy
    • 71. • Biomarkers, such as procalcitonin and B-natriureticpeptide, used for the early detection of bacterial infectioncould guide treatment and reduce misuse of antibiotics.• CRP is an acute phase protein synthesized by the liver. Theplasma half-life of CRP is constant (~19h) with the soledeterminant of circulating CRP concentration is its synthesisrate.• Serum levels of CRP increase ~4-6 h after the start of theinflammatory process, peaking by 48h and eventuallysubsiding once the stimulus disappears, often prior to theclinical resolution of sepsis.
    • 72. • In septic patients, an increase in CRPconcentrations in the first 48 h was associatedwith ineffective antimicrobial therapy.• Persistently increased serum CRPconcentrations after antimicrobial therapy wereindicative of poor outcome and inadequateprescription of antibiotics in critically illpatients.