antibiotics sepsis infection 2021-1.pptx

Sepsis

1. بسم الله الرحمن الرحيم Antibiotic therapy in critically ill patients By Mohamed Saad Elsyaad lecturer of critical care .MD PhD Faculty of medicine ,Alexandria university

2. Is it important ?

3. In 1928 Scottish bacteriologist  Alexander Fleming   noticed that colonies of bacteria growing on a  culture  plate had been unfavorably affected by a  mold ,  Penicillium notatum , which had contaminated the culture. A decade later British biochemist  Ernst Chain , Australian pathologist  Howard Florey , and others isolated the ingredient responsible, penicillin, and showed that it was highly effective against many serious bacterial infections

4. Antibiotics came into worldwide prominence with the introduction of  penicillin  in 1941.

5. The most important discovery in medicine

6. A battle between 2 armies

7. Winners

8. Losers

9. Pseudomonas MDR 25 to 60% mortality Klebsiella MDR upto 50% Acinetobacter MDR upto 35% MRSA upto 50%

10. Economic burden Estimated to be millions of dollars

11. Classification according to spectrum Antibiotics can be categorized by their spectrum of activity N arrow : Narrow-spectrum agents (e.g., penicillin G) affect primarily  gram-positive bacteria .  Broad : Broad-spectrum antibiotics, such as tetracyclines and  chloramphenicol , affect both gram-positive and some  gram-negative bacteria E xtended: An extended-spectrum antibiotic is one that, as a result of chemical modification, affects additional types of bacteria, usually those that are gram-negative.

12. Gram stain Significance ??

13.   G ram-positive  :  are bacteria that have cell walls consisting of a thick meshwork of peptidoglycan [a peptide-sugar polymer] G ram-negative : bacteria that have cell walls with only a thin peptidoglycan layer.

14. Gram positive cocci Staphylococci catalase positive includes aureus, and epidermidis, MRSA and MSSA, Streptococci catalase negative  Streptococcus pneumonia. (syndrome ??) Enterococci catalase negative Enterococcus faecalis .

15. Staphylococci further subdivided into coagulase positive (S aureus ) leading to pneumonia – endocarditis –osteomyelitis –TEN syndrome and TSS . coagulase negative epidermidis usually associated with Catheter associated infection .

16. Austrian syndrome Rare but deadly triad Disseminated infection Consist of : meningitis endocarditis pneumonia

17. Catalase enzyme : common enzyme found in nearly all living organisms exposed to o2 . Catalyze the H202 to h20 to oxygen . It is very important enzyme protect bacteria cell from oxidative damage by reactive species

18. Gram negative cocci Neisseria gonorrhea Neisseria meningitides (syndrome ?? )

19. Waterhouse Fredriksson Life threating infection by Neisseria meningitides Affection of adrenal gland due bleeding and necrosis Symptoms CNS infection sign Rash throughout the body DIC Septic shock

20. Gram positive bacilli

21. Gram positive bacilli Spore forming :clostridium (CL difficle –perfringens – tetani) Non Spore forming ( listeria –diphtheroid )

22. Gram negative bacilli E Coli Proteus Pseudomonas aeruginosa klebsiella Salmonella Hemophilus influenzae

23. Atypical They did not get covered with gram stain so they are not gram positive or negative Legionella Chlamydia Rickettsia

24. Water supply and air conditioning system Mortality may be up to 80% Very young age less than 1y and old age very prone Symptoms: Lethargy and confusion Fibro purulent pneumonia mostly unilateral Diarrhea Fever most common symptom

25. Complications DIC Hyponatremia (unclear but may be due to SIADH) with increased level of ADH PCR test blood or legionella urinary antigen

26. Coccobacilli (Acinetobacter baumannii)

27. Coccobacilli Hemophilus influenzae Gardnerella vaginalis Chlamydia Bordetella pertussis

28. Anaerobes Gram (+): clostridium difficile and perfringes causing gas gangrene .lactobacillus and actinomyces Gram( -): Bacteroides from colon and female genitalia, campylobacter -prevotella

29. Narrow : Target gram positive ex penicillin Broad : Target gram negative ex chloramphenicol and tetracycline Extended : d ue to chemical modification affect many types of bacteria abut still mainly gram negative

30. Classification according to resistance Mult idrug resistant Exten sively drug resistant Pan drug resistant

31. to prevent infection to which patient is high risk outpatient setting : endocarditis prophylaxis inpatient setting : postoperative surgical prophylaxis

32. Inappropriate antibiotic use Absence of a bacterial infection/indication for prophylaxis. Violation of ≥ 1 of 5 D's of optimal antibiotic therapy. Right D rug. Right D ose. Best route of D elivery. Attention to De- escalation. Appropriate D uration of administration.

33. significance is associated with : poor patient outcomes. Adverse drug reactions. organ toxicity. superinfection, e.g. Clostridium difficile. Selection of antibiotic resistance in ICU patients leads to: Prolong hospital stays Excess costs (drug acquisition, complications, MDRP…) Increased mortality.

34. Empirical therapy in sepsis

35. sepsis campaign guidelines2021 Early start of antibiotics is recommended and also sepsis campaign guidelines recommend against waiting procalcitonin for start in antibiotics Do not routinely use 2 antimicrobial for patient low risk for MDR Don't give double gram negative antimicrobial Prolonged infusion of B lactam is recommended We recommend for use of procalcitonin and clinical date for daily assessment for de-escalation We recommend for short term over long term antibiotics course

36. Duration of therapy Clinical assessment Scoring system: CPIS Biomarkers: procalcitonin and CRP. Site of infection (guidelines). -CAP ≥ 5-7 days -HAP ≥ 8 -10 days Ie : antibiotic therapy between 5-7days is recommended over more than 7 days and this is supported by systematic reviews which showed no difference -S aureus bacteremia 14 days and if complicated may be 21 day

37. Systematic reviews revealed that antibiotic course between 5 -7 days is recommended over more than 7 day

38. Procalcitonin vs CRP vs WBC

39. Regarding CRP still considered by IDSA an initial marker of treatment and weaning despite being non specific Sensitivity increased with other factors (WBC - x, ray –lab -clinical symptoms )

40. WBC alone is not enough for starting and de-escalating antibiotics Non specific acute phase reactant (DKA –trauma –MI) Used with other markers

41. Procalcitonin Also false negative (any inflammation – burn – trauma-MI) Higher sensitivity and specificity for treatment and de escalation of therapy 1\2 life 25-30 h rapid response Some recommend initial then day 5-7-on discharge

42. Weaning considered if less than 0,25 ng to 0,5. Or decreased by more than 80% from its peak .

43. CDC CDC recommend against routine sampling for cultures. CDC criteria for mini AL Blood Urine CDC :centers of disease control and prevention

44. MECHANISMS OF RESISTANCE 1-Decreased penetration to the target site : (no longer rely on glycoprotein cell wall) Outer membrane of Gram- ve bacilli provides an efficient barrier to the penetration of β -lactam antibiotics to their target PBPs Major factor in the resistance of P. aeruginosa to many β -lactam 2-Inactivation by a bacterial enzyme : (enzymatic deactivation of antibiotics ) Major mechanism of resistance to the beta-lactam antibiotics May cleave predominantly penicillins (penicillinases) cephalosporins (cephalosporinases) or both (beta-lactamases).

45. 2-Alteration of the target site :  Alterations in PBPs may influence their binding affinity for β -lactam antibiotics and therefore to inhibition responsible for penicillin resistance in pneumococci &streptococci, methicillin ( oxacillin ) resistance in Staphylococci Gonococci enterococci,

46. Genetic mutation : very common in MRSA

47. B- lactamases bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins Carba penemases include : penicillinase Cephalosporinase ESBLs still carbapenem sensetive

48. Extended-spectrum  -lactamases (ESBLs) Plasmid-mediated. Most ESBLs have evolved by genetic mutation from native  -lactamases, Can be difficult to detect Failure during cephalosporin therapy even if test sensitive in the lab Reported as resistant regardless of in vitro testing Use of third generation cephalosporins induces over-expression of the enzymes Transmissible amongst different species of gram negative bacteria

49. Classification of bacteria according to resistance Multi drug resistant :acquired non susceptibility to at least one agent in 3 or more antimicrobial groups Examples : klebsiella pneum- carbamenase producing gram negative organisms

50. Extensively drug resistant : Non susceptibility to at least one agent in all antimicrobial groups except one or 2 categories. Pan drug resistant : non susceptibility to all agents in all antimicrobial groups

51. Home message Don't forget sepsis prevention is very cheap and sepsis treatment is very expensive upto patient life

52. Antibiotic groups Beta lactam group including : Thy have common beta lactam ring in their structure 1-Penicillins 2-Cephalosporins 3-Carbapenems

53. Penicillin 1 st generation :P-G given iv known as aqueous penicillin and procaine –P given IM 2 nd : Methicillin sensitive but also developed resistance via new PBP gene mutation lead to MRSA 3 rd : Ampicillin in listeria infection 2g every 4h 4 th :Piperacillin used with tazobactam and it may cause interstitial nephritis

54. NB All penicillin's can cause seizures

55. Cephalosporin 1 st generation :cefazolin 2 nd generation :cefuroxime 3 rd generation : cefoperazone , ceftriaxone , cefotaxime and ceftazidim 4 th generation : Cefepime

56. Ceftriaxone

57. Ceftriaxone Broad spectrum gram negative more than gram positive Highly stable against beta lactamases (penicillinase and cephalosporinase ) Bactericidal Should not be reconstituted with Ca containing solution like ringers as it cause precipitation May lead to IH cholestasis, No renal modification . Most famous indications : Meningitis -CAP

58. Ceftazidime

59. Ceftazidime G – more than + Anti pseudomonal(pseudomonas aeruginosa ) penetrate CSF (Anti meningitic ) Renal (It has RMD ) (dialyzable )

60. Ceftazidime –avibactam

61. Ceftazidime –avibactam Zavicefta Vial 2,5 g (2 g ceftazidime and 0.5 g avibactam ) Indications : 1- intra abdominal sepsis with flagyl 2-UTI 3-Pneumonia Renal modification acc to cr clearance

62. Pharmacology Ceftazidime – 4 th g cephalosporins Avibactam : B -Lactamase inhibitor. Alone has no antibacterial effect With ceftazidime protect it from degradation by b lactamase enzyme and so extend its spectrum to include G – ve bacteria normally not susceptible to ceftazidime

63. Cefoperazone - sulbactam

64. Cefoperazone 3 rd generation cephalosporin Gram – ve and + ve Including extended spectrum B lactamase producing bacteria and carbapenem resistant Acinetobacter bumannii Bacterial cell wall inhibitor

65. Anti pseudomonal effect Combined with sulbactam as a beta lactamase inhibitor Usual dose 1to 2g every 12h up to 6 to 12g gram per day . RMD :1,5 g iv every 12h in higher doses

66. Cefoperazone -induced coagulopathy The chemical structure of cefoperazone contains a side chain of N- methylthiotetrazole which can inhibit vitamin K metabolism resulting in hypoprothombinemia . Cefoperaone is the offending agent not sulbactam . Vitamin K-dependent coagulation factors include II, VII, IX, and X. Vitamin K deficiency or utilization 2 mechanisms : Inhibit intestinal synthesis of vit k Inhibit carboxylation of vit k dependent factors

67. If we did factor V assay it will be normal which indicates normal liver synthetic function Possible treatment Stop drug and change it FFP-Prothrombin complex –packed rbcs Vit K use

68. Cefepime

69. Cefepime Gram – ve and + ve but greater than ceftazidime toward G – ve and greater than ceftriaxone toward G + ve RMD SEIZURES greater than Fortum Anti meningitis (although poor penetration except in inflamed meninges )

70. Adverse effects Positive comb's test without hemolysis Encephalopathy and seizures Steven Johnson syndrome

71. Carbapenems Imipenem cilastatin Meropenem Ertapenem Doripenem

72. Tienam Imipenem : bacterial cell wall inhibitor Cilastatin : prevent renal metabolism of imipenem by dihydropeptidase - 1 enzyme . G+ve and G- ve , antipseudomonal RMD acc to cr cl . Anti pseudomonas – intra abdominal sepsis Seizures 1,5 % despite poor penetration into CSF

73. May decrease valproic acid level . False positive coomb,s test. Best combination with aminoglycosides for treatment of resistant pseudomonas aeruginosa . Better continuous infusion –time dependent

74. Tienam

75. Meropenem G – and G + Anti pseudomonal Bacterial cell wall inhibitor Used in anti meningitis – IA sepsis ESBL positive organisms MRD acc to cr cl Less convulsions also high penetration into CSF Constipation most common SE

76. Reduce valproic acid level . May be combined with vaborbactam which is a blactamse inhibitor that protect meronem from degradation and alone has no antibacterial action ‘ R/ vabomere Most common indication klebsiella pneumonia cabapenmenase

77. Meropenem

78. Ertapenem Invanz . Usual dose 1g /24h long ½ life so once daily Best in CAP –I A sepsis – complicated UTI and skin No antipseudomonal RMD 0,5 g /24h Diarreha most common SE

79. Ertapenem

80. Glycopeptides 1-Vancomycin 2-Tiecoplanin

81. Vancomycin Bacterial cell wall inhibitor. Vancomycin level trough 15-20 mg/l acc to IDSA Indicated for : MRSA Enterococcus faecalis CL difficile diarrhea (oral) due to poor oral absorption 125 to 250 every 6h IE Septicemia Bone infection

82. Poor CSF penetration except in inflamed meninges increased to 20-30%. Ototoxicity related to amount and duration . Nephro - toxicity elimination ½ increased from 6h in normal renal function to 7days in functionally a nephric patients Mechanism of AKI : tubular cell injury via free radicals and interstitial nephritis Red man syndrome ( hypotension,flushing,erythema ,urticaria ) MRSA

83. Vancomycin trough level Below 10microgram per ml is associated with subtherapeutic level and bacterial resistance Above 20 may lead to increased nephrotoxicity

84. Teicoplanin R,/ targocid Bacterial cell wall inhibitor Narrow spectrum only G + ve bacteria Spectrum similar to vancomycin MRSA coverage

85. May be oral for pseudomembranous colitis ,IM ,IV . Bactericidal. Loading vs maintenance . Doesnot cross BBB highly protein bound 95%. ½ life from 70 to 100 h .

86. Drug induced thrombocytopenia

87. B- lactamase inhibitors Definition : drugs that are co administered with beta lactam antibiotics to prevent degradation by beta lactamase enzyme Except KP carbapenmenase 1 - Sulbactam. 2 -Tazobactam. 3-Clavulanic acid. 4- Avibactam 5- vaborbactam

88. Polymyxin E COLISTIN –coly mycin – colistimethate sodium Colistimethate sodium hydrolyzed to active form which is colistin MDR organisms like Acinetobacter- klebsiella- pseudomonas 2,5 to 5 mg kg per day Nephrotoxic and neurotoxic( higher incidence with higher iv dose) bronchospasm

89. Dealing with toxicity Neurotoxicity decrease dose Nephrotoxicity Aki up to 60% withhold treatment. Colistin base activity 1mg equal to 30,000 iu Colistimethate Na 1mg equal to 12,500 iu

90. VAP LOADING iv :300 mg = 30,000 = 9 million unit Maintenance :300 mg divided in doses 4,5 m IU every 12h begin 12h post loading. Nebulizers :150 mg =30,000 every 8h over 60 min for 14 days

91. Preparation Each vial containing 150 mg CBA in 2 cc SWI then further dilution in D5 , NS Nebulizers : vail containing 150 mg CBA in 10 cc SWI Do not use reconstituted via after 24h Non reconst in temp 20 -25 Reconsti in refringe 2-8 degree

92. Colistin

93. colistin Bacteriostatic Nebulizers before the inhaled form 15 min before Negligible CSF concentration even in inflamed meninges Infuse iv form over 30 to 60 min

94. Colistin nebulizers Off label Use it immediately after preparation Storage may lead to increased lung toxicity

95. Intrathecal – Intraventricular OFF label Immediately after preparation When administered via ventricular drain clamp it for 15 to 60 min

96. Fosfomycin Monuril sch 3g every other day for 3 doses Or 2 gm iv every 8h over 15 min Secreted unchanged in urine Last cell wall inhibitor Diarrhea Hypokalemia May be oral or iv Bactericidal

97. Rapid oral absorption Bioavailability low High Na content – cautious High Na load lead to hypokalemia Liver injury

98. DNA synthesis inhibitors Septrin Pneumocystitis carinii Hepatic metabolism Mechanism : Some antibiotics, such as the  sulfonamides , are competitive inhibitors of the synthesis of  folic acid  (folate), which is an essential preliminary step in the synthesis of  nucleic acids .

99. quinolones 1 st generation nalidixic acid 2 nd ciprofloxacin 3 rd levofloxacin 4 th moxifloxacin

100. Ciprofloxacin Bioavailability 70% May be crushed via NGT Iv infusion over 6o min into large vien due to vein irritation Convulsions (GABA binding disruption – NMDA binding alteration n) Qtc MRD Anti p seudomonal

101. Oral 500 mg every 12h for 7 to 10 days IV may be 400 mg every 12h to every 8h especially in severe infection like meningitis Poor csf penetration except in inflamed meninges

102. Levofloxacin Bioavailability 99% Convulsions but still csf poor penetration Qtc Excellent monotherapy against pseudomonas Dose from 500 mg to 750 mg iv every 24h

103. Anaerobic DNA inhibitor Metronidazole: Metabolized in liver In severe liver injury reduce dose 50% BIOAVAI 80% SEIZURES

104. RNA synthesis inhibitors Rifaximin Used in cl diarrhea and HE Rifampicin Used as carrier in HI and Neisseria carriers 600 mg every 12h for 2days Tuberculosis

105. Protein synthesis inhibitors 1- Aminoglycosides 2-Tetracyclines 3-Macrolides 4-Licosamide 5-Oxazolidione

106. Aminoglycosides 1-Gentamycin 2-Amikacin

107. Gentamycin Inhibit s30 and s50 Coverage of gram negative bacteria Anti pseudomonal Synergistic action with beta lactamase against enterococci Concentration dependent

108. Most common SE nephrotoxicity if trough level > 2 mg/land ototoxicity may be permanent Myopathy May be given nebulizers

109. Amikacin Inhibit 30s Gram negative bacteria including those resistant to gentamycin Concentration dependent Dialyzable Ototoxicity and nephrotoxicity trough level >10 mg /l Myopathy – Nebulizers

110. Tetracycline Tetracycline s30and s50 Discoloration of teeth in young DI in adult

111. Doxycycline Vibramycin 100 mg cap Inhibit s30 s50 Bioavailability reduced with high ph. Anti Acinetobacter Hepatotoxicity

112. Tigecycline Tygacil 50 mg Inhibit s30 leading to protein synthesis inhibition Active against G++ and G– bacteria with MRSA coverage Bacteriostatic but also has some bactericidal activity against pseudomonas . Complicated IA sepsis – CAP –VAP – Skin and soft tissues infection Increased in hospital mortality in HAP especially cardiac ? Unknown

113. Poor CSF penetration and IV administration does not exceed MIC In combination treatment my be considered for treatment for meningitis . Coagulopathy prolonged PT ,PTT and decreased fibrinogen Hepatotoxicity( increased TB ,DB ,SGOT ,SGPT)

114. Warning In a meta analysis of Phase 3 and 4 clinical trials an increase in all cause mortality has been observed The cause of mortality difference not established And use should be reserved for treatment of situation no alternatives available

115. Macrolides Erythromycin Azithromycin Clarithromycin

116. Azithromycin Ribosomal S 50 Bioavailability 37% No MRD Prolonged Qtc monitor HR ,k ,mg levels May lead to diarrhea 52%

117. Clarithromycin Klaccid 500 every 12 MRD 500 every 24h S50 Bioavailability 50 % Cap –H pylori – AECOPD - skin and soft tissue

118. Lincosamide Clindamycin 50s – weak MRSA Bacteriostatic or cidal according to drug concentration level Bioavailability 90% High concentration in bone so osteomyelitis Risk of pseudo membranous colitis

119. Oxazolidinone Linezolid Inhibit s50 Induce non selective MAO inhibition may lead to serotonin syndrome if combined with serotonergic agents like SSRI- TCAs MRSA Thrombocytopenia 13% ? After 2wk exposure

120. Serotonergic syndrome Occurs due to increased serotonin level lead to DLC Dys autonomia Tachycardia Hyperreflexia Hyperthermia Seizures Rhabdomyolysis

121. MRSA This organism related to high morbidity and mortality Vancomycin Taragocid Avrezolid Septrin Tygacil Doxycyline Rifampicin

122. Drugs with no RMD Zithromax Rocephin Avrezolid Tygacil Dalacin

123. Anti meningetic drugs Rocephin Maxipem Fortum Meronem Gram positive and MRSA Avrezoild vancomycin

124. Vancomycin – targocid – avrezoild In pneumonia Linezoild is superior in microbiological and radiological cure only but no clinical difference in MRSA Blood stream vancomycin still the 1 st option line

125. Klebsiella MDR : Colistin , Meronem ,Fosfomycin ,ceftazidime /avibactam plus aminoglycosides Klebsiella MDR including carbapenem: R/ Carbapenem extended infusion especially meronem+Colistin or Tygacil or both +Aminoglycosides Colistin resistant klebsiella pneumonia: Ceftazidime /avibactam +tygacil +gentamycin ,Fosfomycin 4g /6h

126. Treatment options for Acinetobacter If MDR especially carbapenems : 1 st add Sulbactam . 2 nd add Tygacil or colistin . 3 rd add Rifampicin but still clinical trials no proven benefit even in combination with colistin

127. Treatment of pseudomonas MDR The classic regimen for pseudomonas MDR is combination of 2 iv antipseudomonal Ceftazidime /avibactam ( Zavicefta ) 2g/0,5/8h In UTI – Pneumonia – IA sepsis RMD Imipenem + relebactam : recently approved in 2019 by FDA for MDR pseudomonas

128. Antimicrobial stewardship

129. Antimicrobial stewardship Definition : coordinated program that ensures the optimal selection ,dose ,duration of an antibiotic therapy that lead to the best clinical outcome for prevention and treatment of an infection while producing fewest side effects and lowest possible risk of bacterial resistance

130. It includes D ata collection D ocumentation T racking resistance A ction to over come F ollow up action plan

131. Team Infection disease physician Pharmacist Microbiology personnel Information technology

132. ?? Antibiotics in covid 19

133. Its viral infection so not treated with antibiotics . But in some cases antibiotics therapy may be needed. Non optimal use of antibiotics may lead extensive. antimicrobial resistance . Do not rely on single indicator like CRP .

134. Indications A-In co infection with bacterial or fungal infection B-Septic shock Lab markers 1-Procalcitonin 2-Serum galactomannan 3-Bd glucan 4- Cultures especially in severe covid we should withdraw blood cs before antibiotics

135. Who guidelines Suspected or confirmed mild covid 19 cases we suggest against use of prophylactic antibiotics therapy

136. Suspected or confirmed moderate covid 19 cases we suggest against use of prophylactic antibiotics therapy

137. Suspected or confirmed severe covid 19 cases we suggest use of antibiotics therapy base on clinical judgement ,patients host factors and local epidemiology .