Antibiotics requiring therapeutic drug monitoring(1)


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Antibiotics requiring therapeutic drug monitoring(1)

  1. 1. Therapeutic Drug Monitoring (aminoglycosides and vancomycin) Dr. Mahen Kothalawala (MBBS, Dip in Micro, MD, MPH(NZ) Consultant Clinical Microbiologist Teaching Hospital Kandy SriLanka
  2. 2. • Some background knowledge/concepts required to understand the lesson
  3. 3. Pharmacokinetics (ADME) absorption, distribution, metabolism, and elimination What will happen to drug Oral vs IV administration
  4. 4. Oral vs IV Oral Administration • Follows ADME • Hepatic first pass metabolism • Place of absorption depends on pK of the drug • (Effect of enteric coat – acid liable drugs destroyed in stomach, to prevent it a coat is applied) IV administration • All available for biological Activity • No hepatic first pass effect • All drug [] available for action • Free form active • Bound form- inactive
  5. 5. Composition of body water and its effects of drug distribution Hydrophobic drugs – moves to ECF as well ICF (Vd high) Better for intracellular organisms Hydrophillic drugs- Ionized and remain only within ISF and Plasma (Vd less) Better for infections within Interstitial fluid – Majority of infection
  6. 6. When the pK of drug similar to pH of the environment it remain unionized Absorption or Transfer across cells is greater Unionized form↓↓ gradually Unionized form ↑↑↑ Unionized form↓↓ gradually
  7. 7. oral and IV administration of a single dose Clearence Determination of the bioavailability of a drug. (AUC = area under curve.)
  8. 8. Drug concentrations in serum after a single injection of drug at time = 0. Assume that the drug distributes but is not eliminated. Ex- Renally eliminated drug in renal failure Drug concentrations in serum after a single injection of drug at time = 0. Assume that the drug distributes and is subsequently eliminated.
  9. 9. Steady state plasma concentration –Repeat dose given at every t 1/2
  10. 10. Rate of attainment of steady-state concentration of a drug in the plasma during an continuous infusion – Elimination of drug after stoppage of infusion After 3 to 5 t ½, not detectable in plasma
  11. 11. At steady state, input (rate of infusion) equals output (rate of elimination). If Vd – is large a loading dose is necessary If Vd – small, a no loading dose necessary
  12. 12. Effect of infusion rate on the steady-state concentration of drug in the plasma. (Ro = rate of infusion of a drug.)
  13. 13. Pharmacodynamics
  14. 14. Antimicrobial activity • They are not contact poisons • For action – – – – – – • • should reach the target site Should achieve optimal concentration come into contact with micro organisms Bind to target and remain there for sufficient time to exert the effect Should resist inactivity or Clearance Should not be inactivated at target site Above are Pharmacodyamic properties of antibiotics Bacterial destruction is described in following manner – time-dependence, – concentration-dependence, and – persistent effects. • If the rate of killing ᾀ exposure time (time-dependent), • Rate of killing ᾀ (concentration-dependent). • • Persistent effects - Post-Antibiotic Effect (PAE) and PALE .
  15. 15. Pharmacodynamic Predictors of antibiotic efficacy • The target we plan to achieve at the site of infection • Under activity →Treatment Failure, Resistance Development • Over activity at the site- Toxicity and ↑ cost • Three predictors – % T /MIC value – AUC0 to 24hr / MIC – Cmax/MIC
  16. 16. What factor is common to all predictors? • When MIC is high, Efficacy ↓ • When MIC is low, Efficacy ↑
  17. 17. Target parameter for each drug, organisms are different….. Drug type Penicillins PD parameter % T / MIC Cephalosporins Fluoroquinolones AUC0 to 24hr / Glycopeptides MIC Glycylcyclins Aminoglycosides Cmax/MIC Target [ ] least 40% time of day should be above the MIC [ ] at least 50% time of day should be above the MIC ratio should be > 200 Ration should be > 20
  18. 18. Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media No change in bacteriological cure after %T> MIC > 40%
  19. 19. Response rate increases when ratio increases, Higher the ratio, higher the response
  20. 20. target attainment profiles of 3.375 g of piperacillin-tazobactam every 6 or 4 h as a 0.5-h infusion for hospitalized patients target attainment profiles of 3.375 g of piperacillin-tazobactam every 6 or 4 h as a 0.5-h infusion for healthy subjects.
  21. 21. Probability of target attainment PD parameter for pip-tazo Target 40% time of day At least 90% of the target should be above the need to be attained with MIC the dose Probability of target attainment 1. When MIC is < 4, the target is attained with 6hrly as well as 4 hrly dose 2. When MIC < 8, Target is achieved 100% with 4 hrly , regimen while only 90% achieved with 6hrly regime 3. When MIC is 16, 90% of target achieved with 4hrly regime, 70% is achieved with 6hrly regime 4. When MIC is 32, target is achieved only 20% time with 6hrly regime, while only 60% of the target is achieved with 4hrly regime
  22. 22. What did you learn? • Activity of antibiotics in human host depend on many factors • PK parameters decide antibiotic [] reaching the site of infection • PD parameters decide microbial killing at target site • At least 90% of the target should be attained at the site of infection • Human body physiology influence the outcome • MIC of the organism, is the only a in-vitro, parameter which decide on outcome
  23. 23. Introduction • Antibiotic-induced adverse events leads to – host injury – diagnostic confusion – excessive medical costs. • a "spin-off" of antibiotic-induced adverse events is the emergence and dissemination of drug-resistant organisms.
  24. 24. Antibiotic adverse effects occur by three mechanisms • Exaggerated response (to known pharmacological effects) • Immunologic reactions to drug or its metabolites, • Toxic effects of the compound or its metabolites. • Most adverse events due to – drug's normal pharmacology • avoided by→ dosage adjustment.
  25. 25. Effects of Antibiotics Desired Effects Cure Undesired Effects Toxicity and side effects Clinical Cure- Symptomatic Microbiological Cure Dose related -Predictable Dose unrelated -unpredictable
  26. 26. Classification of Adverse drug reactions • According to – Cause – Seriousness and severity – Overall Drug Risk – Location
  27. 27. Classification of Adverse drug reactions Cause Seriousness and severity (FDA) Overall Drug Risk Location of the adverse effect Type A: ↑ pharmacologic effects – dose dependent and predictable Intolerance Side Effects Death Red (high risk) Local Type B: Bizarre effects ---or idiosyncratic - dose independent and unpredictable Life-threatening Orange (elevated risk) Systemic Type C: Chronic effects Hospitalization Yellow (guarded risk) Type D: Delayed effects Disability Blue (general risk) Type D: Delayed effects Congenital anomaly Green (low risk) Type E: End-of-treatment effects
  28. 28. Rare events • Some adverse reactions occur rarely • Unique to certain drugs only. – Chloramphenicol-induced aplastic anemia – Sulfonamide-induced TEN or Stevens-Johnson syndrome
  29. 29. Factors affecting side effects or ADR • Genetic factors • Integrity of drug elimination mechanisms(renal and hepatic dysfunction) • Concomitant medical disorders– in HIV positives infected patients • oxacillin-induced hepatitis a • cutaneous reactions with trimethoprim-sulfamethoxazole or aminopenicillins
  30. 30. Monitoring for toxicity of antibiotics in patients • Direct method – Check for drug levels • Indirect Method – Clinical features suggestive of side effects – Laboratory indicators of end organ damage(in likely organ damage)
  31. 31. Toxicity and adverse events are common to any drugEven with the drugs which tagged safe, • Penicillin group → good safety profiles, well tolerated. • Can cause – wide range of hypersensitivity reactions, including fever, rash (maculopapular and urticarial), – anaphylaxis, – exfoliative dermatitis, erythema multiforme, serum sickness, and hemolytic anemia.[ • IV high doses in renal impairment central nervous system toxicity, – myoclonic jerks, – seizures or – coma. • Some members cause particular side effects – ampicillin, amoxicillin, and amoxicillin/clavulanate with diarrhea and C. difficile colitis, – In CLL pts → nafcillin-induced neutropenia; • Carbenicillin and ticarcillin (with/without clavulanic acid) hypokalemia, – platelet dysfunction, and – fluid overload; • Methicillin and ampicillin – interstitial nephritis.[6
  32. 32. Antibiotics requiring therapeutic drug monitoring
  33. 33. Most drugs are well tolerated Some are not tolerated well Some types of drugs, Ae3s may be common, but under special circumstances Wide therapeutic Index Narrow therapeutic Index β-lactams, macrolides and quinolones Monitoring often not required Aminoglycosides vancomycin, Monitoring of levels indicated in order to prevent toxicities Intermediate Teicoplanin, Flucloxacillin and the antifungal agents itraconazole, flucytosine and fluconazole Monitoring may required in special circumstances exrenal, hepatic failures
  34. 34. Why monitor only aminoglycosides (and Vancomycin?) • Low therapeutic index. • Bactericidal efficacy ᾀ peak concentrations • Toxicity is related to total drug exposure • Nephrotoxicity (usually reversible) and ototoxicity (often irreversible) • The desired plasma concentration-time profile for aminoglycosides differs to most other drugs.
  35. 35. Patho-physiology of Aminoglycoside Nephrotoxicity • AGs → obligate nephrotoxins • Long term treatment→ invariable renal damage • AGs- enter into PCT cells and Inhibit protein (Next Slide) • It accumulates within lysosomes phospholipd complexLead to rupture and cell death • Is a tubulopathy – tubular cell damage and – tubular dysfunction
  36. 36. Aminoglycoside Toxicity • AGs accumulate in the kidney, – Around 40%of the total – About 85% in renal cortex • Drug entry from the lumen through binding to brush border receptor – megalin • Animals made Megalin –Deficient – No renal toxicity • Toxicity varies depending on type of AGs – Gent and Netil > Tobra and AK • This accumulation follows satuarable kinetics – when exceed the capacity no further entry (15 μg/ml) –Basis of once daily ↓ toxicity
  37. 37. Pathophysiology cont….. • Results – ↑ in Tubular Glomerular feedback (TGF), – ↓in GFR, – Activation of RAAM and – contraction of renal vessels and mesangeal cells • Lead to Acute Renal damage (Nephrotoxicity)
  38. 38. .
  39. 39. Influx of AG into proximal tubule • Mediated by a carrier- which follow Zero order kinetics (Saturable) • Intake – dose independent(↑*AG+ in lumen does not increase uptake in to PCT cells • Basis of once daily dose • Demonstrated in animal studies- that renal toxicity occur >>> with divided doses than daily single large doses
  40. 40. Nephrotoxicity ↑ when concurrent administration of • Drugs such as – loop diuretics, – cyclosporin, – cisplatin, and – vancomycin, (not teicoplanin) • And when ↓ Renal blood flow – Dehydration – Diarrhea etc – Renal failure (need to monitor)
  41. 41. Otto toxicity mechanism and manifestations • Ototoxicity – auditory (cochlear) and – vestibular toxicity, • Damage to sensory hair cells (cochlea) and cells in labyrinth • Mechanism of cell damage, similar (start with cloudy swelling and necrosis) • Bot may not occur concurrently • Manifests as – – – – Balance difficulty Bouncing, unsteady vision tinnitus Difficulty multi-tasking, particularly when standing • Irreversible
  42. 42. Ototoxicity • Aminoglycosides penetrate into the endolymph, vestibular and cochlear tissue • Damages sensory hairy cells in cochlear tissue by entering to endolymph – AG enters to the endolymph slowly, – Leaves even slower • Risk factors for oto-toxicity – Prolonged therapy for 10 days or more (safe if discontinue in 5 to 6 days) – Preexisting renal impairment(Dose adjustment) – Prior treatment with AGs. • Damage - manifest as auditory (cochlear) and vestibular toxicity, • Can appear separately (Never together)Oto-toxicity is rare if treatment restricted to 5 to 6 days • Rare herditory condition –Ototoxicity within few doses (avoid if family history of similar event)
  43. 43. Ototoxicity • Degree of damage Corresponds to AUC
  44. 44. Effect of P-kinetics in AG toxicity • V and CL change plasma concentration of drugs. • ↑V is reported with (high doses required to achieve desired effects) – Burns – Edema • ↓ Clearance with dehydration – ↑ toxicity Change with fluid replacement and resolution of the infection.
  45. 45. Measurement of aminoglycosides (for BD or TDS doses • Desired concentration-time profile is – a high peak concentration (for efficacy) – low trough concentration (to prevent accumulation). • Traditionally tested for – Peak [] – for Efficacy – Trough []- for accumulation • With once-daily dosing- Peak trough testing need to reconsider
  46. 46. Gentamicin levels Therapeutic BD or TDS Synergistic for IE Single dose Recommended dose Therapeutic with 1.7 mg/kg per dose divided 1mg/kg BD or TDS BSAC- BD dose SANFORD- TDS dose 5 to 7 mg/kg IV Target Peak Measuring at 15 to 30 minutes after dose , usually measured 3 to 5 doses after initiation Same No peak Target Trough dose Immediately before a dose Same No trough – Measure 12 to 18 hrs after (usually after first dose) Target Peak 6–10 mg l− 3 to 5 mg l−1 According to the value decide next dose by normogram Target Trough ≤ 2 mg l− 1 to 3 mg l−1 Toxicity suspect if, ≥2 ≥2 If target higher, Omit or delay next dose [ ]24hrs of 0.5–2 mg l−1 reflects accumulation, usual [ ]24hrs undetectable
  47. 47. Q’s • A pt with normal renal functions was put on c.pen and gentamicin. • How long would you plan for treatment, • If patient had three blood cultures of a S.viridans sensitive and lower level of MIC • What is the dose you select • C.pen • Gent • When are planning to asses Gent level, Describe the basis? • If levels are as follows, what would be your intervention Peak Trough 4 <.5 8 3 5 3
  48. 48. Once-daily dosing • At 24hrs, levels are un-recordable with normal renal functions • []24hrs of 0.5–2 mg l−1 → accumulation or over dose • Concept of a trough concentration is not relevant to once-daily dosing. • 12 to 18 hrs dosage
  49. 49. Collection of specimens for AG assay • Do not draw from iv line used to give AG • Take one blood sample (ideally 5 to 10mL) between 6 and 14 hours after the start of first infusion in a plain tube (clotted blood) • Document – Patient details and – EXACT time and date infusion was set up and EXACT time and date sample was taken in
  50. 50. Selecting dose interval Falls in area designated 24 hours, 36 hours or 48 hours, dosing interval is 24, 36 or 48 hourly respectively If level falls on a line between dosing intervals, choose longer interval. If level is above 48 hour line then STOP the treatment. If gentamicin is to be continued, take daily levels, but do not give any more gentamicin until level falls below 2mg/L
  51. 51. • Gentamicin_Calculator_110210__revision_on_advice_of_A._Thomson.xls
  52. 52. Repeat monitoring • Check U & Es and creatinine daily to monitor renal function. • If serum creatinine is rising significantly (≥20%) and time is within 6-14 hours of infusion, measure level ASAP, otherwise contact Microbiologist for advice.
  53. 53. Extended interval (once daily) gentamicin / tobramycin • Take a pre-dose level 18-24 hours after 1st dose. • Levels should be <1mg/l • Normal renal function - (creatinine clearance >60ml/min) give next dose when due. • Check pre-dose levels every 3-5 days. • Impaired renal function – monitor levels daily
  54. 54. Hours after Gentamicin dose
  55. 55. Summary Initial Dose Hartford Extended Interval dosing 7mg/kg, with dose frequency altering according to nomogram based upon gentamicin serum concentration Infusion in 50-100ml Sodium Administration Chloride 0.9% over 30 minutes Blood levels One sample taken 6-14 hours taken after the infusion commences Pharmacokinetic Dosing Adults: 2mg/kg loading dose, then refer to pharmacy or microbiology for maintenance dose Synergistic dosing for endocarditis 1mg/kg TDS (or less frequently) Paediatrics: 2.5mg/kg TDS Adjust dose and frequency based upon gentamicin serum concentration Bolus over at least 3 minutes Just before the dose (pre-dose sample) and 1 hour (post-dose sample) Standard: Pre-dose <2mg/L, Post-dose 6-10mg/L Target No target - use the nomogram to concentrations identify the patient's required Synergistic dosing for endocarditis: dosing interval. Pre-dose <1mg/L, Post-dose 3-5mg/L
  56. 56. Rules for Aminoglycoside Treatment • Usually Aminoglycoside should not prescribe for longer than 7 days (Practice at TH Kandy <3d) – Exception – Infective endocarditis, or by inhalation for cystic fibrosis. • Monitoring need to be individualized – If patient is unstable - more often – if stable- Less often • With once-daily dosing it is logical to follow the same rules until new information allows these rules to be re-formulated.
  57. 57. Why monitor vancomycin? • It too has low Therapeutic Index, • Can cause – nephrotoxicity – ototoxicity. • Toxicity of Vancomycin differ to that of Aminoglycoside – – Peak levels – Not necessary – – acceptable PD is %T>MIC • toxicity – related to total exposures than peak – >4g/day toxicity likely • New formulae – No impurities – Less toxicity
  58. 58. PK of Vancomycin • The PK vancomycin relatively simple, – with low protein binding, – 100% renally elimination, – No metabolism – no pharmacogenetic problems. • V is around 0.4 l kg−1 and the CL approximates that of glomerular filtration rate. • t1/2 is approximately 6 h in patients with normal renal function ..
  59. 59. Monitoring Guide of Vanco • No peak is necessary • Trough need to be above the MIC of the targeting organism • VancomycinMIC is approximately 1.5 mg l−1 for many susceptible organisms.
  60. 60. Question on Vancomycin dosing> • Assume 50% protein binding with MIC of the concerned pathogen around, 1.5mg/L, – Calculate the minimum required trough for vacomycin in a person with eGFR of >90. • If you get a report of [Vanc]trough of 20mg/L, – What should you do? Explain what should your advice to the attending physician? • What is your advice to a person who has a eGFR of 50, receiving vancomycin? – If, serum creatinine was 2.9mmol/l, what is your advice? Calculate the dose? – If, serum creatinine is 450mg/l, what is your advice? • What is the level you should achieve for Rx of MRSA Bacteremia?
  61. 61. Question • In severe life threatening situation would you recommend same trough? Or would you sought to a higher trough?
  62. 62. Answer • Total trough concentration necessary should be at least 3 mg l−1 • Average of 5 to 10 mg l−1 would be enough (for mild to moderate infections) • In severe infection – Can have at a trough of 15 to 20 mg/l • MRSA Bacteremia – a trough level of 15 to 20 mg/dl need to be acheived
  63. 63. Individualization of Vancomycin Dose - Normogram Degree of renal failure Initial dose and maintainance Mild to Moderat e Initial dose <15mg/kg Severe Give 250 to 1000mg several days apart than giving frequent small doses Anuria 15mg/lkg until therapeutic [] achieved Maintenance dose is 1.9mg/kg/day, Better to give higher dose over several days apart
  64. 64. Vancomycin Rules, • Take pre-dose levels prior to 3rd dose. – Give the 3rd dose as prescribed and amend 4th dose according to levels • Pre-dose level 5-15mg/l (in severe infection levels up to 20mg/l may be required) • Normal renal function - (creatinine clearance >60ml/min) check levels every 3-5 days. • Impaired renal function – monitor levels daily • For severe infections higher levels may be advised by microbiology.
  65. 65. Monitoring of Teicoplanin • Monitoring is required for impaired renal function / to ensure therapeutic plasma levels. • Ensure that usual BD loading dose is given – Take pre-dose level on day 4 to 7. – Severe infection – • pre-dose level 20-60mg/l – Mild – moderate infection – • pre-dose level 10-60mg/l • Regular monitoring may be required in renal impairment
  66. 66. Monitoring of Amikacin – (multiple daily dosing) • Pre-dose level 5-10mg/l • 1 hour peak 20-25mg/l • When using the normogram, value to calculate next dose should be taken as follows:[Amikacin] 6 to 14hrs level/2;
  67. 67. Voriconazole • Pre-dose level 0.25 - 6.00 mg/l • For further information seek advice from microbiology
  68. 68. Gentamicin levels and outcome Initial serum peak level Died Survived < 5mcg/ml 21% 79% >= 5mcg/ml 2% 98%
  69. 69. Vanco 24h-AUC/MIC ratio Satisfactory Unsatisfactory < 125 4 (50%) 4 > 125 71 (97%) 2
  70. 70. Questions - one • 32 year mother of one child, presented to obstetric casualty in the night with high fever, headache, vomiting with two episodes of LOC. • On presentation→ • Febrile with 102.5F • HR -110/min, BP-90/60 • No rash • PMH- on a VP shunt- inserted 3 years back
  71. 71. • On-call obstetrician rings you in the night. What steps would you take? • What is the tentative diagnosis? • How do you manage the acute episode?
  72. 72. • The following day on-call neurosurgeon sees the patient. • Take the abdominal end out and allows it to drain freely, Headache settles. • Fever remains. Pt becomes conscious and claims that she feels fine compared to time of admission. – What tests would you request? – What microbiological tests would you recommend?
  73. 73. • CSF culture and gram stain? Obtained through the distal end of the VP shunt. – Gram Positive cells seen with diplo arrangement. No pus cells. – Culture – Streptococcus pneumoniae isolated – – – – WBC-17,000 with 87% Neutrophils. Platelet count -170,000/ml CRP ->96 Blood culture – Negative with single
  74. 74. • What information would you like to have? • Describe how you handle the case from time of first contact?
  75. 75. At the time of admission Vancomycin and Meropenem 24hrs Culture positive with pneumococci, Continued 24hrs Zone of oxacillin >20 mm MIC pen 0.01 mg/l Pen along Issue – Penicillin sensitive pneumococcus isolate→ is it a contaminant or not, How to solve the problem?
  76. 76. Case 02 • 73yr old doctors mother admitted to neurologist with sudden onset of LOC. CT scan reveal a SAH. • Managed at Neurology unit. – Pt has no fever, Pulse-90.min – WBC 9500/ 78% N – ESR -60 – CRP 144
  77. 77. • Blood culture obtained at day 6 gave a positivity with gram positive cocci in two occassions, Identified as enterococci – CT Scan - SAH – Pt gives a allergic history for amoxycillin
  78. 78. Questions • What other information would you like? • What treatment would you start?
  79. 79. Treatment – Started IV Vancomycin, • Comment on the dose? • If the patient is severely ill, would you recommend a loading dose? Explain? • After 13th day of treatment, • Vancomycin levels as follows – Pre-dose – 22mg/l, 30 min after 1 hr infusion[]- 55mg/l, • If, laboratory policy is performing only single level on a patient, what level (pre or post)would you request?
  80. 80. Question 3 • A 24 year old patient admitted to cardiology unit with a history of fever for 10 days. He had a history of taking treatment for infective endocarditis from a DGH in North Central Province. • No blood culture results were available • Results of FBC and other tests is shown below Day 1 Day 1 Eve Day 3 Day 4 Total 11,000 14,000 12,000 13,500 N% 76% 80% 75% 75% L% 19% 16% 20% 20% E% 5% 3% 3% 5% Platelet 460,000 530,000 297,000 210,000
  81. 81. Qs • His CRP was 196, ESR was 100mm/hr • • • • • Urine culture – NAD CXR- NAD SAT- O -1/160, A H and Typi H- 1/40 Echo – Oscillating Mass on Mitral Valve Serum Ferritin – 9,000
  82. 82. Qs • Patient was started on IV C.penicillin and IV Gentamicin- contimued it for 4 days, • No responseter 4 days. and patient left against medical advice to TH Kandy, • HE presented to private hospital and admitted to TH Kandy with a letter to microbiologist.
  83. 83. Qs • The night on-call doctor, contacts the microbiologist, • If you are the microbiologist, what questions would you ask from the doctor calling you? • What are you going to start? Give reasons?
  84. 84. Qs • Patient was started IV cetriaxone, IV gentamicin on that night. • The following day the patient was sitting comfortably on bed and reading the “Lankadeepa” news paper. – The following day patient felt ok, appetite ok • Explain how do you ask from the patient about his symptomatic improvement?
  85. 85. Qs • Do you agree with the diagnosis of IE in this patient? • If not, why? • If yes, why? • What investigations would you like?
  86. 86. • Pt was OK for 3 days, and develop very high fever, patients condition was worsening, • Counts as follows – Day 8 Day 9 WBC 5,000 3100 N 60% 62% L 38% 30% Platelets 97,000 45,000 S.creatinen 1.4 1.4 CRP - 197
  87. 87. • Now, what should you do? • Identify the problems/issues? • How would you mange the patient? • Started IV Vancomycin and Gentamicin
  88. 88. • Explain what has gone wrong? • Now patient is really sick. Serum Creatinine is going up. Platelet count is going down. WBC is coming further down. • What should you do?
  89. 89. • Medical Referral done, Heamatologist and nephrologists referral done. • A diagnosis of Heamophagocytic syndrom arrived? Pt was admitted to the MICU. • Early mane, cardiologist called and suggest whether changing to linazolid would be of any use. Microbiologist OKS.
  90. 90. In spite of all efforts, • Patient dies. • What possibly has gone wrong in this case scenario? • If is you, how would you manage the patient.
  91. 91. • Select your treatment option? • Why do you use – 1. AK – 2. CAZ • IF you are using Amikacin, what should you do prior to start it?
  92. 92. • 76 yr old female 5 days after CABG in ICU develop Gram Negative Septicemia, • AST as follows • CAZ – S CN -R • CTX- R Netil -R • CPM- R AK -S • Cipro –R AZT -R • Levo – S Pip-TZ- R • Mero –R • Imp -R
  93. 93. • What dosage /frequency do you use? – 7mg/12hrly – 15 mg daily • If, 6 hrs after first dose, AK levels were found to be 6 mg/l, when do you give the next dose? • If, you fail to collect the first dose, at 6hrs, when can you collect blood for AK levels?
  94. 94. • Then what would be the AK level? • In once daily therapy, do you arrange for a pre dose []? Explain why? • If after 8 hours, [AK] = 6ng/l, when do you administer the next dose?
  95. 95. If levels are not available For Empirical therapy → Gentamicin maximum of 48 hr for all The initial dose → based on age and weight, Interval for subsequent doses -depends on renal functions For a patient with normal renal function MAXIMUM OF three doses 0, 24 and 48 hours. monitoring of plasma concentrations is not required as it not exceeding 3 doses Subsequent doses for treatment should guided by AST • Susceptibility results should be used to guide ongoing therapy. • If susceptibility results are not available by 72 hours and empirical intravenous therapy is still required, the gentamicin containing regimen should be ceased and an alternativeregimen used.
  96. 96. Remember • Drug level monitoring is a compulsory requirement when potentially toxic drugs. • It is done to monitor for side effects as well as find out whether adequate concentration has achieved at the site for optimum activity. • It is a way of “optimizing antibiotic therapy”