Antibiotherapy for dummies

Antibiotherapy for dummies

Anaesthesia and Surgery Day 5th December 2015 Dr AurĂŠlie Godard (intensive care referent) OCP

Some concepts • Antibiotic classes • Antibiotic effectiveness –

Bactericidal vs bacteriostatic

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Narrow vs broad spectrum activity

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Multi-drug resistant strains (ESBL, MRSA, and more…)

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Diffusion into infected tissues

–

(Drug volume of distribution / protein binding)

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(Post antibiotic effect)

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Toxicity / adverse effects

• Time vs concentration-dependent drugs • Concentrations –

Minimal inhibitory concentration (MIC)

ß- Lactams

Aminoglycosides

Gram positif

Staphylocoque Aureus methycilline sensible (SAMS) Staphylocoque Aureus methycilline résistant (SARM) Streptocoques

– capable of inhibiting growth/reproduction

GPC, GNB …

– Narrow spectrum – Peni G < peni A

Enterocoque faecium

– C1G < C2G

pneumoniae – Klebsiella capable of killing

Cloxacilline

Clindamycine

Ciprofloxacine

Chloramphenicol

Ceftriaxone

Cefxime

Cefazoline

Azitrhomycine

Ampicilline

• Predictable spectrum of activity

Enterocoque faecalis

• Bactericidal Gram négatif

Amox + A.clav

Amoxiciline

• Bacteriostatic

Amikacine

Definitions

– Broad spectrum37

E.Coli non BLSE

– carboxy-peni < ureido-peni

Salmonella/Shigella

– C3G < C4G

Enterobacterie BLSE (environ 50% à Bangui)* Pseudomonas aeruginosa Anaérobies (bacteroides fragilis, clostridium)

• Mechanisms of resistance bacteria, and antibiotic !

of

Mechanisms of resistance…

Intrinsic « genetic » resistance

≠

Acquired or induced resistance

Mortality

Enzymatic antibiotic Nothing to do degradation - Beta lactamase  clavulanic acid - Cephalosporinase - ESBL = extended Everything spectrum to do !ß lactamase  and….. ?

Decreased susceptibility of Streptococcus pneumoniae to penicillins

Pharmacodynamic / cinetics • Protein binding / distribution volume • Diffusion into infected tissue –

IV / IM / PO administration : absorption, hepatic 1st pass metabolism …

–

Tissues difficult to reach : bone, meninges, ischemic tissues …

• Hepatic / renal clearance • Post antibiotic effect (aminoglycoside) • Inoculum / other therapeutic measures (surgery…)

Antibiogram and concentrations (I)

• Result of lab testing for bacterial sensitivity to different antibiotics • “In vitro” sensitivity • Results: Susceptible / Intermediate / Resistant – S = high probability that usual doses of ATB will kill bacteria – R = no chance of killing bacteria Wild-type E. Coli + E.–Coli, penicillinase, I = ??? « S » for all « R » to amox

E. Coli + cephalosporinase, « R » to many ATB

• Pre-defined thresholds for each strain and antibiotic

Antibiogram and concentrations (II)

• Minimal Inhibitory Concentration (MIC) – Lowest concentration of an antibiotic to inhibit growth of bacteria – Underlying concept of « R », « S » and « I » results of antibiogram

Time vs concentration dependant drugs • Concentration-dependent –

Higher the concentration reached at site of infection, greater the effect

–

Effectiveness: Peak / MIC

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Aminoglycosides, Fluoroquinolone

• Time-dependent –

Longer a certain concentration (MIC) maintained at site of infection, greater the effect

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Higher concentration does not result in more effect

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Effectiveness: time > MIC

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ß lactams, Vancomycin …

Adverse effects • Dose-dependent –

Overdose

–

Underdose

• Dose-independent: allergy…

• Administration route dependent • Benefits and risks according to patient severity

Some practical examples (specific classes ATB)

Aminoglycosides (I) gentamycin, amikacin

• Bactericidal / basteriostatic ?

• Bactericidal

• Narrow / broad spectrum ?

• Broad spectrum :

 Useful for severe infection  Frequent drug, for frequent

• Genetic/inducible resistance ? infections (peritonitis, UTI…)

 Once daily dose

• Diffusion into infected tissue ?  High dose (« weight dose »)

– GPC = staph (gentamicin) – GNB (gentamicin / amikacin)

• Little resistance : still very effective after many years

• NO enteral route. IV or IM. • Poor diffusion bone/ CSF

• Time / concentration dependent drug ?

• Concentration drug. Peak (/MIC) fundamental

• Toxic ?

• Nephrotoxic

Aminoglycosides (II) • Once-daily high dosing over 30 min – Predictible effectiveness if Cmax/MIC > 8-10 – No MIC available in field … wager on high concentration

• Nephrotoxicity… yes… BUT saturable process !

– Higher dose ≠ higher toxicity – Lower dose = risk being outside appropriate Cmax/MIC ratio – Acute renal failure = longer dosing interval, NOT lower dose ! one « real » dose – Critically-ill patients (those at risk of renal failure) have greatest need (even if only one !)

Consider giving only for high dose

– Avoid other nephrotoxic drugs (NSAIDs …) and other risk factors for renal failure (hypovolaemia,…)

Aminoglycosides : take home messages • Gentamicin = (3-)5 mg/kg • Amikacin = (15-)25 mg/kg

• Difficult to treat infections (bone…)

 high dose

or severe sepsis • Give as 30 min infusion • 1 x /day • If acute renal failure (oliguria,…) consider with-holding other doses

ß- Lactams (I) • Penicillins – Penicillin G (IV/IM) – Penicillin V – Penicillin M = cloxacillin – Ampicillin – amoxicillin (+/- clav. ac) – Ticarcillin – piperacillin (+/- clav. ac)

• Cephalosporins – C1G : cefazoline (IV) / cefalexine (PO) – C2G : cefoxitine (IV) / cefuroxime (PO) – C3G : ceftriaxone (IV) / cefixime (PO)

• Carbapenems – Imipenem (IV) – Ertapenem – Meropenem

ß- Lactams (II) • Bactericidal / basteriostatic ?

• Bactericidal

• Narrow / broad spectrum ?

• Broad spectrum :

 Useful for severe infection

– GPC / GNB – Broader for ureido-carboxy peni, C3G

 Frequent drug, for frequent infections resistance ?

• Genetic/inducible

•

 Common genetic / inducible resistance,into for almost all bacteria Diffusion infected tissue  Time-dependent  several doses / day

• Lots of resistance… predictable spectrum and previous antibiotherapy

?

• IV / IM / PO (mild gastric absorption) • Poor diffusion in bone/CSF

• Time / concentration dependent drug ?

• Time-dependent drug.

Time > MIC fundamental

• Toxicity ?

• Rare

ß- Lactams (III)

MIC

ß- Lactams take home messages • Time dependant : « high » loading dose, then maintenance with repeated doses at regular intervals • IV > oral • Many mecanisms of resistance : consider changing drug or class, if treatment failure

Clinical cases (I) • 28 yo male Abdominal gunshot  laparotomy  colic perforation  resection + anastomosis • What does the protocol say ?

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Cefazoline 2g/12h IV

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Gentamycin 4 mg/kg/d IV – 3 days

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Metronidazole 500 mg/8H IV

• After 6 days, apparition of severe sepsis with frank peritonitis.

Surgery  anastomotic leak + faecal peritonitis • Options for antibiotherapy ?

Clinical cases (II) • Nosocomial peritonitis • Factors to be considered to adapt antibiotherapy –

Huge bacterial inoculum (GNB +++, anaerobes, GPC)

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Gastrointestinal route inappropriate

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Potential resistant strains (almost 1 week treatment)

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Urgent treatment required

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Acute renal failure due to sepsis / previous treatment

• Broad spectrum/ bactericidal / IV / « high » doses / renal function surveillance  Ceftriaxone 2g (loading dose) then 1g / 12h + Amikacine 25 mg/kg x 1 / day over 30 min (1-2 doses) + Metronidazole 500 mg IV / 8h OR ls a s o p roPiperacillin – tazobactam 4g / 6h p +/- Amikacine

Clinical cases (III) • 21 yo male GSW L tibia  open fracture  debridement, external fixator, 72 h antibioprophylaxis • 2 weeks later, pus coming from the fracture site.

• What do you do ?

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Take appropriate specimens

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Probabilist antibiotherapy : Cloxacillin 2g IV x 4/day + Gentamicin 4mg/kg, 1x/day

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To cover Staphylococcus

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Adapt later according to bacteriological results

Conclusion • Few new drugs in the pipeline • Bacteria more capable of adaptation than us • Use the drugs we have sparingly • Do NOT give unecessay antiobiotics …

• And if necessary, give it/them correctly: –

Right drug

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To the right patient

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At the right dose

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At the right interval

Questions ?

Thanks for your attention