Inappropriate Antibiotic Treatment. * p
Aznan Lelo & Zulkarnain Rangkuty Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran Universitas Sumatera Utara 21 Oktober 2009, KBK, TROPMED
Antimicrobial Chemotherapy Use of drugs to combat infectious agents Antibacterials Antivirals Antifungals Antiparasitic/Antiprotozoals Antihelminths
Three basic principles of antimicrobial therapy: 1 Selective toxicity - to exploit differences in structure and metabolism of pathogens and host cells (to kill organisms not man!) 2 Reach the site of infection at inhibitory concentrations 3 Penetrate and bind to target, avoiding inactivation and extrusion
Rational Antimicrobial Therapy SOP INFECTION
ANTIMICROBA DOSAGE & ADM.
EVALUATION
SENSITIVITY
CULTURE
TEST EDUCATED GUESS THERAPY
resistance intolerable side effect high cost
Manifestation of Infection Local Inflammation • erythema, warmth, swelling, and pain • malaise, fever ( >380C), chills • purulent drainage
• loss of function – dysphagia, – trismus, – dyspnea)
Systemic Inflammation • fatigue, malaise, anorexia, myalgia, arthralgia, and fever • BP ↓ • WBC ↑ • CRP ↑ • urine output ↓
Mortality rate (%)
Inappropriate Antibiotic Treatment 100 90 80 70 60 50 40 30 20 10 0
Appropriate antibiotic treatment
Inappropriate antibiotic treatment
*
*
*
Micek (n=102)
Harbarth (n=904)
*
pMIC)
– Time dependent with moderate to prolonged persistent effect • Macrolides, azalides, clindamycin, tetracyclines, glycopeptides, oxazolidinones • Correlated with AUC/MIC
PAE Craig, 4th ISAAR, Seoul 2003
PK/PD parameters predictive of outcome Parameter correlating with efficacy
T>MIC
Representative
Penicillins Antimicrobial Cephalosporins Carbapenems Agents Macrolides
AUC:MIC
Azithromycin Fluoroquinolones Fluoroquinolones Aminoglycosides Ketolides Metronidazole
Organism kill Time-dependent ConcentrationTherapeutic goal
Optimise duration of exposure
Cmax:MIC
dependent
Concentrationdependent
Maximize concentration exposure
Maximize concentration exposure
Drusano & Craig. J Chemother ;9:38–44,1997 Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S27–41,1998 Vesga et al. 37th ICAAC 1997
Pharmacodynamics of Bacterial Killing Concentration-dependent (greater bacterial kill at higher concentrations) vs. Concentration-independent
Administration • Schedule at regular intervals to maintain steady blood levels • Assess allergies prior to administration • Monitor for adverse and therapeutic effects • Drug interactions • Importance of completing full course • IV therapy changing to oral • Patient education
White blood cell count x 103/µL
Mean log CFU/mL
17 16 15 14 13 12 11 10 9
7 6 5 4 3 2 1 0 -1 0
3
6
9
12
Antibiotic day
15
Highest temperature (°C) 40
Duration of Antibiotic Therapy 0 2 4 6 8 10 12 14 16
Antibiotic day
PaO2:FiO2 ratio (KPa) 50 45
39
40 35
38
30 25
37
20 0 2 4 6 8 10 12 14 16
Antibiotic day
0 2 4 6 8 10 12 14 16
Antibiotic day
Adverse Reactions to Antimicrobial Agents • There are three general types of adverse reactions to antimicrobial agents: • hypersensitivity reactions (which are not dose related), • direct drug toxicity (which usually is dose related and manifests in a single organ or, occasionally, in several organs), and • microbial superinfection.
Side Effect of Commonly Used Antibiotics Antibiotics 1. Penicillin 2. Cephalosporin 3. Clindamycin 4. Erythromycin 5. Metronidazole* 6. Fluoroquinolon* 7. Tetracyclin* 8. Chloramphenicol 9. Aminoglycoside
Side effects hypersensitivity hypersensitivity diarrhea, pseudo-membrane colitis mild GI disturbance GI disturbance, seizures spontaneous tendon rupture tooth discoloration, photosensitivity bone marrow suppression damage to kidney, 8th neurotoxicity
Direct Drug Toxicity Antibiotics
Toxicity
aminoglycosides, polymyxins, amphotericin B
azotemia and renal tubular damage
Penicillins, cephalosporins, tetracyclines, rifampin
hemolytic anemia, thrombocytopenia, and leukopenia
Macrolides, trimethoprimsulfamethoxazole
agranulocytosis
Trimethoprim
anemia, leukopenia, thrombocytopenia; the effect is reversible with folinic acid.
Amphotericin B
reversible normocytic-normochromic anemia
Flucytosine
bone marrow suppression (leukopenia or pancytopenia)
Linezolid
myelosuppression
Rates of Torsades de Pointes Associated With Ciprofloxacin, Ofloxacin, Levofloxacin, Gatifloxacin, and Moxifloxacin • Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. • In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. • Conclusion. – Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. – Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Richard Frothingham, 2001
Stephens Johnson syndrome
Approach to antimicrobial therapy : ethical dilemnas Ethical principles: autonomy beneficence and nonmaleficence justice
Goal of the treatment life-sustaining treatment symptom-control prolongation of life
FUTILITY
Costs of the treatment expensive drugs discomfort side effects treatment failure
Important Host Determinants a)
b)
c)
Hepatic function: Erythromycin, clindamycin, rifampin, Chloramphenicol, etc depend on liver metabolisms for the inactivation of antimicrobial mechanisms. Patients with impaired liver function may accumulate in the body active form of the drugs to a toxic level if the dosage adjustment is not made. Kidney function: Normal kidney function is essential for disposal of β-lactams, aminoglycosides, vancomycin, etc. Active form of these drugs may accumulate in the patient with renal diseases. Host defense mechanism: A chemotherapeutic regimen that is perfectly adequate for immuno-competent patient may be totally ineffective for immuno-incompetent patient. Immunoincompetence may be due to deficiencies in (1) immunoglobulin, (2) phagocytic cells and (3) cellular immune system.
Factors influencing choice of antimicrobial agent: drug interactions IV fluids: incompatible drug mixtures
Kidney: Effect on passive readsorbtion & active secretion
Bowel: Other drug or food modifies absorbtion
Drug interaction
Liver: Induction of liver enzymes modified excretion
Plasma: Competitition for protein binding sites
Receptor sites: Drugs may compete at binding site
Examples of drug interactions Site
Antimicrobial
Interacting drug/effects
IV fluids
Many
Many - Do not mix IV fluids
GI tract
Tetracyclines Quinolones
Absorbtion reduced by food Absorbtion reduced by iron
Protein binding
Chloramphenicol Warfarin (antiocoagulant), SulphonylCo-trimoxazole ureas (antidiabetic) effects increased
Liver enzyme induction
Rifampicin
Oral contraceptive, warfarin, antidia betics, cyclosporin, etc, metabolism increased, i.e., diminished effect
Kidney
Aminoglycosides
Loop diuretics (frusemide) increase ototoxicity
Factors influencing choice or route of administration of antibiotics: GI tract disease Disease Drug absorbtion increased Crohn’s disease Coeliac disease Post-gastrectomy Drug absorbtion decreased Achlorhydria Coeliac disease Diarrhoea Post-gastrectomy
Drugs Co-trimoxazole, erythromycin Co-trimoxazole, erythromycin Penicillin V
Penicillin V Penicillins, rifampicin Rapid transit time affects absorbtion of many drugs Ethambutol
Factors influencing choice of antibiotics: Examples of drug toxicity System
Condition
Drug
Liver
Cholestasis Hepatitis
Prolonged flucloxacillin Antituberculous drugs
Marrow
Aplastic anaemia
Chloramphenicol, co-trimoxazole
Blood
Haemolysis (G6PD) Sulphonamides, primaquine
CNS
Convulsions
Amantadine
Ears
Deafness/ataxia
Aminoglycosides (monitor levels)
Kidney
Renal failure
Aminoglycosides (monitor levels)
Cardiovascular Anaphylaxis
Penicillins, cephalosporins
Dentition
Tetracycline
Hypoplasia
Always check in the BNF
Factors influencing risk of drug toxicity: examples of age-related effects Factor
Drug
Effect
Sulphonamides Chloramphenicol
Displaced bilirubin - kernicterus Mitochondrial function - Gray syndrome
Children
Tetracyclines Penicillin
Enamel hypoplasia Gastric pH reduce absorbtion
Elderly
Isoniazid Aminoglycosides
Increased risk of hepatitis Oto- and nephrotoxicity
Age Neonates
Always check in the BNF
Factors influencing risk of drug toxicity: examples of effects during pregnancy Trimester
Drug
Effect
First
Ethionamide Chloramphenicol
May be teratogenic Mitochondrial function - Gray syndrome
Second
-
-
Third
Chloramphenicol Co-trimoxazole
Gray syndrome Haemolysis, methaemoglobinaemia
Any
Quinolones Tetracyclines
Arthropathy in animals Skeletal, dental effects, maternal hepatotoxicity
Always check in the BNF
Factors influencing risk of drug toxicity: examples of effects with breastfeeding Drug
Effect
Chloramphenicol Tetracyclines
May suppress bone marrow Possible effect on dentition, but tetracyclines may be chelaed by calcium in breast milk Small risk of kernicterus and haemolysis in G6PD deficient infants
Sulphonamides
Always check in the BNF
Factors influencing risk of drug toxicity: examples of genetic effects Drug
Effect
Chloramphenicol Sulphonamides
Isoniazid
} Haemolysis in G6PD deficiency Fast acetylators - hepatoxicity Slow acetylators - neuropathy
Always check in the BNF
Factors influencing choice of antimicrobials: Renal dysfunction System
Drug
Complication
CNS
Amantadine
Convusions, ataxia
Kidneys/ears
Aminoglycosides
Nephro- & ototoxicity
Kidneys
Co-trimoxazole Tetracyclines
Interstitial nephritis Further deterioration in renal function
Always check in the BNF
What is the ideal antibiotic Have the appropriate spectrum of activity for the clinical setting. Have no toxicity to the host, be well tolerated. Low propensity for development of resistance. Not induce hypersensitivies in the host. Have rapid and extensive tissue distribution Have a relatively long half-life. Be free of interactions with other drugs. Be convenient for administration. Be relatively inexpensive
Thank you
Principles / Definitions • Minimum Inhibitory Concentration (MIC) - minimum concentration of antibiotic required to inhibit the growth of the test organism. • Minimum Bactericidal Concentration (MBC) - minimum concentration of antibiotic required to kill the test organism. • • • •
Bacteriostatic Bactericidal Time dependent killing Concentration dependent killing
Principles / Definitions • Treatment vs prophylaxis • Prophylaxis - antimicrobial agents are administered to prevent infection • Treatment - antimicrobial agents are administered to cure existing or suspected infection
EFFECTIVENESS OF COMBINATION THERAPY 1.Synergistic Effect: When two bactericidal antibiotics are used in combination. One of the two drugs must show at least 4fold increase in antibacterial activities (or a decrease in MIC to ¼) for a synergism is said to exist between the two drugs. (e.g. penicillin + streptomycin).
2. Additive Effect: When two bacteriostatic agents with the same mechanisms of action are used.
3. Antagonism: Usually bacteriostatic antibiotics are antagonistic to bactericidal agents. (e.g. Chloramphenicol has been shown to antagonize the bactericidal activities of penicillin in the treatment of Pneumococcal meningitis.
Anti-microbial agents • Concentration dependent killing implies greater bactericidal activity with higher concentration of antibiotic e.g. ; aminoglycosides and fluroquinolones
Anti--microbial agents Anti
Anti-microbial agents • Time –dependent killing : There is little or no enhancement of drug activity above MIC but depend on maintaining the concentration above the MIC as much as possible e.g. ; Penicillins and Cephalosporins
Anti--microbial agents Anti
Anti-microbial agents Post-antibiotic effect : • It is the persistent suppression of growth of organisms after the levels of antibiotic has fallen below the MIC. • Antibiotics with long post-antibiotic effect needs one dose per day. • E.g., Aminoglycosides and Quinolones
Aznan Lelo & Zulkarnain Rangkuty Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran Universitas Sumatera Utara 21 Oktober 2009, KBK, TROPMED
Antimicrobial Chemotherapy
Use of drugs to combat infectious agents Antibacterial Antiviral Antifungal Antiparasitic
Antimicrobial Chemotherapy
Differential toxicity: • based on the concept that the drug is more toxic to the infecting organism than to the host Majority of antibiotics are • naturally occurring compounds • semi-synthetic or • synthetic
What is the ideal antibiotic Have the appropriate spectrum of activity for the clinical setting. Have no toxicity to the host, be well tolerated. Low propensity for development of resistance. Not induce hypersensitivies in the host. Have rapid and extensive tissue distribution Have a relatively long half-life. Be free of interactions with other drugs. Be convenient for administration. Be relatively inexpensive
Anti-microbial agents • Antibiotics : These are the substances produced by the microorganisms,which suppress the growth or kill the microorganisms at very low concentrations.
Anti-microbial agents • Bacteriostatic drugs : Sulfonamides, Tetracyclines, Erythromycin • Bacteriocidal drugs : Penicillin, Cephalosporins , Aminoglycosides , Quinolones
Anti-microbial agents • Narrow spectrum – INH • Extended spectrum - Ampicillin • Broad spectrum - Tetracycline
Principles / Definitions Spectrum of Activity: • Narrow spectrum - drug is effective against a limited number of species • Broad spectrum - drug is effective against a wide variety of species • Gram negative agent • Gram positive agent • Anti-anaerobic activity
Principles / Definitions • Minimum Inhibitory Concentration (MIC) - minimum concentration of antibiotic required to inhibit the growth of the test organism. • Minimum Bactericidal Concentration (MBC) - minimum concentration of antibiotic required to kill the test organism. • • • •
Bacteriostatic Bactericidal Time dependent killing Concentration dependent killing
Principles / Definitions • Treatment vs prophylaxis • Prophylaxis - antimicrobial agents are administered to prevent infection • Treatment - antimicrobial agents are administered to cure existing or suspected infection
Combination Therapy • To prevent the emergence of resistance - M.tuberculosis • To treat polymicrobial infections • Initial empiric therapy • Synergy
Combination Therapy Why not use 2 antibiotics all the time? • • • •
Antagonism Cost Increased risk of side effects May actually enhance development of resistance inducible resistance • Interactions between drugs of different classes • Often unnecessary for maximal efficacy
What influences the choice of antibiotic? • • • •
Activity of agent against proven or suspected organism Site of infection Mode of administration Metabolism and excretion – renal and hepatic function • Duration of treatment / frequency of dose • Toxicity / cost • Local rates of resistance
How do antimicrobial agents work • must bind or interfere with an essential target • may inhibit or interfere with essential metabolic process • may cause irreparable damage to cell
Targets of antibacterial agents • Inhibit cell wall production - penicillin binding proteins • Inhibit protein synthesis - bind 30s or 50s ribosomal subunits • Inhibit nucleic acid synthesis - binding topoisomerases / RNA polymerase • Block biosynthetic pathways - interfere with folate metabolism • Disrupt bacterial membranes - polymixins
Anti-microbial agents • Drug resistance : It refers to the unresponsiveness of the microorganisms to the AMA. • Natural resistance – Some microbes are resistant to certain AMA eg ; gram –ve bacilli are normally resistant to the penicillin
Anti-microbial agents • Acquired resistance : It is the development of resistance by an organism (which was sensitive before) due to the use of an AMA over a period of time.
Anti-microbial agents Resistance is developed by • Mutation : It is a stable and heritable genetic change that occurs spontaneously and randomly among microorganism e.g., Rifampin resistant mycobacterium tuberculosis
Anti-microbial agents Resistance Gene transfer : by • Conjugation : R factor transferred • Transduction : transfer of resistance gene by bacteriophage • Transformation: by release of the resistance carrying DNA into the medium
Anti-microbial agents Resistance Due to alteration of expression of proteins in drug resistant organism. • Lack or alteration of binding site -penicillin • Lowered penetration – beta lactams • Increased efflux - tetracycline • Antibiotic activating enzyme – beta lactams
Antimicrobial resistance • Resistance: the inability to kill or inhibit the organism with clinically achievable drug concentrations • Resistance may be innate (naturally resistant) • Resistance may be acquired - mutation - acquisition of foreign DNA
Antimicrobial resistance • Factors which may accelerate the development of resistance - inadequate levels of antibiotics at the site of infection - duration of treatment too short - overwhelming numbers of organisms - overuse / misuse of antibiotics
Antimicrobial resistance General mechanisms of resistance Altered permeability Inactivation / destruction of antibiotic Altered binding site Novel (new) binding sites Efflux (pumps) mechanisms Bypass of metabolic pathways
Antimicrobial Chemotherapy part II
Antibiotic Classes
Antibiotic Classes • Cell Wall Active Agents bactericidal, time dependent killing • B-lactams - penicillins / cephalosporins / - cephamycins / carbapenems • Glycopeptides - vancomycin / teicoplanin - gram positive agents
Structure of β-lactam drugs
Penicillins • Penicillin G / V - good gram positive (not Staph) -moderate anaerobic activity • Synthetic penicillins (Ampicillin) - good gram positive (not Staph) - moderate gram negative (not Pseudomonas) • Anti-staphylococcal penicillins - Cloxacillin • Anti-pseudomonal penicillins - Piperacillin
Cell Wall Active Agents • B-lactams bind to “penicillin binding proteins” (PBP) -PBP are essential enzymes involved in cell wall synthesis -weakened / distorted cell wall leading to cell lysis and death • Glycopeptides bind to the terminal D-ala of nascent cell wall peptides and prevents cross-linking of these peptide to form mature peptidoglycan
Vancomycin: Mechanism of Action • Inhibit peptidoglycan synthesis in bacterial cell wall by complexing with the D-alanyl-D-alanyl portion of the cell wall precurser 2L-ala racemase
2D-ala ligase (ddl)
D-ala-D-ala UDP-L-ala-D-glu-L-lys adding enzyme
carboxypeptidase -L-ala-D-glu-L-lys-D-ala-D-ala transpeptidase -L-ala-D-glu-L-lys-D-ala-D-ala
-L-ala-D-glu-L-lys-D-ala-D-ala transglycosidase -L-ala-D-glu-L-lys-D-ala-D-ala
UDP-L-ala-D-glu-L-lys-D-ala-D-ala pentapeptide--
--L-ala-D-glu-L-lys-D-ala-D-ala
vancomycin
Cell Wall Active Agents • B-lactam resistance 1. Production of a B-lactamase (most common) 2. Altered PBP (S.pneumoniae) 3. Novel PBP (MRSA) 4. Altered permeability • Glycopeptide resistance - primary concern is Enterococcus / S.aureus - altered target - bacteria substitutes D-lac for D-ala - vancomycin can no longer bind
Cephalosporins History
• • • •
– Discovered in sewage in Sardinia in the mid 1940s. – Cephalosporium sp was recovered and proved a source of cephalosporin. – Subsequently, four generations of cephalosporins have emerged 1st generation- mainly gram pos, some gram neg (cefazolin) 2nd generation- weaker gram pos, better gram neg (cefuroxime) 3rd generation - excellent gram neg, some gram pos (ceftriaxone) 4th generation - excellent gram neg, good gram pos (cefepime)
First-Generation Cephalosporins: What do they cover? • Cefazolin (Kefzol) and cephalexin (Keflex) – Activity includes: • Methicillin susceptible staphylococci • Streptococci excluding enterococci • E. coli, Klebsiella sp., and P. mirabilis • Many anaerobes excluding B. fragilis
Where do you think they should be used?
• • • •
Simple mixed aerobic infections. In penicillin allergic (not immediate) patients. Surgical prophylaxis. Convenience drug for S. aureus and streptococci?
What about second generation cephalosporins? • Cefuroxime
• Cefoxitin/cefotetan – Think Haemophilus in – 1st generation plusaddition to 1st anaerobes generation specturm – A mixed, non-serious – A respiratory drug infection surgeon drug – Think cefazolin/metro which is what we would use
Third-Generation Cephalosporins • Cefotaxime, ceftriaxone (IV) – Enhanced activity against Enterobacteriaceae – Enhanced activity against streptococci, including penicillin resistant S. pneumoniae. – Long half life favors ceftriaxone – Less diarrhea favors cefotaxime • Ceftazidime (IV) – Active against P. aeruginosa. – Decreased activity against gram positive cocci.
Fourth generation cephalosporins • Cefepime – Marginal improvements – Not available at the QE II
Carbapenems: What don’t they get? • Everything except: – MRSA and MRSE – Enterococcus faecium – Stenotrophomonas maltophilia – Burkholderia cepacia
When to use carbapenems? • Life threatening polymicrobial infections – Intra abdominal sepsis in ICU esp nosocomial in origin – Gram negative/ nosocomial pneumonia in intubated patient
• Monotherapy of febrile neutropenia (high risk patients)
What are the beta-lactamase inhibitors?
• Clavulanate (with amoxicillin or ticarcillin) • Tazobactam (with piperacillin)
What additional bugs do they cover? • • • • •
S. aureus H. influenzae Neisseria sp. Bacteroides fragilis E. coli and Klebsiella
• Not better for Pseudomonas or Enterobacter
Inhibitors of protein synthesis • Ribosomes are the site of protein synthesis • many classes of antibiotics inhibit protein synthesis by binding to the ribosome • binding may be reversible or irreversible • Macrolides, ketolides, lincosamides, streptogramins Tetracyclines Aminoglycosides
Inhibitors of protein synthesis • Macrolides (erythromycin, clarithromycin, azithromycin) - primarily gram positive, mycoplasma, chlamydia - bacteriostatic, time dependent killing Lincosamides (clindamycin) - gram positive, anaerobic activity • Resistance (acquisition of a gene) - M phenotype: macrolides only efflux - MLSB phenotype: macrolides, lincosamides, streptogramins target site modification constitutive, inducible
Inhibitors of protein synthesis • Aminoglycosides: gentamicin, tobramycin, amikacin - excellent gram negative, moderate gram positive - bactericidal, concentration dependent • Resistance Primarily due to aminoglycoside modifying enzymes
Inhibitors of nucleic acid synthesis • Fluoroquinolones (ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin) - bactericidal, concentration dependent - bind to 2 essential enzymes required for DNA replication - DNA gyrase and topoisomerase IV - gram pos and gram neg - atypical bacteria, some have anaerobic activity • Resistance - altered permeability (porin channels) - altered target site - efflux
Inhibitors of metabolic pathways • Trimethoprim/sulfamethoxazole (Septra, TMP/SMX) - good gram negative, some gram positive • block folic acid synthesis at two different points TMP and SMX act synergistically • Resistance may arise if the organism can “bypass” the pathway making it redundant
Mechanism of action of TMP-SMX
Anti-microbial agents Patient factors : • Immune system -- important • Renal dysfunction -- aminoglycosides • Hepatic dysfunction -- erythromycin • Age – neonates and elderly • Pregnancy and lactation
Anti-microbial agents Combination of anti-microbials : • Advantages – synergy • Disadvantages – interference in one others action
Anti-microbial agents Prophylactic antibiotics • Prevention of streptococcal infections in RHD • Treatment of mother with zidovudine to protect fetus in HIV –infected, pregnant woman. • Prevention of close contacts of tuberculosis patients.
Anti-microbial agents Complications of antibiotic therapy • Hypersensitivity • Direct toxicity • Super infection
Anti-microbial agents Sites of action of anti-microbials : • Inhibitors of folic acid metabolism – sulfonamides • Inhibitors of cell wall synthesis – penicillin • Inhibitors of protein synthesis – tetracycline • Inhibitor of cell membrane - amphotericin
Rational Antimicrobial Therapy SOP INFECTION
ANTIMICROBA DOSAGE & ADM.
EVALUATION
SENSITIVITY
CULTURE
TEST EDUCATED GUESS THERAPY
resistance intolerable side effect high cost
Manifestation of Infection Local Inflammation • erythema, warmth, swelling, and pain • malaise, fever ( >380C), chills • purulent drainage
• loss of function – dysphagia, – trismus, – dyspnea)
Systemic Inflammation • fatigue, malaise, anorexia, myalgia, arthralgia, and fever • BP ↓ • WBC ↑ • CRP ↑ • urine output ↓
The tree of antibiotics
Bacterial Targets for Antibiotics
Mortality rate (%)
Inappropriate Antibiotic Treatment 100 90 80 70 60 50 40 30 20 10 0
Appropriate antibiotic treatment
Inappropriate antibiotic treatment
*
*
*
Micek (n=102)
Harbarth (n=904)
*
pMIC)
– Time dependent with moderate to prolonged persistent effect • Macrolides, azalides, clindamycin, tetracyclines, glycopeptides, oxazolidinones • Correlated with AUC/MIC
PAE
Craig, 4th ISAAR, Seoul 2003
AUIC: Pharmacodynamic Modeling
.
Dudley MN. In DiPiro ed. Pharmacotherapy A Pathophysiological Approach 3rd ed. Appleton & Lange.
PK/PD parameters predictive of outcome Parameter correlating with efficacy
T>MIC
Representative
Penicillins Antimicrobial Cephalosporins Carbapenems Agents Macrolides
AUC:MIC
Azithromycin Fluoroquinolones Fluoroquinolones Aminoglycosides Ketolides Metronidazole
Organism kill Time-dependent ConcentrationTherapeutic goal
Optimise duration of exposure
Cmax:MIC
dependent
Concentrationdependent
Maximize concentration exposure
Maximize concentration exposure
Drusano & Craig. J Chemother ;9:38–44,1997 Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S27–41,1998 Vesga et al. 37th ICAAC 1997
Pharmacodynamics of Bacterial Killing Concentration-dependent (greater bacterial kill at higher concentrations) vs. Concentration-independent
Administration • Schedule at regular intervals to maintain steady blood levels • Assess allergies prior to administration • Monitor for adverse and therapeutic effects • Drug interactions • Importance of completing full course • IV therapy changing to oral • Patient education
White blood cell count x 103/µL
Mean log CFU/mL
17 16 15 14 13 12 11 10 9
7 6 5 4 3 2 1 0 -1 0
3
6
9
12
Antibiotic day
15
Highest temperature (°C) 40
Duration of Antibiotic Therapy 0 2 4 6 8 10 12 14 16
Antibiotic day
PaO2:FiO2 ratio (KPa) 50 45
39
40 35
38
30 25
37
20 0 2 4 6 8 10 12 14 16
Antibiotic day
0 2 4 6 8 10 12 14 16
Antibiotic day
Adverse Reactions to Antimicrobial Agents • There are three general types of adverse reactions to antimicrobial agents: • hypersensitivity reactions (which are not dose related), • direct drug toxicity (which usually is dose related and manifests in a single organ or, occasionally, in several organs), and • microbial superinfection.
Side Effect of Commonly Used Antibiotics Antibiotics 1. Penicillin 2. Cephalosporin 3. Clindamycin 4. Erythromycin 5. Metronidazole* 6. Fluoroquinolon* 7. Tetracyclin* 8. Chloramphenicol 9. Aminoglycoside
Side effects hypersensitivity hypersensitivity diarrhea, pseudo-membrane colitis mild GI disturbance GI disturbance, seizures spontaneous tendon rupture tooth discoloration, photosensitivity bone marrow suppression damage to kidney, 8th neurotoxicity
Direct Drug Toxicity Antibiotics
Toxicity
aminoglycosides, polymyxins, amphotericin B
azotemia and renal tubular damage
Penicillins, cephalosporins, tetracyclines, rifampin
hemolytic anemia, thrombocytopenia, and leukopenia
Macrolides, trimethoprimsulfamethoxazole
agranulocytosis
Trimethoprim
anemia, leukopenia, thrombocytopenia; the effect is reversible with folinic acid.
Amphotericin B
reversible normocytic-normochromic anemia
Flucytosine
bone marrow suppression (leukopenia or pancytopenia)
Linezolid
myelosuppression
Rates of Torsades de Pointes Associated With Ciprofloxacin, Ofloxacin, Levofloxacin, Gatifloxacin, and Moxifloxacin • Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. • In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. • Conclusion. – Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. – Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Richard Frothingham, 2001
Stephens Johnson syndrome
Approach to antimicrobial therapy : ethical dilemnas Ethical principles: autonomy beneficence and nonmaleficence justice
Goal of the treatment life-sustaining treatment symptom-control prolongation of life
FUTILITY
Costs of the treatment expensive drugs discomfort side effects treatment failure
The role of antibiotics in various dental infection • Prescribe the right antibiotic • Start a treatment as soon as possible • Select a treatment adapted to the clinical conditions of the patient and the local conditions • Think of side-effects before to start • Use a loading dose to rapidly achieve therapeutic blood levels. • Avoid combinations of bacteriostatic and bacteriocidal drugs
Objectives • Mechanisms of actions of different groups of antibiotics. • Mechanisms by which pathogens acquire and express resistance to antibiotics. • Combination therapy (use of two or more drugs concomitantly). • Host determinants that influence the selection and efficacy of antibiotics.
EFFECTIVENESS OF COMBINATION THERAPY 1.
Synergistic Effect: When two bactericidal antibiotics are used in combination. One of the two drugs must show at least 4-fold increase in antibacterial activities (or a decrease in MIC to ¼) for a synergism is said to exist between the two drugs. (e.g. penicillin + streptomycin).
2.
Additive Effect: When two bacteriostatic agents with the same mechanisms of action are used.
3.
Antagonism: Usually bacteriostatic antibiotics are antagonistic to bactericidal agents. (e.g. Chloramphenicol has been shown to antagonize the bactericidal activities of penicillin in the treatment of Pneumococcal meningitis.
Important Host Determinants a)
b)
c)
Hepatic function: Erythromycin, clindamycin, rifampin, Chloramphenicol, etc depend on liver metabolisms for the inactivation of antimicrobial mechanisms. Patients with impaired liver function may accumulate in the body active form of the drugs to a toxic level if the dosage adjustment is not made. Kidney function: Normal kidney function is essential for disposal of β-lactams, aminoglycosides, vancomycin, etc. Active form of these drugs may accumulate in the patient with renal diseases. Host defense mechanism: A chemotherapeutic regimen that is perfectly adequate for immuno-competent patient may be totally ineffective for immuno-incompetent patient. Immunoincompetence may be due to deficiencies in (1) immunoglobulin, (2) phagocytic cells and (3) cellular immune system.
Untoward Effects of Antibiotics
1. 2. 3.
Reactions due to toxic properties of antibiotics. Hypersensitivity reactions Superinfection (or also called Suprainfection)
ANTIMICROBIAL DRUGS
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Mechanism of action include: – Inhibition of cell wall synthesis – Inhibition of protein synthesis – Inhibition of nucleic acid synthesis – Inhibition of metabolic pathways – Interference with cell membrane integrity
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Inhibition of Cell wall synthesis – Bacteria cell wall unique in construction • Contains peptidoglycan
– Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell • Due to the lack of cell wall in animal cells and differences in cell wall in plant cells
– These drugs have very high therapeutic index • Low toxicity with high effectiveness
– Antimicrobials of this class include • β lactam drugs • Vancomycin • Bacitracin
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Penicillins and cephalosporins – Part of group of drugs called β – lactams • Have shared chemical structure called β-lactam ring
– Competitively inhibits function of penicillin-binding proteins • Inhibits peptide bridge formation between glycan molecules • This causes the cell wall to develop weak points at the growth sites and become fragile.
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • The weakness in the cell wall causes the cell to lyze.
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • The weakness in the cell wall causes the cell to lyze. • Penicillins and cephalosporins are considered bactericidal. • Penicillins are more effective against Gram+ bacteria. This is because Gram + bacteria have penicillin binding proteins on their walls.
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • The cephalosporins – Chemical structures make them resistant to inactivation by certain β-lactamases – Tend to have low affinity to penicillinbinding proteins of Gram + bacteria, therefore, are most effective against Gram – bacteria. – Chemically modified to produce family of related compounds • First, second, third and fourth generation cephalosporins
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Vancomycin – Inhibits formation of glycan chains • Inhibits formation of peptidoglycans and cell wall construction • Does not cross lipid membrane of Gram – Gram - organisms innately resistant
– Important in treating infections caused by penicillin resistant Gram + organisms – Must be given intravenously due to poor absorption from intestinal tract – Acquired resistance most often due to alterations in side chain of NAM molecule • Prevents binding of vancomycin to NAM component of glycan
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Bacitracin – Interferes with transport of peptidoglycan precursors across cytoplasmic membrane – Toxicity limits use to topical applications – Common ingredient in non-prescription first-aid ointments
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Inhibition of protein synthesis – Structure of prokaryotic ribosome acts as target for many antimicrobials of this class • Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity
– Drugs of this class include • • • •
Aminoglycosides Tetracyclins Macrolids Chloramphenicol
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Aminoglycosides – Irreversibly binds to 30S ribosomal subunit • Causes distortion and malfunction of ribosome • Blocks initiation translation – Causes misreading of mRNA
– Not effective against anaerobes, enterococci and streptococci – Often used in synergistic combination with β-lactam drugs • Allows aminoglycosides to enter cells that are often resistant
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS – Examples of aminoglycosides include • Gentamicin, streptomycin and tobramycin
– Side effects with extended use include • Otto toxicity • Nephrotoxicity
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Tetracyclins – Reversibly bind 30S ribosomal subunit • Blocks attachment of tRNA to ribosome – Prevents continuation of protein synthesis
– Effective against certain Gram + and Gram – Newer tetracyclines such as doxycycline have longer half-life • Allows for less frequent dosing
– Resistance due to decreased accumulation by bacterial cells – Can cause discoloration of teeth if taken as young child
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Tetracyclins – Reversibly bind 30S ribosomal subunit • Blocks attachment of tRNA to ribosome – Prevents continuation of protein synthesis
– Effective against certain Gram + and Gram – Newer tetracyclines such as doxycycline have longer half-life • Allows for less frequent dosing
– Resistance due to decreased accumulation by bacterial cells – Can cause discoloration of teeth if taken as young child
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS – Resistance due to decreased accumulation by bacterial cells – Can cause discoloration of teeth if taken as young child
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Macrolids – Reversibly binds to 50S ribosome • Prevents continuation of protein synthesis
– Effective against variety of Gram + organisms and those responsible for atypical pneumonia – Often drug of choice for patients allergic to penicillin – Macrolids include • Erythromycin, clarithromycin and azithromycin
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS – Resistance can occur via modification of RNA target • Other mechanisms of resistance include production of enzyme that chemically modifies drug as well as alterations that result in decreased uptake of drug
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Chloramphenicol – Binds to 50S ribosomal subunit • Prevents peptide bonds from forming and blocking proteins synthesis
– Effective against a wide variety of organisms – Generally used as drug of last resort for lifethreatening infections – Rare but lethal side effect is aplastic anemia
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Chloramphenicol – Binds to 50S ribosomal subunit • Prevents peptide bonds from forming and blocking proteins synthesis
– Effective against a wide variety of organisms – Generally used as drug of last resort for life-threatening infections – Rare but lethal side effect is aplastic anemia
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Inhibition of nucleic acid synthesis – These include • Fluoroquinolones • Rifamycins
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Fluoroquinolones – Inhibit action of topoisomerase DNA gyrase • Topoisomerase maintains supercoiling of DNA
– Effective against Gram + and Gram – Examples include • Ciprofloxacin and ofloxacin
– Resistance due to alteration of DNA gyrase
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Rifamycins – Block prokaryotic RNA polymerase • Block initiation of transcription
– Rifampin most widely used rifamycins – Effective against many Gram + and some Gram - as well as members of genus Mycobacterium – Primarily used to treat tuberculosis and Hansen’s disease as well as preventing meningitis after exposure to N. meningitidis – Resistance due to mutation coding RNA polymerase • Resistance develops rapidly
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Inhibition of metabolic pathways – Relatively few – Most useful are folate inhibitors • Mode of actions to inhibit the production of folic acid
– Antimicrobials in this class include • Sulfonamides • Trimethoprim
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Sulfonamides – Group of related compounds • Collectively called sulfa drugs
– Inhibit growth of Gram + and Gram - organisms • Through competitive inhibition of enzyme that aids in production of folic acid
– Structurally similar to para-aminobenzoic acid • Substrate in folic acid pathway
– Human cells lack specific enzyme in folic acid pathway • Basis for selective toxicity
– Resistance due to plasmid • Plasmid codes for enzyme that has lower affinity to drug
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Trimethoprim – Inhibits folic acid production • Interferes with activity of enzyme following enzyme inhibited by sulfonamides
– Often used synergistically with sulfonamide – Most common mechanism of resistance is plasmid encoded alternative enzyme • Genes encoding resistant to sulfonamide and trimethoprim are often carried on same plasmid
MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Interference with cell membrane integrity – Few damage cell membrane • Polymixn B most common – Common ingredient in first-aid skin ointments
– Binds membrane of Gram - cells • Alters permeability – Leads to leakage of cell and cell death
• Also bind eukaryotic cells but to lesser extent – Limits use to topical application
RESISTANCE TO ANTIMICROBIAL DRUGS • Mechanisms of resistance – Drug inactivating enzymes • Some organisms produce enzymes that chemically modify drug – Penicillinase breaks β-lactam ring of penicillin antibiotics
– Alteration of target molecule • Minor structural changes in antibiotic target can prevent binding – Changes in ribosomal RNA prevent macrolids from binding to ribosomal subunits
SUSCEPTIBILITY OF BACTERIAL TO ANTIMICROBIAL DRUG • Mechanisms of resistance – Decreased uptake of the drug • Alterations in porin proteins decrease permeability of cells – Prevents certain drugs from entering
– Increased elimination of the drug • Some organisms produce efflux pumps – Increases overall capacity of organism to eliminate drug » Enables organism to resist higher concentrations of drug » Tetracycline resistance
ANTIMICROBIAL SUSCEPTIBILITY TESTING • Probably the most widely used testing method is the disk-diffusion method, also known as the Kirby-Bauer test.
SUSCEPTIBILITY OF BACTERIAL TO ANTIMICROBIAL DRUG • Conventional disc diffusion method – Kirby-Bauer disc diffusion routinely used to qualitatively determine susceptibility – Standard concentration of strain uniformly spread of standard media – Discs impregnated with specific concentration of antibiotic placed on plate and incubated
– Clear zone of inhibition around disc reflects susceptibility • Based on size of zone organism can be described as susceptible or resistant
EFFECTS OF COMBINATIONS OF DRUGS • Sometimes the chemotherapeutic effects of two drugs given simultaneously is greater than the effect of either given alone. • This is called synergism. For example, penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter.
EFFECTS OF COMBINATIONS OF DRUGS • Other combinations of drugs can be antagonistic. • For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth.
EFFECTS OF COMBINATIONS OF DRUGS •
Combinations of antimicrobial drugs should be used only for: 1. To prevent or minimize the emergence of resistant strains. 2. To take advantage of the synergistic effect. 3. To lessen the toxicity of individual drugs.
