Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Rational use ab


Published on

Published in: Health & Medicine

Rational use ab

  1. 1. Rational Use of Antibiotics Dr Ruzilawati Abu Bakar Jabatan Farmakologi ext 6126 4th Year Medical Posting 2009/2010
  2. 2. Outline of the lecture 1)Indications for antibacterial therapy – definitive, empiric & prophylaxis 2) Selection of antimicrobial agents 3) Methods of administration of antimicrobials 4) Antibiotics Resistance 5) Classification of antibacterial agents
  3. 3. Indications for antibacterial therapy: 1. Definitive therapy •This is for proven bacterial infections •Attempts should be made to confirm the bacterial infection by means of staining of secretions/fluids/exudates, culture & sensitivity, serological tests & other tests •Based on the reports, a narrow spectrum, least toxic, easy to administer & cheap drug should be prescribed.
  4. 4. 2. Empirical therapy • Empirical antibacterial therapy should be restricted to critical cases, when time is inadequate for identification & isolation of the bacteria & reasonably strong doubt of bacterial infection exists: - septicemic shock/sepsis syndrome - immunocompromised patients with severe systemic infection - hectic temperature - neutropenic patient (reduction in neutrophils) In such situations, drugs that cover the most probable infective agent/s should be used. Empiric antibiotic is antibiotic therapy that is begun before a specific pathogen is identified
  5. 5. 3. Prophylactic therapy • Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections. • In all these situations, only narrow spectrum & specific drugs are used • The duration of prophylaxis is dictated by the duration of the risk of infection. • eg. 1. Prevention for persons from non-malarious areas who visit areas endemic for malaria. 2. Treatment prior to certain surgical procedures to prevent infections
  6. 6. Bacteria vs Host Bacteria Host Pathogen Vs non pathogen Virulence Host defence antibiotic Disease
  7. 7. Selection of antimicrobial agents
  8. 8. Factors should be considered before prescribing antibacterial agent 1. Site of infection 2.Type of infection 3.Severity of infection 4.Isolate & its sensitivity 5.Source of infection 6.Patient factors 7.Drug-related factors
  9. 9. 1. Site of infection Infection above the diaphragm: •URTI eg pharyngitis, tonsilitis, sinusitis, otitis, epiglottitis etc. - commonly caused by organism like Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci (rarely Mycoplasma, H. influenzae) - Can be treated with drugs like penicillins macrolides cephalosporins
  10. 10. 1. Site of infection…con’t Lower respiratory tract infections: Eg. Bronchitis, pneumonitis, pneumonia, lung abscess etc -generally caused by the organisms Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci, Staph aureus (rarely Mycoplasma, H. influenzae, Moraxella, Klebsiella) etc. - can be treated penicillins, cephalosporins, macrolides & tetracylines
  11. 11. 1. Site of infection …. con’t Infection below the diaphragm: •Eg UTI, intra-abdominal sepsis, pelvic infections etc --- these are caused by the organisms like E. coli, Klebsiella, Proteus, Pseudomonas, Bacteroides etc. • Quinolones, aminoglycosides, 3rd generation cephalosporins & metronidazole alone or in combination are useful in these infections. Rule of the thumb Infections above the diaphragm Cocci & Gram +ve organisms Infections below the diaphragm Bacilli & Gram -ve organisms
  12. 12. 1. Site of infection …. con’t • There are certain sites where the infection tends to be difficult for treatment : - meningitis (impenetrable BBB), - chronic prostatitis (non-fenestrated capillaris), - intra-ocular infections (non-fenestrated capillaries), - abscesses (thick wall, acidic pH, hydrolizing enzymes etc.), - cardiac & intravascular vegetations (poor reach & penetration), - osteomyelitis (avascular sequestrum) etc In such cases:- Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugs may have to be used
  13. 13. 2. Type of infection Infections can be localised/extensive; mild/severe; superficial/deep-seated; acute/sub acute/chronic & extracellular/intracellular. For extensive, severe, deep-seated, chronic & intracellular infections – • Higher & more frequent dose • Longer duration of therapy • Combinations • Lipophilic drugs may have to be used
  14. 14. 3. Severity of infections • Bacteremia / sepsis syndrome / septic shock; • abscess in lung / brain/ liver/ pelvis/ intra-abdominal; • meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperal sepsis; • Severe soft tissue infections / gangrene & hospital acquired infections For severe infections only IV route - to ensure adequate blood levels. only bacterial drugs - to ensure faster clearance of the infection. dose should be higher & more frequent. - If the site is unknown, attempt should be made to cover all possible organisms, including drug resistant Staphylococcus, Pseudomonas, & anaerobes. - A combinations of Penicillins / 3rd generation cephalosporins, aminoglycosides & metronidazole may be used.
  15. 15. 4. Isolate & sensitivity • Ideal management of any significant bacterial infection requires culture & sensitivity (C&S) study of the specimen. • If the situation permits, antibacterials can be started only after the sensitivity report is available. • Narrow spectrum, least toxic, easy to administer & cheapest of the effective drugs should be chosen. If the patient is responding to the drug that has already been started, it should not be changed even if the in vitro report says otherwise
  16. 16. 5. Source of infection Community-acquired infections are less likely to be resistant whereas Hospital-acquired infections are likely to be resistant & more difficult to treat (eg. Pseudomonas, MRSA etc)
  17. 17. 6. Patient factors • Factors should be considered in choosing the antibacterial agent: - Age of the patient - immune status - pregnancy & lactation - associated conditions like renal failure, hepatic failure, epilepsy etc. • In infants, chloramphenicol (can cause grey baby) & sulpha drugs (can cause kernicterus) are contraindicated
  18. 18. • In the elderly, achlorhydria may affect absorption of anticbacterial agents; drug elimination is slower, requiring dose adjustments & ototoxicity of aminoglycosides may be increased. Patient factors…….con’t Children Elderly - Tetracycline are contraindicated < 8 years because they discolour the teeth - < 18 years ALL fluoroquinolones are contraindicated because they cause arthropathy by damaging the growing cartilage.
  19. 19. • In patients with likelihood of compromised immune status, like extremes of age, HIV infection, diabetes mellitus, neutropenia, splenectomy, using corticosteroids or immunosuppresants, patients with cancers/blood dyscrasias, ONLY bactericidal drugs should be used. Patient factors…….con’t Patients with compromised immune status
  20. 20. Patient factors…….in pregnancy Contraindicated in all trimesters Contraindicated in the last trimesters Safe in pregnancy Contraindicated in lactating mothers • tetracylines • quinolones • streptomycin • clarithromycin • sulpha drug • nitrofurantoin • chloramphenicol •penicillins •cephalosporins •erythromycin •isoniazid •ethambutol • sulpha drug • tetracylines •nitrofurantoin • quinolones •metronidazole Drugs with limited data on safety like aminoglycoside, azithromycin, clindamycin, vancomycin, metronidazole, trimethoprim, rifampicin & pyrazinamide should be used with caution when benefits overweigh the risks
  21. 21. Patient factors…….in patients with renal failure Absolutely contraindicated Relatively contraindicated Relatively safe It is better to avoid combinations of cephalosporins & aminoglycosides in these patients because both classes can cause nephrotoxicity • tetracycline •Penicillins •Macrolides •Vancomycin •Metronidazole •Isoniazid •Ethambutol •Rifampicin •Aminoglycoside •Cephalosporins •Fluoroquinolones •Sulpha drug
  22. 22. Patient factors…….in patients with hepatic failure No drugs are absolutely contraindicated. Relatively contraindicated Safe •Chloramphenicol •Erythromycin estolate •Fluoroquinolones •Pyrazinamide •Rifampicin •Isoniazid •Metronidazole •Penicillins •Cephalosporins •Ethambutol •Aminoglycosides
  23. 23. 7. Drug factors 1. Hypersensitivity: If the patient has prior history of hypersensitivity the antibacterial agent should be avoided. It is therefore important to elicit this history in all patients (common with penicillin) 2. Adverse reactions: Certain ADRs warrant discontinuation of therapy & the doctor should adequately educate the patients on these adverse effects.
  24. 24. 7. Drug factors 3. Cost: It should always be remembered that just because as particular drug is expensive, it need not be superior than the cheaper ones. Eg. Cheaper drug like doxycycline or co-trimoxazole are as effective as the costlier clarithromycin or cephalosporins in the management of lower RTI.
  25. 25. 7. Drug factors…….con’t 4. Interactions: Interactions with food & other concomitant drugs should be considered before instituting antibacterial therapy so as to maximize efficacy & minimize toxicity. a) Interactions include enhanced nephrotoxicity or ototoxicity when aminoglycosides are given with loop diuretics, vancomycin or cisplatin. b) Rifampicin, a strong inducer of hepatic drug-metabolizing enzymes, decreases the effects of digoxin, ketoconazole, oral contraceptives, propranolol, quinidine & warfarin. c) Erythromycin inhibits the hepatic metabolism of a number of drugs, including phenytoin, terfenadine, theophylline & warfarin.
  26. 26. Methods of administration of antimicrobials Route of administration The route of administration depends on the site, type & severity of the infection & the availability of a suitable drug - Oral route is the most preferred, easy & cheap, but may not be reliable in all circumstances, esp. in patients with severe infections, non-compliant patients, in the presence of vomiting etc. Certain drugs like the aminoglycosides & most 3rd generations cephalosporins are not available for oral administration. - IM route should generally be restricted for the administration of procaine & benzathine penicillin. The absorption is not very reliable & it is painful & dislike by the patients.
  27. 27. Route of administration…….con’t - IV route is the best for the management of severe & deep-seated infections since it ensures adequate serum drug levels. Procaine penicillin & benzathine penicillin should never be given IV. •However, some drugs are not available for parental use (eg. Most macrolides, sulpha drugs, tetracyclines) • Chloramphenicol, the fluoroquinolones & trimethoprim- sulphamethoxazole (TMP-SMZ) are also available orally. • Antibacterials are also used topically
  28. 28. Dosage - Dosage depends on patient’s age, weight, associated conditions like pregnancy, renal & hepatic failure & site, type & severity of infection. - Generally the dose should be higher in cases of severe, deep-seated infections & lower in cases of renal-failure. - Unnecessary overdosage only adds to the cost & adverse effects.
  29. 29. Frequency of administration • The drug should be administered 4-5x the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day. • Frequency can be:- - increased in cases of severe, deep seated & sequestrated infections - reduced in cases of renal & hepatic failure.
  30. 30. Duration • Duration of therapy depends on the site 1) Tonsilitis – 10 days 2) Bronchitis – 5-7 days 3) UTI – single shot to 21 days 4) Lung abscess- 2-4 weeks 5) Tuberculosis – 6-24 months • Longer courses of therapy are usually required for infections due to fungi or mycobacteria • Endocarditis & osteomyelitis require longer duration of treatment
  31. 31. Combinations 1) For synergistic effect: eg: combination of 2 bacteriostatic drugs such as trimethoprim + sulfamethoxazole = Co-Trimoxazole (bacterim®) Therapeutic advantage of sulphonamide + trimethoprim 1) Synergistic effects 2) Bactericidal activity 3) Decrease resistance 4) Bigger spectrum of activity 5) Reduced toxicity
  32. 32. 2) Treatment of infections with multiple organisms: Mixed infections in lung abcess, peritonitis, soiled wounds etc naturally require multiple antibiotics for complete clearance of the infection – penicillins (for Gram +ve & certain anaerobes) & aminoglycosides (for Gram –ve); metronidazole for bacteroides. penicillins + aminoglycosides + metronidazole Combinations…….con’t
  33. 33. 3) To prevent resistance: Use of combination is a well known method of preventing drug resistance. The classic example is the antiTB therapy, Eg isoniazid + ethambutol + rifampicin 4) To overcome resistance: Combination of specific drugs can be useful in overcoming that resistant infections, eg Penicillins + β-lactamase inhibitors (Co-amoxiclav/augmentin) Combinations…….con’t
  34. 34. The following combinations are irrational, not useful or even harmful: 1) Bactericidal with bacteriostatic eg. Penicillins (bactericidal) with tetracyclines ( bacteriostatic) Bactericidal a/b (kill bacteria) – tend to be used in combination with one another Bateriostatic a/b (prevent bacteria’s reproduction) – tend to be used on its own 2) Combinations of drugs with similar toxicity eg. Chloramphenicol & sulpha drug 3) Combining drugs for non-existing “mixed infections” eg. Tablets of ciprofloxacin + metronidazole/tinidazole
  35. 35. Clinical failure of antimicrobial therapy
  36. 36. Failure of an antibiotic regimen (1) 1) Drug factors • incorrect choice, • poor tissue penetration • inadequate dose • pH – low pH reduces effectiveness of aminoglycosides, erythromycin, clindamycin Inadequate clinical or microbiological response to antimicrobial therapy can result from multiple causes, including;
  37. 37. Failure of an antibiotic regimen (2) 2) Host factors • poor host defense, • age • renal & liver function • pre-existing dysfunction of other organs 3) Pathogen factors  resistance  superinfection
  38. 38. Antibiotic Resistance
  39. 39. “Penicillin Era”  1942-1950 available without a prescription1942-1950 available without a prescription Public demand followed by production of throatPublic demand followed by production of throat sprays, cough lozenges, mouthwashes, soaps and othersprays, cough lozenges, mouthwashes, soaps and other products containing penicillinproducts containing penicillin  Alexander FlemingAlexander Fleming  Warned that excessive use could result inWarned that excessive use could result in antimicrobial resistanceantimicrobial resistance  ““the microbes are educated to resist penicillin andthe microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred outa host of penicillin-fast organisms is bred out which can be passed to other individuals and fromwhich can be passed to other individuals and from them to others until they reach someone who getsthem to others until they reach someone who gets a pneumonia or septicemia which penicillin cannota pneumonia or septicemia which penicillin cannot savesave.” The New York Times 1945.” The New York Times 1945  Fleming’s words proved to be correct....Fleming’s words proved to be correct....
  40. 40. The Problem of Antibiotic Resistance  Penicillin resistance first identified in 1940’sPenicillin resistance first identified in 1940’s  Since then, antibiotic resistance hasSince then, antibiotic resistance has developed faster than new drugsdeveloped faster than new drugs  Estimated cost of infections: $4-5 million perEstimated cost of infections: $4-5 million per yearyear  Antibiotic resistance previously concentratedAntibiotic resistance previously concentrated in hospitals, especially ICUsin hospitals, especially ICUs  MRSA recently estimated to kill 18,000MRSA recently estimated to kill 18,000 Americans yearlyAmericans yearly
  41. 41. History APPEARANCE DRUG INTRODUCTION OF RESISTANCE Penicillin 1943 1946 Streptomycin 1945 1959 Tetracycline 1948 1953 Erythromycin 1952 1988 Vancomycin 1956 1988 Methicillin 1960 1961 Ampicillin 1961 1973 Cephalosporins 1964 late 1960’s
  42. 42. Antibiotic Resistance Relative or complete lack of effect of antimicrobial against a previously susceptible microbe • Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not stop their growth.
  43. 43. What causes the rapid occurrence of widespread resistance? (1) Incomplete treatment: - people fail to finish the full course of their medication - 25% of previously-treated tuberculosis patients relapsed with drug resistant strains; most had failed to complete their initial course What Factors Promote Antimicrobial Resistance?
  44. 44. (2) Mis-prescription: - patients demand antibiotics for cold - widespread inappropriate use: up to 50% of prescriptions in developing countries are for viral infections that cannot respond What Factors Promote Antimicrobial Resistance? (3) Exposure to microbes carrying resistance genes
  45. 45. Inappropriate Antibiotic Use  Prescription not taken correctlyPrescription not taken correctly  Antibiotics for viral infectionsAntibiotics for viral infections  Antibiotics sold without medical supervisionAntibiotics sold without medical supervision  Spread of resistant microbes in hospitals dueSpread of resistant microbes in hospitals due to lack of hygieneto lack of hygiene  Lack of quality control in manufacture or outdatedLack of quality control in manufacture or outdated antimicrobialantimicrobial  Use of broad-spectrum agents when a narrow-Use of broad-spectrum agents when a narrow- spectrum drug would sufficespectrum drug would suffice  (eg, use of third-generation cephalosporins for community-(eg, use of third-generation cephalosporins for community- acquired pneumonia)acquired pneumonia)
  46. 46. • The four main mechanisms by which microorganismsThe four main mechanisms by which microorganisms exhibit resistance to antibiotics are:exhibit resistance to antibiotics are: (1) Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases. (2) Alteration of target site: e.g. alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria – resulting in decreased binding of the antibiotic to its target. Mechanisms of Antibiotic Resistance (1)
  47. 47. (3) Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, they turn to utilizing preformed folic acid. (4) Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface. Mechanisms of Antibiotic Resistance (2)
  48. 48. Resistance: β-lactamase Enzymes •Bacteria produce β-lactamase enzymes to hydrolyze the β-lactam ring before drugs can reach inner membrane where PG synthesis occurs •A cell may produce 100,000 β- lactamase enzymes, each of which can destroy 1,000 penicillins per second 100 million molecules of drug destroyed per second • β-Lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.
  49. 49. β-lactamases  Enzymes produced by bacteria whichEnzymes produced by bacteria which destroydestroy ββ-lactam antibiotics-lactam antibiotics  Many different typesMany different types Penicillinases, cephalosporinases,Penicillinases, cephalosporinases, carbapenemasescarbapenemases  Most are plasmid mediatedMost are plasmid mediated
  50. 50. Overcoming β-lactam Resistance slow to hydrolyze  As a response to bacterial resistance to β-lactam drugs, there are drugs, such as Augmentin, which are designed to disable the β-lactamase enzyme.  Augmentin is made of amoxicillin, a β-lactam antibiotic, and clavulanic acid, a β-lactamase inhibitor.  The clavulanic acid is designed to overwhelm all β-lactamase enzymes, bind irreversibly to them, and effectively serve as an antagonist so that the amoxicillin is not affected by the β-lactamase enzymes.
  51. 51. Amoxicillin (β-lactam antibiotic) + clavulanic acid (a β-lactamase inhibitor) = Co-amoxiclav (Augmentin®) Ampicillin (β-lactam antibiotic) + sulbactam (a β-lactamase inhibitor) = Unasyn® Overcoming β-lactam Resistance
  52. 52. Resistance in Simpler Terms… BA By-pass Altered target Efflux Impermeability Inactivation (alteration of metabolic pathway) (reduced drug accumulation) (reduced drug accumulation)
  53. 53. Genetic alterations in drug resistance  Acquired antibiotic resistance requires theAcquired antibiotic resistance requires the temporary or permanent gain or alterationtemporary or permanent gain or alteration of bacterial genetic information.of bacterial genetic information.  Resistance develops due to the ability ofResistance develops due to the ability of DNA:-DNA:- 1.1. To undergo spontaneous mutationTo undergo spontaneous mutation 2.2. To move from one organism to anotherTo move from one organism to another (DNA/gene transfer)(DNA/gene transfer)
  54. 54. Spontaneous mutation of DNA  Stable and heritable genetic change  Not induced by antimicrobial agents  Resistance variant will proliferate  Eg. The emergence of rifampicin-resistant M.tuberculosis when rifampicin is used as a single antibiotic
  55. 55. DNA/Gene transfer of drug resistant transduction conjugation transformation  DNA Most resistance genes are plasmid mediated  Plasmid may enter cells by processes such as conjugation, transduction (phage mediated) & transformation
  56. 56. Measuring Antimicrobial Sensitivity Disk DiffusionDisk Diffusion E- testE- test (antimicrobial(antimicrobial gradient method)gradient method) Serial dilutionSerial dilution
  57. 57. MIC increase in the case of resistance (Minimal inhibitory concentration) - important in diagnostic laboratories to confirm resistance of microorganisms to an antimicrobial agent Measuring Antimicrobial Sensitivity
  58. 58. Consequences of Antimicrobial Resistance InfectionsInfections resistant toresistant to availableavailable antibioticsantibiotics Increased costIncreased cost of treatmentof treatment
  59. 59. Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use Narrow spectrum Combination in long term use (TB) Direct observed dosing (TB) Appropriate dose and duration  Use more narrow spectrum antibioticsUse more narrow spectrum antibiotics  Use antimicrobial cocktailsUse antimicrobial cocktails Prevention of resistance
  60. 60. Classification of antibacterial agents
  61. 61.  Chemical structureChemical structure  Mechanism of actionMechanism of action  Spectrum of activitySpectrum of activity Broad, extended, narrowBroad, extended, narrow  Types of actionsTypes of actions Bactericidal, bacteriostaticBactericidal, bacteriostatic Classification of antibacterial agents
  62. 62. Chemical structure  SulfonamidesSulfonamides  sulfadiazinessulfadiazines  DiaminopyrimidinesDiaminopyrimidines  TrimethoprimTrimethoprim  QuinolonesQuinolones  Nalidixic acid, ciprofloxacinNalidixic acid, ciprofloxacin  b-lactam antibioticsb-lactam antibiotics  Penicillins, cephalosporins,Penicillins, cephalosporins, carbapenems, monobactamscarbapenems, monobactams  TetracyclinesTetracyclines  Tetracycline, doxycyclineTetracycline, doxycycline  Nitrobenzene derivativesNitrobenzene derivatives  ChloramphenicolChloramphenicol  AminoglycosidesAminoglycosides  GentamicinGentamicin  MacrolidesMacrolides  ErythromycinErythromycin  Nitrofuran derivativesNitrofuran derivatives  NitrofurantoinNitrofurantoin  GlycopeptideGlycopeptide  VancomycinVancomycin  NitroimidazolesNitroimidazoles  MetronidazolesMetronidazoles
  63. 63. TermsTerms DefinitionsDefinitions Narrow-spectrumNarrow-spectrum antibioticsantibiotics Antibiotics acting only on a single or aAntibiotics acting only on a single or a limited group of microorganismslimited group of microorganisms Eg.-Eg.- isoniazid active only againstactive only against mycobacteriamycobacteria Extended-spectrumExtended-spectrum antibioticsantibiotics Antibiotics that are effective against gramAntibiotics that are effective against gram +ve organisms & also against a significant+ve organisms & also against a significant no. of gram -ve of gram -ve organisms. Eg.-Eg.- ampicillin – acts against gram +ve– acts against gram +ve organisms (Listeria monocytogenes) & someorganisms (Listeria monocytogenes) & some gram -ve organisms (gram -ve organisms (E. coliE. coli).). Broad-spectrumBroad-spectrum antibioticsantibiotics Antibiotics affect a wide variety ofAntibiotics affect a wide variety of microbial speciesmicrobial species Eg.-Eg.- tetracycline active against chlamydia,active against chlamydia, mycoplasma, actinomyces, anaerobicmycoplasma, actinomyces, anaerobic organisms, gram –ve rods (organisms, gram –ve rods (E. coliE. coli)) Spectrum of activity
  64. 64. Spectrum of activity
  65. 65. Summary of antibiotic’s spectrum Narrow Spectrum • Aztreonam • Benzylpenicillin • Cloxacillin • Phenoxymethyl- penicillin • Cephalexin Broad Spectrum •Amoxycillin •Aminoglycoside •Ciprofloxacin •Chloramphenicol •Imipenam •Tetracycline •Vancomycin •Carbenicillin •3rd generation cephalosporins
  66. 66. Bactericidal vs. bacteriostatic BactericidalBactericidal agentsagents outright killoutright kill bacteria.bacteria. Bacteriostatic agents inhibit growth but don’t kill. They rely on body defenses to clear the infection. Penicillins Cephalosporins Macrolides Tetracyclines
  67. 67. Mechanism of actions Mechanism of actionMechanism of action Antibacterial agentAntibacterial agent Inhibition of cell wall synthesisInhibition of cell wall synthesis PenicillinPenicillin CephalosporinsCephalosporins MonobactamsMonobactams VancomycinVancomycin Inhibition of DNA gyrase,Inhibition of DNA gyrase, RNA polymeraseRNA polymerase QuinolonesQuinolones RifampicinRifampicin Inhibition of protein synthesisInhibition of protein synthesis AminoglycosidesAminoglycosides TetracyclinesTetracyclines ChloramphenicolChloramphenicol MacrolidesMacrolides Inhibition of folic acid metabolismInhibition of folic acid metabolism TrimethoprimTrimethoprim SulfonamidesSulfonamides
  68. 68. 1. Beta-lactam antibiotics 1) Penicillin derivatives 2) Cephalosporins 3) Monobactams 4) Carbapenems 1) Penicillin 2) Cephalosporins β-lactam ring in red A. Cell wall Inhibitors 2. Glycopeptides 1) Vancomycin 3. Beta-lactamase inhibitors 1) Clavulanic acid 2) Sulbactam
  69. 69. Cell wall inhibitors 1.1. ββ-lactam antibiotics-lactam antibiotics PenicillinsPenicillins CephalosporinsCephalosporins CarbapenemsCarbapenems MonobactamsMonobactams 2. Glycopeptide2. Glycopeptide VancomycinVancomycin TeicoplaninTeicoplanin Penicillin core structure. "R" is variable group.
  70. 70. Bacterial cell wall β-lactam antibiotics inhibit transpeptidases enzymes that form these crosslinkages Glycopeptides bind D-alanine and prevent crosslinkage
  71. 71. A schematic of peptidoglycan’s structure. The NAM and NAG sugars are shown as green and blue spheres respectively. The tetrapeptides linked to NAM are cross-linked by a pentaglycine peptide, shown as red lines linking the D-glutamine (L) to the D- alanine (A). β-lactam antibiotics inhibit transpeptidases enzymes that form these crosslinkages Glycopeptides bind D-alanine and prevent crosslinkage
  72. 72. Penicillins - structure
  73. 73. Penicillins - classifications  Penicillin G like drugs  Penicillin G (Benzylpenicillin)Penicillin G (Benzylpenicillin)  Penicillin VPenicillin V  Procaine penicillin GProcaine penicillin G  Benzathine penicillin GBenzathine penicillin G  Penicillinase- resistant penicillins (anti staph)  Cloxacillin FlucloxacillinCloxacillin Flucloxacillin  MethicillinMethicillin  Extended spectrum penicillin  Ampicillin-like drugsAmpicillin-like drugs AmpicillinAmpicillin AmoxicillinAmoxicillin  Broad-spectrum (antipseudomonal) penicillinsBroad-spectrum (antipseudomonal) penicillins CarbenicillinCarbenicillin PiperacillinPiperacillin
  74. 74. Penicillins - pharmacokinetics Given parenterally – well distributed Crosses inflamed biological barrier Mainly excreted via kidney Inhibited by probenecid
  75. 75. Penicillins - indication  Penicillin GPenicillin G  Gram +ve infectionGram +ve infection StreptococciStreptococci MeningococciMeningococci PneumococciPneumococci ClostridiumClostridium  SyphilisSyphilis  Penicillinase-resistant penicillinsPenicillinase-resistant penicillins  Staph infectionStaph infection ImpetigoImpetigo AbcessAbcess  Extended spectrum penicillinExtended spectrum penicillin  Gram +ve & Gram –veGram +ve & Gram –ve Pneumonia, otitis mediaPneumonia, otitis media
  76. 76. Penicillins – adverse reaction Relatively non-toxicRelatively non-toxic Allergic reactionAllergic reaction AnaphylaxisAnaphylaxis - will occur in approximately in- will occur in approximately in 0.01% patients0.01% patients A rash on the back of a person with anaphylaxis
  77. 77. Cephalosporins
  78. 78. 1. 1st generation cephalosporins 2. 2nd generation cephalosporins -best for Gram +ve & -ve -Extended Gram –ve coverage - eg. Cefuroxime, Cefaclor - best for Gram +ve - eg. Cephalexin, Cephazoline 3. 3rd generation cephalosporins -best for Gram –ve -antipseudomonas - eg. Ceftazidime, Ceftriaxone, Cefotaxime, Cefoperazone 4. 4th generation cephalosporins -Good coverage for both Gram +ve & -ve - antipseudomonal activity -Eg. Cefipime
  79. 79. Cephalosporins – adverse reactions Fairly safeFairly safe Allergic reactionAllergic reaction Cross reaction with penicillinCross reaction with penicillin SuperinfectionSuperinfection (an infection following a previous infection, esp. when caused by(an infection following a previous infection, esp. when caused by microorganisms that have become resistant to the antibioticsmicroorganisms that have become resistant to the antibiotics used earlier)used earlier)
  80. 80. Carbapenem  ExamplesExamples ImipenemImipenem MeropenemMeropenem  Wide spectrumWide spectrum  Resistant againstResistant against ββ-lactamase-lactamase  Good activity against both Gram +ve & -veGood activity against both Gram +ve & -ve  Active against pseudomonasActive against pseudomonas  Use in resistant organismsUse in resistant organisms Hospital acquired infectionHospital acquired infection
  81. 81. Monobactam  Example Aztreonam  Resistant against β-lactamase  Antipseudomonal activity  Inactive against Gram +ve  GIT side effects – diarrhea, nausea & vomiting  IV – poorly absorbed when given via oral route.
  82. 82. β- lactamase inhibitors  ResembleResemble ββ-lactam molecules-lactam molecules  No antibacterial activityNo antibacterial activity  Inhibits bacterialInhibits bacterial ββ -lactamase-lactamase  Use in combination with penicillinsUse in combination with penicillins Ampicillin–sulbactamAmpicillin–sulbactam Piperacillin-tazobactamPiperacillin-tazobactam Amoxycillin-clavulanate (clavulanic acid)Amoxycillin-clavulanate (clavulanic acid)
  83. 83. Glycopeptides  Vancomycin, teicoplaninVancomycin, teicoplanin  Active against Gm +ve esp staphActive against Gm +ve esp staph  Not active against Gm –veNot active against Gm –ve  Use in MRSA infectionUse in MRSA infection  Nephrotoxicity, red man syndromeNephrotoxicity, red man syndrome
  84. 84. B. PROTEIN SYNTHESIS INHIBITOR 1) Aminoglycosides 2) Tetracyclines 3) Chloramphenicol 4) Macrolides 5) Fusidic Acid
  85. 85. Aminoglycosides  BactericidalBactericidal  From variousFrom various StreptomycesStreptomyces speciesspecies StreptomycinStreptomycin NeomycinNeomycin AmikacinAmikacin GentamicinGentamicin TobramycinTobramycin NetilmicinNetilmicin
  86. 86. Aminoglycosides – physical properties Water soluble (polar)Water soluble (polar) Poorly absorbed from gutPoorly absorbed from gut Given parenterallyGiven parenterally Less able to cross biologicalLess able to cross biological barrierbarrier More active at alkaline pHMore active at alkaline pH
  87. 87. Aminoglycosides - MOA  Irreversible inhibitor ofIrreversible inhibitor of protein synthesisprotein synthesis  Passive diffusion via porinPassive diffusion via porin channels of outerchannels of outer membranemembrane  Actively transport intoActively transport into cytoplasmcytoplasm  Bind to 30S subunitBind to 30S subunit ribosomeribosome  Interfere with synthesisInterfere with synthesis of proteinof protein
  88. 88. Use against Gram –ve infection Usually combined with β-lactam antibiotic Better coverage Synergistic effect No activity against anaerobe Aminoglycoside: clinical use
  89. 89. Aminoglycosides - pharmacokinetic  Polar substancePolar substance  Given i.m. or i.v.Given i.m. or i.v.  Poorly penetrate CSF or eyePoorly penetrate CSF or eye  20% blood level in inflamed meninges20% blood level in inflamed meninges  May be given intrathecalMay be given intrathecal  t1/2 = 2-3 hours= 2-3 hours  Excreted unchanged by the kidneysExcreted unchanged by the kidneys  Adjust dosage with renal impairmentAdjust dosage with renal impairment  Can be calculated based on creatinine clearanceCan be calculated based on creatinine clearance
  90. 90. Aminoglycosides: PK-PD  Concentration dependent killingConcentration dependent killing Rate of killing depend on concentrationRate of killing depend on concentration  Post antibiotic effectPost antibiotic effect Antibacterial activity persist after theAntibacterial activity persist after the level reduce to below MIClevel reduce to below MIC  Can be given single daily doseCan be given single daily dose Same efficacySame efficacy Reduce risk of toxicityReduce risk of toxicity convenienceconvenience
  91. 91. Aminoglycosides: toxicity  OtotoxicOtotoxic  Auditory damageAuditory damage  Vestibular damageVestibular damage  NephrotoxicNephrotoxic  Potentiated by otherPotentiated by other nephrotoxic drugsnephrotoxic drugs  Need to measureNeed to measure level (TDM)level (TDM)  Peak and troughPeak and trough  High doseHigh dose  Block neuromuscularBlock neuromuscular junctionjunction
  92. 92. Streptomycin  Mainly use in the treatment of TBMainly use in the treatment of TB Combine with other anti TBCombine with other anti TB  Resistance easily developed withoutResistance easily developed without combinationcombination  Side effectSide effect Fever, rashesFever, rashes Impair vestibular functionImpair vestibular function  Contraindicated in pregnancyContraindicated in pregnancy Deafness in newbornDeafness in newborn
  93. 93. Gentamicin  Active both in Gram +ve & -veActive both in Gram +ve & -ve StaphylococciStaphylococci Resistance rapidly developedResistance rapidly developed Pseudomonas, klebsiellaPseudomonas, klebsiella  No activity against streptococci andNo activity against streptococci and enterococcienterococci But can enhance the effect ofBut can enhance the effect of ββ-lactam or-lactam or vancomycinvancomycin
  94. 94. Gentamicin – clinical uses  Combine with cell wall inhibitor in severeCombine with cell wall inhibitor in severe infectioninfection  With penicillin G inWith penicillin G in Strept viridansStrept viridans endocarditisendocarditis  Should not be used alone for pneumoniaShould not be used alone for pneumonia Poor penetrationPoor penetration  Requires TDMRequires TDM If use more than 5 daysIf use more than 5 days Renal impairmentRenal impairment
  95. 95. Amikacin  Semi synthetic aminoglycosideSemi synthetic aminoglycoside  More resistant than genta towardsMore resistant than genta towards inactivating enzymesinactivating enzymes  Active against MDRActive against MDR M. tuberculosisM. tuberculosis  Usually use as second line antibioticUsually use as second line antibiotic
  96. 96. Spectinomycin Structure related to aminoglycoside but lack of amino sugars Given i.m. Only use as an alternative to penicillin in gonorrhoea therapy Penicillin sensitivity Resistant gonococcal Rarely nephrotoxic
  97. 97. Macrolides azithromycin erythromycin clarithromycin
  98. 98. Macrolides  MOAMOA Bind reversibly toBind reversibly to the 50S subunitthe 50S subunit Inhibit elongationInhibit elongation of the proteinof the protein • Streptomycin obtained fromStreptomycin obtained from StreptomycesStreptomyces erythreuserythreus • Clarythromycin & azithromycin are semisyntheticClarythromycin & azithromycin are semisynthetic
  99. 99. Erythromycin- spectrum  Gram +veGram +ve  Pneumococci, streptococci, staphPneumococci, streptococci, staph  Atypical organismAtypical organism  Mycoplasma, clamydiaMycoplasma, clamydia  MycobacteriaMycobacteria  M. kansasiiM. kansasii  Gram –veGram –ve  Neiserria sp,Neiserria sp, B pertussis,B pertussis, CorynebacteriaCorynebacteria  Treponema pallidumTreponema pallidum (syphilis)
  100. 100. Erythromycin - pharmacokinetics  Destroyed by stomach acidDestroyed by stomach acid Enteric coated tabletEnteric coated tablet  Food interferes absorptionFood interferes absorption  tt1/21/2 = 1.5 hours= 1.5 hours  Well distributed except CSFWell distributed except CSF  Excreted in bilesExcreted in biles
  101. 101. Erythromycin- uses  CorynebacterialCorynebacterial infectioninfection  DiphteriaDiphteria  Clamydial infectionClamydial infection  Community acquiredCommunity acquired pneumoniapneumonia  PertussisPertussis  SyphilisSyphilis  Penicillin allergyPenicillin allergy
  102. 102. Erythromycin- ADR  GITGIT Nausea, vomiting,diarrhoeaNausea, vomiting,diarrhoea  Liver toxicityLiver toxicity Cholestatic jaundiceCholestatic jaundice  Drug interactionDrug interaction Inhibit cytochrome P450Inhibit cytochrome P450
  103. 103. Clarithromycin  Improved acid stabilityImproved acid stability  Better absorptionBetter absorption  Longer tLonger t1/21/2 BD dosingBD dosing  Metabolised by liverMetabolised by liver  More active againstMore active against MycobacteriumMycobacterium avianavian complexcomplex  More expensiveMore expensive
  104. 104. Azithromycin  More active againstMore active against M avianM avian complexcomplex Toxoplasma gondiiToxoplasma gondii  Penetrates well into tissuesPenetrates well into tissues Concentration > 10 – 100 times serumConcentration > 10 – 100 times serum  Tissue tTissue t1/21/2 = 2-4 days= 2-4 days Single daily doseSingle daily dose Short coursesShort courses
  105. 105. Tetracyclines
  106. 106. Tetracyclines - MOA  Bind reversibly to the 30S subunit  Misalignment of anticodons of the charged tRNAs with the codons of the mRNA.  Failure of protein synthesis
  107. 107. Tetracyclines  Introduced in 1948 (chlortetracycline)Introduced in 1948 (chlortetracycline)  BacteriostaticBacteriostatic  CoverageCoverage  Gram +ve & -veGram +ve & -ve  Atypical bacteriaAtypical bacteria  RickettsiaeRickettsiae  ChlamydiaChlamydia  mycoplasmamycoplasma  ProtozoaProtozoa  AmoebasAmoebas
  108. 108. Tetracyclines – P’kinetics  GI absorptionGI absorption  tetracycline (60-80%),tetracycline (60-80%),  doxycycline (95%),doxycycline (95%),  minocycline (100%)minocycline (100%)  Impaired by food (esp with MgImpaired by food (esp with Mg2+2+ ,, CaCa2+2+ ))  Ditributed widely except intoDitributed widely except into CSFCSF  Crosses placentaCrosses placenta  Excreted both thru bile andExcreted both thru bile and urineurine  TT1/21/2  Short acting (6 hrs)Short acting (6 hrs)  TetracyclineTetracycline  Intermediate (12 hrs)Intermediate (12 hrs)  demeclocyclinedemeclocycline  Long (18 hrs)Long (18 hrs)  doxycycline, minocyclinedoxycycline, minocycline
  109. 109. Tetracyclines - uses  Drug of choice in atypical bacteria infectionDrug of choice in atypical bacteria infection  RicketsiaeRicketsiae  Used in combination to treat gastric orUsed in combination to treat gastric or duodenal ulcerduodenal ulcer  To eradicateTo eradicate H. PyloriH. Pylori  CholeraCholera  AcneAcne  Lyme diseaseLyme disease ((Borelia burgdorferiBorelia burgdorferi))
  110. 110. Tetracyclines - ADR  GITGIT  Nausea, vomiting,Nausea, vomiting, diarrhoeadiarrhoea  Damage growingDamage growing bone & teethbone & teeth  Due to CaDue to Ca2+2+ chelatingchelating propertyproperty  Yellow discolourationYellow discolouration  Contraindicated inContraindicated in children < 8 years oldchildren < 8 years old  Hepatic injuryHepatic injury  Increased duringIncreased during pregnancypregnancy  NephrotoxicityNephrotoxicity  PhotosensitizationPhotosensitization  Severe sunburn ;Severe sunburn ; doxy/demeclocyclinedoxy/demeclocycline
  111. 111. Chloramphenicol  Binds to 50 S ribosomalBinds to 50 S ribosomal subunitsubunit  Mainly bacteriostaticMainly bacteriostatic  BactericidalBactericidal H. influenzaH. influenza N. meningitidisN. meningitidis  Broad spectrum (includingBroad spectrum (including rickettsiae)rickettsiae)
  112. 112. Chloramphenicol – P’kinetics  IV (prodrug) or orallyIV (prodrug) or orally  Complete oral absorptionComplete oral absorption  Excretion depends on conversion in liverExcretion depends on conversion in liver to glucuronide, then secretion in kidneyto glucuronide, then secretion in kidney  Slow excretion in liver impairmentSlow excretion in liver impairment
  113. 113. Chloramphenicol - uses Staph brain abscess Typhus As an alternative in meningitis Conjunctivitis – eye preparation
  114. 114. Chloramphenicol - ADR Blood dyscrasias Idiosyncratic aplastic anemia Gray baby syndrome Neonates if doses not adjusted
  115. 115. D. FOLIC ACID METABOLISM INHIBITOR 1) Trimethoprim 2) Sulfonamides
  116. 116. Sulphonamide - MOA  Bacteria cannotBacteria cannot transport folate intotransport folate into cellscells  Tetrahydrofolate is aTetrahydrofolate is a DNA precursorDNA precursor  p-aminobenzoic acidp-aminobenzoic acid (PABA) is a precursor(PABA) is a precursor for folate synthesisfor folate synthesis  Sulfonamides areSulfonamides are structurally similar tostructurally similar to PABAPABA  Inhibits synthesis ofInhibits synthesis of dihydropteroatedihydropteroate sythase (DHPS)sythase (DHPS)  DHPS & DHFR absent inDHPS & DHFR absent in mammalian cellsmammalian cells
  117. 117. Sulfonamides - effect Bacteriostatic Active against Both Gram +ve & -ve E. coli, Klebsiella, Salmonella Clamydia Some protozoa – Pneumocystis carinii Not active against rickettsiae
  118. 118. Sulfonamides - Pharmacokinetics  Preparation availablePreparation available TopicalTopical OralOral Well absorbed from gutWell absorbed from gut  Distributed widely including CSFDistributed widely including CSF  Metabolized in liverMetabolized in liver  Excreted via kidneyExcreted via kidney
  119. 119. Sulfonamides - uses  TopicalTopical Sulfacetamide ophthalmic solutionSulfacetamide ophthalmic solution ConjunctivitisConjunctivitis TrachomaTrachoma Silver sulfadiazine (SSD)Silver sulfadiazine (SSD) burnsburns  SystemicSystemic Use in combinationUse in combination
  120. 120. Sulfonamides - ADR  Fever  Skin rash  Exfoliative dermatitis  Steven Johnson syndrome  Crystalluria
  121. 121. Sulfonamides - combination  Sulfadiazine + pyrimethamineSulfadiazine + pyrimethamine  Pyrimethamine inhibit protozoanPyrimethamine inhibit protozoan DHFRDHFR  SynergisticSynergistic  Penetrates CSFPenetrates CSF  11stst line for acute toxoplasmosisline for acute toxoplasmosis  Sulfadoxin + pyrimethamine (Fansidar)Sulfadoxin + pyrimethamine (Fansidar)  Long actingLong acting  Prophylaxis & treatment forProphylaxis & treatment for malariamalaria
  122. 122. Trimethoprim + sulfamethoxazole (TMP + SFX = co-trimoxazole)  TMPTMP  Inhibit DHFRInhibit DHFR  Synergistic whenSynergistic when combined with SFXcombined with SFX  Combination isCombination is bactericidalbactericidal
  123. 123. co-trimoxazole – p’kinetics TMP:SFX = 1:5 Available in IV and oral Oral Well absorbed T1/2 = 10 hrs (both) Penetrates well into CSF, prostate Excreted in urine Usually given BD dose
  124. 124. co-trimoxazole - uses  Infection caused byInfection caused by  ShigellaShigella  SalmonelaSalmonela  UTIUTI  TreatmentTreatment  prophylaxisprophylaxis  Community acquired pneumoniaCommunity acquired pneumonia  PCP pneumonia (PCP pneumonia (P. jiroveciP. jiroveci))  TreatmentTreatment  prophylaxisprophylaxis
  125. 125. Co-trimoxazole - ADR Sulfonamides ADR Megaloblastic anaemia Leukopenia Granulocytopenia
  126. 126. C. DNA gyrase / RNA polymerase (Nucleic Acid Synthesis) INHIBITOR 1) Quinolones Essential structure of all quinolone antibiotics 2) Metronidazole Fluoroquinolones
  127. 127. Fluoroquinolones  Synthetic fluorinated analogs ofSynthetic fluorinated analogs of nalidixic acidnalidixic acid  Inhibit bacterial DNA synthesisInhibit bacterial DNA synthesis  Inhibit DNA gyrase & topoisomeraseInhibit DNA gyrase & topoisomerase  ExamplesExamples CiprofloxacinCiprofloxacin NorfloxacinNorfloxacin PerfloxacinPerfloxacin
  128. 128. Required for normal transcription and replication Inhibition of topoisomerase IV prevents separation of replicated DNA
  129. 129. Fluoroquinolones Spectrum depend on drugs Earlier fluoroquinolones (ciprofloxacin) Mainly cover Gram –ve Later drug (gatifloxacin) Better coverage for Gram +ve Also useful in Atypical pneumonia TB, M. avian
  130. 130. Fluoroquinolones - uses Usually used in multidrug resistant infection UTI Bacterial AGE Gonorrhea Eradication of meningococci from carriers
  131. 131. Fluoroquinolones - ADR Usually well tolerated GIT upset Allergic reaction May damage growing cartilage (rat)
  132. 132. Metronidazole - anaerobes - It is used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. - It is used to treat ameobic dysentry, giardiasis, gangrene, pseudomonas coitis & various abdominal infections, lung abscess & dental sepsis. Mechanism of actions - The nitro group of metronidazole is chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and the products are responsible for disrupting the DNA helical structure, thus inhibiting nucleic acid synthesis.
  133. 133. Metronidazole - anaerobesanaerobes Side Effects PK It is well absorbed after oral or rectal administration •Nausea & vomiting •Peripheral neuropathy •Convulsions, headaches •Hepatitis
  134. 134. Pathogen Drug (s) of first choice Alternative Drug (s) Gram +ve cocci PneumococcusPneumococcus Penicillin G, AmpicillinPenicillin G, Ampicillin Erythromycin, CephalosporinErythromycin, Cephalosporin Streptococcus (common)Streptococcus (common) Penicillin GPenicillin G Erythromycin, CephalosporinErythromycin, Cephalosporin StaphylococcusStaphylococcus (penicillase-producing)(penicillase-producing) AugmentinAugmentin®® , Unasyn, Unasyn®® , Cloxacillin,, Cloxacillin, Methicillin, Nafcillin, TimentinMethicillin, Nafcillin, Timentin®® CephalosporinCephalosporin StaphylococcusStaphylococcus (methicillin resistance)(methicillin resistance) VancomycinVancomycin TMZ-SMZTMZ-SMZ EnterococcusEnterococcus Penicillin G plus gentamicinPenicillin G plus gentamicin Vancomycin plus gentamicinVancomycin plus gentamicin Gram -ve cocci GonococcusGonococcus CetrriaxoneCetrriaxone Penicillin G, Ampicillin,Penicillin G, Ampicillin, SpectinomycinSpectinomycin MeningococcusMeningococcus Penicillin G, AmpicillinPenicillin G, Ampicillin Cefotaxime, Cefuroxime,Cefotaxime, Cefuroxime, ChloramphenicolChloramphenicol Gram -ve rods E.coliE.coli, Proteus, Klebsiella, Proteus, Klebsiella Aminoglycosides, 3Aminoglycosides, 3rdrd generationgeneration cephalosporincephalosporin TMZ-SMZ, Fluoroquinolone,TMZ-SMZ, Fluoroquinolone, extended spectrum penicillinextended spectrum penicillin ShigellaShigella FluoroquinoloneFluoroquinolone TMZ-SMZ, AmpicillinTMZ-SMZ, Ampicillin Enterobacter, Citrobacter,Enterobacter, Citrobacter, SerratiaSerratia Imipenam, FluoroquinoloneImipenam, Fluoroquinolone TMZ-SMZ, extended spectrumTMZ-SMZ, extended spectrum penicillinpenicillin Hemophilus sppHemophilus spp Cefuroxime or 3Cefuroxime or 3rdrd generationgeneration cephalosporincephalosporin TMZ-SMZ, Ampicillin,TMZ-SMZ, Ampicillin, ChloramphenicolChloramphenicol Pseudomonas aeruginosa Aminoglycosides plus extendedAminoglycosides plus extended spectrum penicillinspectrum penicillin Ceftazidime, Aztreonam, ImipenamCeftazidime, Aztreonam, Imipenam Bacteroides fragillis Metronidazole, ClindamycinMetronidazole, Clindamycin Imipenam, Chloramphenicol,Imipenam, Chloramphenicol, Ampicillin/sulbactamAmpicillin/sulbactam
  135. 135. THANK YOU