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Antibiotic therapy (Focus on pneumonia)
- 1. Antibiotic therapy (Focus on community-acquired pneumonia) Nehal M. Ramadan Lecturer of clinical pharmacology MSc, PhD.
- 2. Based on the most likely pathogensβ¦ + CP & local resistance patterns D of pneumonia CURB 65 score 0-1 Outpatient Inpatient Previously healthy & No comorbidities - Presence of comorbidities - Antibiotic therapy within past 3 months - Smoking & Alcohol use CURB 65 score 2 Non severely ill CURB 65 score β₯ 3 Severely ill Strep. pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae Same + π± lactamase producing bacteria H. influenzae S. pneumoniae (resistant) MSSA Gram-negative bacilli (structural lung disease) Same + Gram-negative bacilli π± lactamase producing bacteria H. influenzae S. pneumoniae (resistant) MSSA MRSA suspected Amoxicillin monotherapy OR Amoxicillin + Macrolide or Doxycycline Altern β 2nd/3rd gen. Cephalosporin + Macrolide or Doxycycline OR Resp. fluoroquinolones Amoxicillin/Clavulanate + Macrolide or Doxycycline Altern β 2nd/3rd gen. Cephalosporin + Macrolide or Doxycycline OR Resp. fluoroquinolones + Pseudomonas suspected IV Ξ²-Lactam + Macrolide (Azithromycin) OR IV Ξ²-Lactam + Respiratory fluoroquinolone IV Ξ²-Lactam + Macrolide or Doxycycline OR IV Respiratory fluoroquinolone Add vancomycin OR linezolid Antipseudomonal Ξ²-Lactam + Antipseudomonal fluoroquinolone (levofloxacin & ciprofloxacin) Altern β levofloxacin + Aztreonam + Aminoglycosides For more detailed information, please refer to https://www.uptodate.com/contents/overview-of-community-acquired- pneumonia-in-adults?search=pneumonia- &source=search_result&selectedTitle=1~150&usage_type=default&display_ran
- 3. Classification of antibiotics based on mech. Of action
- 5. Cell wall inhibitors Beta lactams Vancomycin
- 6. Ξ²-Lactam Antibacterials β¦ β Penicillins β Cephalosporins β Monobactams β Carbapenems All drugs in this class β have a Ξ²-lactam ring β must be intact for them to be active Ξ²-Lactam β susceptible to inactivation by bacterial Ξ²-lactamases β split the Ξ²-lactam ring Cephalosporins, monobactams & carbapenems β have structural modifications β show some resistance to Ξ²-lactamases.
- 7. Mech. of action β¦ 1. Ξ²-lactam antibiotics β bind to penicillin-binding proteins PBPs (transpeptidases) in bacteria, which is required for the last step of the bacterial cell wall synthesis (cross-linking of the peptidoglycan layer) β inhibit transpeptidation reaction β inhibits cell wall synthesis β exposure of the osmotically unstable cell membrane β bacterial cell swelling, rupture and death of the bacterium. All beta lactam antibiotics (penicillins, cephalosporins, carpebenems, aztreonam) share same mech.
- 8. a. Penicillins Anti-staph penicillins Flucloxacillin Methicillin Antipseudomonal penicillins Piperacillin + tazobactam Ticarcillin + clavulanate Animo-penicillins Amoxicillin +/- clavulanate Ampicillin +/- sulbactam Natural penicillins Penicillin G Penicillin V Extended spectrum Narrow spectrum Broad spectrum Intermediate spectrum
- 9. Bacterial resistance to Ξ²-Lactams 1. Production of Ξ²-lactamases β hydrolyse the Ξ²-lactam ring β Methicillin sensitive Staph. aureus (MSSA) β release extracellular Ξ²-lactamases. β Gram-negative bacteria β secrete Ξ²-lactamases between the inner and outer cell membranes in the periplasmic space. 1. Mutation in PBP β transformed into PBP2A β do not bind Ξ²- lactam antibacterials β Meticillin-resistant S. aureus (MRSA) MRSA MSSA
- 10. b. Cephalosporins Cephalosporins β more resistant to hydrolysis by Ξ²-lactamases Classified into 5 generations As a rule β¦ β Successive generations β have β activity against Gram-negative bacilli. β Moving from the 1st to 3rd generations β β Gram-positive activity & moving from 3rd to 5th generations β progressively β Gram-positive activity again
- 11. Monobactams (Aztreonam) β Spectrum of activity β limited to Gram-negative bacteria, including Pseudomonas β No cross-allergenicity with the penicillins β given to people with penicillin allergy Carbapenems β Ertapenem, imipenem, meropenem β Extremely broad spectrum of activity β Gram-positive cocci + Gram-negative bacilli including Pseudomonas + many anaerobic bacteria. β Only ertapenem is inactive against Pseudomonas. c. Carbapenems & Monobactams
- 12. Vancomycin MOA β bind to the terminal D-Ala-D-Ala portion of pentapeptide β block transpeptidation and inhibit cross-linking of peptidoglycan β interfere with cell wall synthesis Vancomycin β narrow spectrum β gram +ve, including MRSA β last resort β should only be used for serious infections caused by Ξ² lactamβresistant gram +ve bacteria (MRSA) 3 4
- 13. Side effects of Ξ²-Lactams β GIT β Nausea, vomiting β most common with oral preparations Diarrhoea (Clostridium difficile -related colitis) β a result of disturbance of normal colonic flora β especially with broad- spectrum penicillins. β Allergic reactions β common (5% of exposed individuals). Manifestations β Urticaria, wheeze and anaphylaxis (IgE- mediated reactions); Vasculitis and serum sickness (immune complex-mediated reactions). Nonspecific maculopapular rash, and the rare serious StevensβJohnson syndrome (T-cell- mediated allergy) Cross-allergenicity β with cephalosporins is < 2%; with carbapenems is < 1%; no cross-allergenicity with monobactams. β Aminopenicillins β frequently produce a nonallergic maculopapular rash in people with glandular fever (infectious mononucleosis with Epstein-Barr virus) Not associated with other types of penicillin.. β Encephalopathy β excessively high concentrations in the CSF β occurs in severe renal failure or after mistaken intrathecal injection Penicillins Safest of all antibiotics. β GIT β same as penicillins β more common with cephalosporins β Allergic reactions β A history of IgE-mediated reaction to penicillin (e.g. anaphylaxis, wheeze, urticaria) β contraindicates use of cephalosporins. β Allergic reactions β Neurotoxicity with seizures, β more common with imipenem Cephalosporins Carbapenems Vancomycin β Too rapid infusion β βred man syndromeβ β β BP, wheezing, urticaria, pruritus, flushing,muscle spasm β due to histamine release β Ototoxicity β Nephrotoxicity.
- 15. MOA β 30S ribosomal subunit β 1. Aminoglycosides β gentamicin β bind irreversibly to the 30S β misreading of bacterial mRNA code 2. Tetracyclines β doxycycline β binds reversibly to the 30S β interfere with the attachment of tRNA to the mRNA-ribosome complex 50S ribosomal subunit β 1. Macrolides β reversibly bind to the 50S β prevent the translocation movement of the ribosome along mRNA 2. Linezolid β bind to a unique site on the 50S β prevent formation of the functional 70S
- 16. 1. Macrolides β broad spectrum β gram +ve, gram -ve, including atypicals 2. Tetracyclines β broad spectrum β gram +ve, gram -ve & atypicals Clarithromycin & azithromycin > erythromycin β β penetration into lung tissues + β activity against H. influenza 1. Aminoglycosides β gram -ve, including pseudomonas 4. Linezolid β narrow spectrum β gram +ve, including MRSA
- 17. Adverse effects Macrolides β inhibit CYP450 microsomal enzyme system β Erythromycin & Clarithromycin β drug-drug interactions. Azithromycin is much less inhibitory. β GI adverse effects β Erythromycin β Intrahepatic cholestasis β erythromycin estolate Tetracyclines β Bone growth retardation β Tooth discoloration β Photosensitivity Aminoglycosides β Ototoxicity β reversible hearing loss β Nephrotoxicity β reversible acute tubular necrosis β Neuromuscular junction blockade β muscle weakness β high doses Chelation with multivalent ions CI in pregnancy & in children < 8 y β plasma concentration of other drugs, including warfarin, carbamazepine, cyclosporine and simvastatin.
- 18. Quinolones
- 19. Fluoroquinolones MOA β inhibit DNA gyrase or topoisomerase IV β inhibit relaxation of DNA supercoils β inhibit bacterial DNA replication, transcription, and repair β promote double stranded DNA breaks β DNA gyrase β gram -ve β or topoisomerase IV β gram +ve 3rd generation Levofloxacin 4th generation Moxifloxacin 2nd generation Ciprofloxacin 1st generation Norfloxacin
- 20. β 2nd generation β ciprofloxacin β mainly gram -ve, including pseudomonas β Resp. quinolones β 3rd & 4th generation quinolones β 3rd generation β levofloxacin β β activity against some gram + ve gram -ve, including pseudomonas & atypicals β 4th generation β moxifloxacin β extremely wide spectrum of activity β gram +ve, gram -ve & atypicals 3rd gen cephal 4th gen cephal amino-penicil Antipseudo penici Carpebenems 2nd gen quinol 3rd gen quinol 4th gen quinol
- 21. Adverse effects 1. Tendon rupture β The U.S. FDA boxed a warning β Increased risk of tendonitis and tendon rupture associated with fluoroquinolones. 2. Should be avoided during pregnancy 3. Fluoroquinolones prolong QT interval in ECG. 4. Photosensitivity 5. Psychosis
- 23. How important... β While Supportive care (supplemental O2, PPV, or endotracheal intubation), rehydration, antipyretics, and analgesics (provided when needed) β Antibiotics(targeting the most likely pathogenic microorganisms) β should be initiated as soon as the D of pneumonia is made or strongly suspected. β When antibiotics were administered within 4β8 hours of hospital admission β β mortality & hospital stay in patients with CAP β For most patients with CAP, the etiology is not known at the time of diagnosis β antibiotic treatment is empiric (targeting the most likely pathogens).
- 24. Host factors Pregnancy, drug allergies, age, the presence of comorbidities. 3 Drug factors 1. Antimicrobial spectrum of activity β β Microbial culture and sensitivity or β Empiric selection β based on knowledge of the most common organisms causing various types of infections and the preferred drugs for these organisms β used to treat serious infections until lab test results are available or to treat mild upper respiratory and urinary tract infections 1. Pharmacokinetic Properties β oral bioavailability, peak serum concentration, distribution to particular sites of infection, routes of elimination, and t1/2. 2. Adverse effect profile 2 Selection of an antibiotic for the treatment of a particular infection 1
- 25. Does the patient have either - Septic shock requiring vasopressor? - Respiratory failure requiring mechanical ventilation? Transfer to ICU Is patient O2 saturation is < 92% on room air? Calculate CURB-65 score inpatient score 0-1 score β₯ 3 score 2 Outpatient Inpatient (ward) Inpatient (ICU) No Yes Yes No For more detailed information on how to Define severity and site of care of CAP patients, please refer to https://www.uptodate.com/contents/image?imageKey=ID%2F113076&topicKey=ID%2F117561&searc h=pneumonia-&rank=1%7E150&source=see_link Working diagnosis of CAP For inpatients obtain the following: β Sputum Gram stain and culture β Blood cultures β Urinary antigen testing for S. pneumoniae β Testing for Legionella spp (if suspected) β SARS-CoV-2 testing
- 26. Based on the most likely pathogensβ¦ + CP D of pneumonia CURB 65 score 0-1 Outpatient Inpatient Previously healthy & No comorbidities - Presence of comorbidities - Antibiotic therapy within past 3 months - Smoking & Alcohol use CURB 65 score 2 Non severely ill CURB 65 score β₯ 3 Severely ill Strep. pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae Same + π± lactamase producing bacteria H. influenzae S. pneumoniae (resistant) MSSA Gram-negative bacilli (structural lung disease) Same + Gram-negative bacilli π± lactamase producing bacteria H. influenzae S. pneumoniae (resistant) MSSA MRSA suspected + Pseudomonas suspected
- 28. Based on the most likely pathogensβ¦ + CP & local resistance patterns D of pneumonia CURB 65 score 0-1 Outpatient Inpatient Previously healthy & No comorbidities - Presence of comorbidities - Antibiotic therapy within past 3 months - Smoking & Alcohol use CURB 65 score 2 Non severely ill CURB 65 score β₯ 3 Severely ill Strep. pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae Same + π± lactamase producing bacteria H. influenzae S. pneumoniae (resistant) MSSA Gram-negative bacilli (structural lung disease) Same + Gram-negative bacilli π± lactamase producing bacteria H. influenzae S. pneumoniae (resistant) MSSA MRSA suspected Amoxicillin monotherapy OR Amoxicillin + Macrolide or Doxycycline Altern β 2nd/3rd gen. Cephalosporin + Macrolide or Doxycycline OR Resp. fluoroquinolones Amoxicillin/Clavulanate + Macrolide or Doxycycline Altern β 2nd/3rd gen. Cephalosporin + Macrolide or Doxycycline OR Resp. fluoroquinolones + Pseudomonas suspected IV Ξ²-Lactam + Macrolide (Azithromycin) OR IV Ξ²-Lactam + Respiratory fluoroquinolone IV Ξ²-Lactam + Macrolide or Doxycycline OR IV Respiratory fluoroquinolone Add vancomycin OR linezolid Antipseudomonal Ξ²-Lactam + Antipseudomonal fluoroquinolone (levofloxacin & ciprofloxacin) Altern β levofloxacin + Aztreonam + Aminoglycosides For more detailed information, please refer to https://www.uptodate.com/contents/overview-of-community-acquired- pneumonia-in-adults?search=pneumonia- &source=search_result&selectedTitle=1~150&usage_type=default&display_ran
- 29. Thank you... With my best wishes...
Editor's Notes
- Tetracyclines β the broadest spectrum of activity among protein synthesis inhibitors.