Antibiotics for pneumonia

A guide to select the most appropriate antibiotic for different clinical settings of pneumonia

1. Antibiotics for Pneumonia Dr. M. Ahsan MBBS, MD

2. Learning Outcomes… By the end of the presentation, the students must be able to: Classify pneumonia List the antibiotics commonly used for different types of pneumonia Describe the pharmacokinetics and pharmacodynamics of different antibiotics used in pneumonia Describe the adverse effects and contraindication of different antibiotics used in pneumonia

3. Pneumonia Pneumonia is as an acute respiratory illness associated with recently developed radiological pulmonary shadowing, which may be segmental, lobar or multilobar

4. Pneumonia The context in which pneumonia develops is highly indicative of the causative organism Pneumonia is usually classified into: Community acquired pneumonia (CAP) Hospital acquired pneumonia (HAP) Pneumonia in immunocompromised host

5. Community acquired pneumonia Affects all age groups: Common at the extremes of age Streptococcus pneumoniae is the most common infecting agent

6. Organisms causing CAP

7. Community acquired pneumonia A ‘best guess’ as to the likely organism may be made from the context in which pneumonia develops Mycoplasma pneumoniae: more common in young people and rare in elderly Haemophilus influenzae: more common in elderly (underlying lung disease) Legionella pneumophila: local outbreaks (contaminated cooling towers) Staphylococcus aureus: more common after an episode of influenza

8. Community acquired pneumonia Mild to moderate CAP: No need for identification of the organism Managed at home with standard antibiotics 7 days course is adequate in uncomplicated pneumonia Severity is assessed by CURB-65 (or CRB-65) score CURB -65 score C : confusion present U : plasma ureas >7 mmol R : respiratory rate > 30/min B : systolic BP<90 mm Hg; diastolic BP< 60 mm Hg 65 : age > 65 years 1 point for each of the above Scare 0-1: Treat as outpatient Score 2: Admit to hospital Score 3+ : Often requires ICU

9. Antibiotics for CAP Co-amoxiclav 1.2g ×3 daily intravenously PLUS clarithromycin 500mg ×2 daily intravenously (fluoroquinolone if Legionnaire’s disease suspected) Alternative: Penicillin allergy: IV cephalosporin (e.g. ceftriaxone 2g daily) PLUS clarithromycin 500mg ×2 daily Benzylpenicillin 1.2g ×4 daily OR 4 hourly PLUS a fluoroquinolone (levofloxacin or moxifloxacin) Or Or Or Or Or

10. Amoxicillin: extended spectrum penicillin MOA: Inhibits cell wall synthesis by inhibiting the enzyme transpeptidase (no cross-linking) Like penicillin G, it is inactivated by many β lactamases Spectrum of action: Has greater activity than penicillin against gram negative bacteria Most active of the oral β-lactam antibiotics against pneumococci MOA: Inhibits cell wall synthesis

11. Amoxicillin: extended spectrum penicillin In comparison to ampicillin: Oral absorption of amoxicillin is better Food does not interfere with absorption Higher and more sustained blood levels are produced Incidence of diarrhoea is lower Amoxicillin can cause skin rash which is not allergic in nature Contraindicated in patients with penicillin allergy

12. Co-amoxiclav Fixed dose combination of amoxicillin and clavulanic acid ( β lactamase inhibitor) Clavulanic acid: Obtained from Streptomyces clavuligerus It has a β-lactam ring but no antibacterial activity of its own Rapid oral absorption and a bioavailability of 60%; can also be injected. Elimination t½ of 1 hr and tissue distribution matches amoxicillin , with which it is combined (called coamoxiclav )

13. Co-amoxiclav Rationale for adding clavulanic acid to amoxicillin: Addition of clavulanic acid re-establishes the activity of amoxicillin against β- lactamase producing organisms Especially resistant Staph. aureus (but not MRSA that have altered PBPs), H. influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella and Shigella. β-lactamases are a family of enzymes produced by many gram-positive and gram-negative bacteria that inactivate β-lactam antibiotics by opening the β-lactam ring AMOXICILLIN AMOXICILLIN β lactamase β lactamase C OPENS the Beta lactam ring

14. Co-amoxiclav Adverse effects: Same as for amoxicillin alone But g.i. tolerance is poorer—especially in children Candida stomatitis/vaginitis (superinfection) Dose combinations: Amoxicillin (250 mg) + Clavulanic acid (125 mg) Amoxicillin (500 mg) + Clavulanic acid (125 mg) Amoxicillin 1 g + Clavulanic acid (0.2 g) vial……deep im or iv

15. Clarithromycin: Macrolide antibiotic MOA: Binds irreversibly to 50S subunit of the bacterial ribosomes Inhibits translocation steps of protein synthesis Stable in gastric acidity and readily absorbed Food can increase absorption of clarithromycin Widely distributed in body tissues Extensively metabolized in the liver and excreted in urine Interferes with metabolism of theophylline, statins and antiepileptics: DRUG-DRUG Interactions Macrolides are effective against many of the organisms sensitive to Penicillin G: May be considered as an alternative in patients of penicillin allergy

16. Clarithromycin Adverse effects: Gastric distress Cholestatic jaundice (most commonly with estolate form of erythromycin) QTc prolongation (should be used with caution in patients with pro-arrhythmic conditions) Should be used cautiously in patients with hepatic dysfunction Resistance: Inability of organism to take up the antibiotic Presence of efflux pumps Decreased affinity of 50S ribosomal subunit for the antibiotic Presence of plasmid-associated erythromycin esterases in gram negetive organisms

17. Doxycycline: Tetracycline antibiotic MOA: Bacteriostatic Enters susceptible organism via passive diffusion and by an energy-dependent transport protein Binds reversibly to 30S subunit of the bacterial ribosome and prevents binding of t-RNA to mRNA-ribosome complex: INHIBITS PROTEIN SYNTHESIS Resistance: Presence of efflux pimps that expels the drug Enzymatic inactivation of the drug Production of bacterial proteins that prevent the drug from binding to ribosomes

18. Doxycycline: Tetracycline antibiotic Adequately absorbed orally Dairy production, Calcium and iron decrease absorption (esp. tetracycyline ) Binds to teeth and bones (rich in calcium) Concentrates in bile, liver, kidney, gingival fluid, skin Cross placenta: teratogenic Eliminated via bile into faeces

19. Doxycycline Adverse effects: Gastric discomfort Children: Discoloration and hypoplasia of teeth and temporary stunting of growth Hepatotoxicity Phototoxicity Vestibular dysfunction Pseudotumor cerebri Contraindication: Pregnant or breast feeding women Children less than 8 years

20. Levofloxacin: Fluoroquinolone Active against gram-negative bacilli (including P.aeruginosa ) Enhanced activity against S.pneumoniae MOA: Bactericidal Inhibits bacterial DNA gyrase [DNA gyrase: responsible for reducing torsional stress ahead of replication forks by breaking double-stranded DNA and introducing negative supercoils]

21. Levofloxacin: Fluoroquinolone 1 st generation: (active against gm- ve organisms but not P.aeruginosa ) Nalidixic acid 2 nd generation: (gm – ve including P.aeruginosa plus some gm+ve , but not S.Pneumoniae ) Ciprofloxacin, Ofloxacin, Pefloxacin 3 rd generation: ( all above plus expanded gm+ve coverage including S.pneumoniae and atypical pathogens ) Levofloxacin 4 th generation: ( same as 3 rd generation plus broad anerobic coverage) Moxifloxacin, Gemifloxacin, delafloxacin

22. Levofloxacin: Fluoroquinolone Well absorbed orally: bioavailability of levofloxacin is 90% Sucralfate, antacids, iron and zinc interfere with absorption Widely distributed in body fluids Excreted by kidneys (dose adjustments needed in renal disease) Adverse effects: Nausea, vomiting, headache, dizziness Tendinitis, tendon rupture, peripheral neuropath CNS effects (hallucination, anxiety, insomnia, seizures) Phototoxicity Used with caution in paediatric patients: Arthralgia and arthritis Can prolong QTc interval

23. Moxifloxacin Enhanced activity against gram-positive organisms ( S.pneumoniae ), gram-negative anaerobes and Mycobacterium Used for CAP but not for HAP (poor activity against P.aeruginosa ) MOA and other features similar to all fluoroquinoles

24. Hospital acquired pneumonia New episode of pneumonia occurring at least 2 days after admission to hospital Early-onset HAP (within 4–5 days of admission): Same organisms as CAP Late onset HAP: Gram-negative bacteria (e.g. Escherichia, Pseudomonas, Klebsiella species and Acinetobacter baumannii ) Staph. aureus (including MRSA) Anaerobes

25. Antibiotics for HAP Early-onset HAP: Patients who have received no previous antibiotics : co-amoxiclav or cefuroxime. If the patient has received a course of recent antibiotics: piperacillin/tazobactam or a third generation cephalosporin Late-onset HAP: The choice of antibiotics must cover the Gram-negative bacteria, Staph. aureus (including MRSA) and anaerobes. Antipseudomonal cover: carbapenem (meropenem) or a third-generation cephalosporin combined with an aminoglycoside MRSA cover: vancomycin or linezolid .

26. Cephalosporin β lactam antibiotic : inhibit cell wall synthesis 5 generations based on chronological order Cefepime Cefpirome Ceftaroline Ceftobiprole Individual cephalosporins differ in antibacterial spectrum and potency, susceptibility to beta- lactamses and pharmacokinetic properties (many have to be injected, some are given orally)

27. Cephalosporin Adverse effects: Pain after i.m injection Thrombophlebitis Diarrhoea Hypersensitivity Nephrotoxicity Bleeding Resistance to cephalosporins is due to hydrolysis of beta-lactam ring by beta-lactamases or reduced affinity for PBPs

28. Piperacillin Also called anti-pseudomonal penicillin It has good activity against Klebsiella, many Enterobacteriaceae and some Bacteroides Used for treating serious gram-negative infections in neutropenic/ immunocompromised or burn patients Elimination t½ is 1 hr. Combined with tazobactam ( β lactamase inhibitor) to extend the antibacterial spectrum to include penicillinase producing organisms

29. Carbapenem Synthetic beta-lactam antibiotic Active against: beta-lactamase producing gram-positive and gram-negative organisms, anaerobes, P.aeruginosa Administered intravenously Widely distributed in body tissues and fluids Excreted by glomerular filtration Adverse effects: Nausea, vomiting, diarrhoea Eosinophila and neutropenia are less common Seizures with imipinem Imipinem Meropenem Doripenem Ertapenem Imipinem is co-administered with cilastatin to protect the parent drug from renal dehydropeptidase , thus prolonging its activity in the body

30. Vancomycin Tricyclic glycopeptide active against aerobic and anaerobic gram positive bacteria including MRSA, MRSE, Enterococcus and C.difficile Frequency of administration depends on renal function: 90% of drug is eliminated by glomerular filtration Monitoring of creatinine clearance is required for optimal dosing Optimal cure rates are seen at trough concentration = 10-20 mcg/ml MOA: Bactericidal Binds to peptidoglycan precursors, disrupting polymerization and cross-linking in the cell wall

31. Vancomycin Adverse effects: Nephrotoxicity Infusion related reaction (red-man syndrome and phlebitis) Ototoxicity Given parenterally (poorly absorbed from GIT) Oral vancomycin: used for antibiotic-associated colitis caused by C.difficile 90% of the drug is removed by glomerular filtration

32. Linezolid Synthetic oxazolidinone Used for MRSA, VRE and penicillin-resistant Streptococci Resistance is via reduced binding to target site Protein synthesis inhibitor MOA: Binds to bacterial 23S ribosomal RNA of 50S subunit  Inhibits formation of 70S initiation complex  inhibits translation of bacterial proteins Adverse effects: Gastrointestinal upset, nausea, diarrhoea, headache, rash Thrombocytopenia Can cause serotonin syndrome Irreversible neuropathies and optic neuritis: on long-term use

33. Pneumonia in immunocompromised patient Patients immunocompromised by drugs or disease ( eg. HIV) are at high risk of pulmonary infection Organisms: Gram-negative bacteria ( esp Pseudomonas aeruginosa), viral agents, fungi, mycobacteria, and less common organisms such as Nocardia asteroids Infection is often due to more than one organism Broad-spectrum antibiotic therapy is required: third-generation cephalosporin or a quinolone, plus an antistaphylococcal antibiotic, OR antipseudomonal penicillin plus an aminoglycoside

34. Thank you

35. References Lippincott Illustrated Reviews: Pharmacology (6th ed.). Philadelphia, PA: Wolters Kluwer. Clinical Medicine: A Textbook for Medical Students &amp; Kumar PJ and Clark ML (8 th ed.); Elsevier Saunders