Case 28 Pharmacology

1. Case 28Pharmacology by Kongkrapun Pajeenboorawun sec.c

2. Casse No. 28 • A 65 y/o male retired government employee came in ER because of dyspnea, high grad fever and chills of 2 days duration. • He has productive cough for 1 week with purulent sputum. • PE done revealed presence of rales on mid to basal portions. • Gram stain of bronchial secretions showed gram-positive lancet shaped diplococci in short chain.

3. Diagnosis • High grad fever and chills of 2 days duration due to infection. • Gram stain of bronchial secretions showed gram-positive lancet shaped diplococci in short chain. • This case is infection of Streptococcal pneumoniae

4. Streptococcal pneumoniae • Gram positive diplococci, also called pneumococci. • Lancet-shaped or arranged in chains • Polysaccharide capsule. • Positive in the Quellung Reaction for specific capsular polysaccharide. • Symptomsinclude sudden onset of fever and chills and sharp pleural pain,feeling short of breath

5. Epidemiology • Pneumococcal pneumonia is most common in elderly, debilitated, or immunosuppressed individuals. • Most infectious during the course of other infections. Initial infection will spreads to the lobes of the lungs during mucous-producing viral infections. • The disease often sets in after a preceding viral infection damages the respiratory ciliated epithelium.Incidence therefore peaks in the winter • Type 1-8 pneumococci are responsible for about 75% of the reported adult cases and nearly half of all fatalities (usually bacterial pneumonia). Usually carriers are adults (pharyngeal).

6. Pathological Process • S. pneumoniae is normal member of the respiratory tract flora; invasion results in pneumonia • Infection causes an outpouring of fibrinous fluid into the alveoli. • Portions of the lung may become consolidated. • Exudate carries bacteria away from infected foci. • Complications include inflammation of the sinuses and inner ear S. pneumoniae(small dark dots)under the microscope

7. Laboratory examination • Conventional methods for diagnosing pneumonia, primarily using sputum Gram Stain (blood or cerebrospinal fiuid), are lengthy • Capsular antigen can be detected serologiccally • Streptococcus pneumoniae Test is an in vitro rapid immunochromatographic assay for the qualitative detection of S. pneumoniae antigen in the urine of patients with pneumonia and in the cerebral spinal fluid (CSF) of patients with meningitis. In conjunction with culture and other methods, it is intended to aid in the diagnosis of both pneumococcal pneumonia and pneumococcal meningitis. Streptococcus pneumoniae (Gram-positive diplococci are located outside neutrophils.

8. TREATMENT • Penicillin:is the DRUG OF CHOICE (DOC: this term will be used commonly through out the bacteriology section). • New penicillin G-resistant pneumococci : have been reported in the U.S. and elsewhere. These are a severe management problem in meningitis, (limited access of alternative antibiotics to the central nervous system). • Erythromycin : is the secondary DOC for penicilin allergic • Vancomycin,cephalosporins:for severe infection with penicillin resistant strains

9. Penicillin • Penicillin (sometimes abbreviated PCN) refers to a group of β-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. • The name “penicillin” can also be used in reference to a specific member of the penicillin group. • Some penicillins possess the rare Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain.

10. Penicillin • Absorption vary with the preparation depending on their acid stability and protein binding • Absorption of most oral penicillins(except amoxicillin) impaired by food and drugs • Should be given 1-2 hrs before or after meal • Cannot penetrate the blood brain barrier; but 50% of plasma concentration can pass through in the presence of imflammation • Metabolized by the liver • Excreted primarily by the kidneys (90% tubular secretion, 10% glomerular filtration)

11. Penicillin-G • Penicillin-G where R = an ethyl pheny group, is the most potent of all penicillin derivatives. It has several shortcomings and is effective only against gram-positive bacteria. • It may be broken down in the stomach by gastric acids and is poorly and irregularly absorbed into the blood stream. • In addition many disease producing staphylococci are able to produce an enzyme capable of inactivating penicillin-G. • Various semisynthetic derivatives have been produced which overcome these shortcomings.

12. Machanism of action • All penicillin derivatives produce their bacteriocidal effects by inhibition last step in the peptidoglycan synthesis of bacterial cell wall. • Specifically, the cross linking of peptides on the mucosaccharide chains is prevented. • Inhibition of traspeptidase enzymes and activation of penicillin binding proteins(PBSs) • Activation of autolysis(murein hydrolases), If cell walls are improperly made cell walls allow water to flow into the cell causing it to burst.

13. Adverse effects • Hypersensitivity reaction is most common • Gastrointestinal disturbances after oral administration • Convulsions following rapid IV injection • Chronic use may cause - hepatitis - overgrowth of minor/atypical organism following use broad spectumpreparation

14. Erythromycin • Prototype • Distributed to total body water • Poor CSF penetration • Food interferes with interaction • Serum half life is 1.5 h normally and 5 hrs in patients with anuria • Not removed by dialysis • Metabolized in the liver • Transverse the placenta and reaches the fetus

15. Erythromycin • Mechanism : Bacteriostatic antibiotic macrolide produced by Streptomyces erythreus; in sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits; this binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. • Adult Dose:500 mg PO qid or 333 mg PO tidHospitalized patients with severe pneumonia: 1 g IV q6hAlternative: 15-20 mg/kg/d IV divided q6h • Pediatric Dose:7.5 mg/kg/d PO divided bidAlternative: 20-40 mg/kg/d IV divided q6h or as constant infusion; not to exceed 4 g/d

16. Erythromycin • Interactions:Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis • Contraindications:Documented hypersensitivity; hepatic impairment • Adverse effects:Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

17. Vancomycin • Poorly absorbed from intestinal tract • 99% excreted by glomerular filtration • Half life 6-10 day, not removed by dialysis • Mechanism :Inhibition of cell wall synthesis by mechanism distinct to that of penicillin (binds to D-Ala-D-Ala moiety of precursor subunit blocking transpeptidation) • Adult Dose:500 mg IV q6h or 1 g IV q12h • Pediatric Dose:10 mg/kg IV q6h • Contraindications:Documented hypersensitivity

18. Vancomycin • Interactions: Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; with concurrent use, risk of nephrotoxicity may increase above that associated with aminoglycoside use alone; neuromuscular blockade may be enhanced when used concurrently with nondepolarizing muscle relaxants • Advease effects:Caution in renal failure, neutropenia; red man syndrome is caused by too-rapid IV infusion (dose given over a few min) but rarely happens when dose given as 2-h administration or PO or IP; red man syndrome is not an allergic reaction

19. Cephalosporins • Fourth Generation ( Cefepime, Cefpirome) • Fourth generation cephalosporins are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. They also have a greater resistance to beta-lactamases than the third generation cephalosporins. • Good activity against most penicillin resistant strain of streptococci • Penetrates well into CSF • Cleared by kidneys • Half life2hrs • Indications:Cephalosporins are indicated for the prophylaxis and treatment of bacterial infections caused by susceptible organisms. Good activation against S.pneumoniae, P. aeruginosa, Enterobacteriaceae, Staph aureus.

20. Cephalosporins • Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). • Mechanism:Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). • Contraindicated:in patients with a history of severe of immediate allergic reactions (urticaria, anaphylaxis, interstitial nephritis, etc) to penicillins, carbapenems or cephalosporins

21. Cephalosporins • Interactions: Some cephalosporins cause diarrhea. Certain diarrhea medicines, such as diphenoxylate-atropine (Lomotil), may make the problem worse. Check with a physician before taking any medicine for diarrhea caused by taking cephalosporins. • Advease effects:diarrhea, nausea, rash, electrolyte disturbances, and/or pain and inflammation at injection site. Infrequent ADRs (0.1–1% of patients) include: vomiting, headache, dizziness, oral and vaginal candidiasis, pseudomembranous colitis, superinfection, eosinophilia, and/or fever.

22. Prevention • Pneumococcal polysaccharide vaccine • (Pneumovax™ is one brand) gives at least 85% protection in those under 55 years of age for five years or longer. Immunization is suggested for those at highest risk of infection, including those 65years or older, and generally should be a single lifetime dose (high risk side effects if repeated). • The standard 23-valent vaccines are ineffective for children under two years old.

23. Prevention • Vaccines: A multivalent vaccine consisting of 23 types of S. pneumoniae capsules is available. • Recommended for infants and the elderly who are at risk of exposure to the organism; also immunosuppressed or debilitated patients.

24. Thank You