ANTI INFECTIVES I Principles of Antimicrobial Therapy Sulfonamides Folate Antagonists o Colonization formation of population groups of the invasion multiplication of microorganisms in body tissues localized eg UTI prostatitis otitis media meningitis wounds systemic throughout the body such as blood borne infection Terminology o Infection may refer to normal flora or presence of pathogens in a particular tissue may be an active infectious disease or just potential for infection o Septicemia o Sepsis as may occur in puncture wounds cuts scrapes dental work a maladaptive reaction to severe infection including inflammation presence of living bacteria in blood o Bacteremia a systemic infection caused by bacteria living growing in bloodstream multiple organs infected damaged due to microbes their toxins in the blood same microbe narrow spectrum extended spectrum broad spectrum Sub groups of Anti infective Agents o Antimicrobial agents Antibacterial agents Antiviral agents Antimycobacterial agents Antifungal agents Drugs to treat tuberculosis mycobacterium Antiparasitic agents Antiprotozoal agents Anthelminthic agents General Mechanisms of Antimicrobial Agents o Enzyme inhibition anti metabolite EI the enzyme inhibition leads to the decrease in the formation of a product AM the enzyme binds to a substance that they think is the substrate but it transforms it into an anti metabolite sulfonamides trimethoprim bacterial enzymes acyclovir saquinavir viral enzymes o Cell wall synthesis inhibition beta lactams vancomycin o Protein synthesis inhibition Want this in the infectious organism Not the host These drugs need to be monitored becaused used at borderline toxic levels Aminoglycosides IV in hospital setting tetracyclines macrolides chloramphenicol o Nucleic acid synthesis inhibition fluoroquinolones rifampin o Cell wall permeability disruption polyene imidazole antifungals polymixins Bacteriostatic vs Bacteriocidal o Bacteriostatic agents o sulfonamides trimethoprim o most protein synthesis inhibitors chloramphenicol clindamycin macrolides erythromycin tetracyclines only inhibit microbial growth These drugs are more dependent upon host immune defense mechanism to eradicate infection than bacteriocidal agents o Bacteriocidal agents kill bacteria higher level of efficacy cell wall synthesis inhibitors time dependent killing the most important thing with this type of treatment is not stopping the treatment because the drug needs time to be effective beta lactams penicillin cephalosporins vancomycin o aminoglycosides only protein synthesis inhibitor that is cidal concentration dependent killing TDM therapeutic drug monitoring need the highest concentration to create the effect o quinolones conc dependent killing o bacitracin polymyxins triple antibiotic o metronidazole o isoniazid rifampin pyrazinamide MIC vs MBC o MIC minimum conc that inhibits cell growth o MBC minimum conc that will kill 99 9 of initial inoculum Complications of Antimicrobial Therapy o Hypersensitivity reactions minor rash fever itching chills major anaphylaxis Stevens Johnson syndrome toxic epidermal necrolysis o Hematologic effects o Nephrotoxicity o VIIIth cranial nerve damage Acoustic impairs balance and or hearing o Superinfection secondary infections Something that occurs as a result of the treatment If a patient has an infection with as a consequence of 1 drug Need use of another drug to treat the 2nd infection Tetracyclins over a long period of time o Acquired resistance derived from microbe not the host o ase damaging or splitting up the infective molecule Antimicrobial Resistance Mechanisms o Production of drug inactivating enzymes beta lactam antibiotics penicillins cephalosporins over 100 beta lactamases o Changes in drug targets receptors alteration in penicillin binding proteins PBP resulting in lower affinity for binding meaning the drug wont work unless the concentration is much higher o Development of alternative metabolic pathways sulfonamide resistance resistant bacteria produce high levels of PABA will oppose the actions of the sulfa drug or utilize preformed folic acid from environment o Changes in drug permeation transport an efflux pump extrudes drug eg tetracycline from cell active transport microbe hydrolyzes drug as it enters cell Antimicrobial Resistance Risk Factors o Broad spectrum agents By eradicating some other bacteria as well can increase resistance o Dose is too low or dosing frequency insufficient or drug stopped prematurely Blood levels are not going to be above the MIC to be effective o Prophylactic use of antimicrobial agents preventive reserved for STD exposure recurrent urinary tract infections neutropenia surgery bacterial endocarditis o Conjugation a form of sexual reproduction where two microbes form temporary union to exchange genetic material Drug Resistant Strains o Methicillin resistant Staph Aureus MRSA o Penicillin resistant Strept Pneumoniae o Vancomycin resistant enterococci VRE o Multidrug Resistant MDR tuberculosis How does drug resistance emerge o Spontaneous mutations random occurrence acquisition of DNA from external source plasmids can code for ability to conjugate F factor fertility plasmids must code for drug resistance R factor Principles of Antimicrobial Therapy o ID the organism cultures stains o ID effective drugs sensitivity testing o Consider specific site s of infection systemic localized o Consider status of pt Renal liver hematologic function Immune status Pt History drug allergies G 6 PD pregnancy breast feeding mothers age o Pick the best drug based on these factors Sulfonamides not antibiotics o Oldest antibacterial agents pre dates penicillin o active as false PABA analogs anti metabolites o competitively inhibit dihydropteroate synthetase in bacteria o sensitive bacteria must synthesize folic acid o mammalian cells do not form folic acid they require folic acid preformed from the diet o Drug class also known as folate antagonist o see image Sulfonamides o Sulfamethoxazole trimethoprim SMZ TMP o Sulfisoxazole o Sulfasalazine Sulfamethoxazole trimethoprim SMZ TMP o Most widely used sulfa drug o Sequential blockade o Broad spectrum resistance less likely than monotherapy o Trimethoprim inhibits dihydrofolate reductase of folate biosynthetic pathway can cause folate deficiency resulting in megaloblastic anemia leukopenia deficiency treated with folinic acid does not enter bacteria Sulfonamides Clinical Considerations o Sulfas are well absorbed