Antimicrobial Therapy PDF

Antimicrobial Therapy  History of Antimicrobials (a very brief) 1600s Quinine for malaria Emetine for amebiasis (Entamoeba histolytica) 1900-1910 Arsphenamines for syphilis  1935 A red dye that was found to have antib...

Antimicrobial Therapy  History of Antimicrobials (a very brief) 1600s Quinine for malaria Emetine for amebiasis (Entamoeba histolytica) 1900-1910 Arsphenamines for syphilis  1935 A red dye that was found to have antibacterial properties Sulfonamides - broadly active Initial marketing in US didn’t go to well…. A chemical analogue of antifreeze  1940 Penicillin - substantially more active than sulfa drugs Originally discovered in 1929 by Alexander Fleming (Scottish) Nobel Prize, 1945 Knighted, 1944 Produced by fungus Penicillium chrysogenum History and Development of Antimicrobial Drugs Alexander Fleming Discovered penicillin while working with Staphylococcus Noticed there were no Staph colonies growing near a mold contaminant The colonies appeared to be melting Identified mold as Penicillium It produced a bactericidal substance that was effective against a wide range of microbes History and Development of Antimicrobial Drugs In 1941 tested on human subject with life threatening Staphylococcus aureus infection Treatment effective initially Supply of penicillin ran out before disease under control Mass production of penicillin during WWII  In 1943, Selman Waksman, Nobel prize winner, isolated streptomycin from soil bacterium Streptomyces griseus (but not really). His 23-year old graduate student, Albert Schatz, was the first to isolate the bacteria, but Waksman got the patent and all the royalities! Antimicrobial Drugs Chemicals used to treat microbial infections Before antimicrobials, large number of people died from common illnesses Now many illnesses easily treated with antimicrobials Mantimicrobial drugs are becoming less useful Antimicrobial Drugs Different types of antimicrobial drugs: Antibacterial drugs Antifungal drugs Antiprotozoan drugs Antihelminthic drugs Features of Antimicrobial Drugs Most modern antibiotics come from species of microorganisms that live in the soil  To commercially produce antibiotic: 1. Select strain and grow in broth 2. When maximum antibiotic concentration reached, extract from medium 3. Purify 4. Chemical alter to make it more stable Features of Antimicrobial Drugs Selective toxicity Antibiotics cause greater harm to microorganisms than to human host (hopefully) Generally by interfering with biological structures or biochemical processes common to bacteria but not to humans Toxicity of drug is expressed as therapeutic index Lowest dose toxic to patient divided by dose typically used for treatment High therapeutic index = less toxic to patient Features of Antimicrobial Drugs: Selective Toxicity Features of Antimicrobial Drugs Antimicrobial action Drugs may kill or inhibit bacterial growth Inhibit = bacteriostatic Kill = bacteriocidal Bacteriostatic drugs rely on host immunity to eliminate pathogen Bacteriocidal drugs are useful in situations when host defenses cannot be relied upon to control pathogen Bactericidal vs. Bacteriostatic Features of Antimicrobial Drugs: Spectrum of Activity Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit Some kill only limited range : Narrow- spectrum antimicrobial While others kill wide range of microorganisms: Broad-spectrum antimicrobial Features of Antimicrobial Drugs: Effects of Combining Drugs Combinations are sometimes used to fight infections Synergistic: action of one drug enhances the activity of another or vice versa. Antagonistic: activity of one drug interferes with the action of another. Features of Antimicrobial Drugs: Adverse Effects 1. Allergic Reactions: some people develop hypersensitivities to antimicrobials 2. Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects 3. Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers Features of Antimicrobial Drugs: Resistance to Antimicrobials Some microorganisms inherently resistant to effects of a particular drug Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes (more later). Resistance to Antimicrobial Drugs Mechanisms of resistance Drug inactivating enzymes Some organisms produce enzymes that chemically modify drug Penicillinase breaks β-lactam ring of penicillin antibiotics Alteration of target molecule Minor structural changes in antibiotic target can prevent binding Changes in ribosomal RNA prevent macrolides from binding to ribosomal subunits Resistance to Antimicrobial Drugs Acquisition of resistance Can be due to spontaneous mutation Alteration of existing genes Spontaneous mutation called vertical evolution Or acquisition of new genes Resistance acquired by transfer of new genes called horizontal transfer Resistance to Antimicrobial Drugs Drug resistance limits use of ALL known antimicrobials Penicillin G: first introduced, only 3% of bacteria resistant Now, over 90% are resistant Resistance – Staphylococcus Aureus Common cause of nosocomial infections Becoming increasingly resistant In past 50 years most strains acquired resistance to penicillin Due to acquisition of penicillinase genes Until recently most infections could be treated with methicillin (penicillinase resistant penicillin) Many strains have become resistant MRSA → methicillin resistant Staphylococcus aureus Resistance -Streptococcus pneumoniae Has remained sensitive to penicillin Some strains have now gained resistance Resistance due to modification in genes coding for penicillin-binding proteins Changes due to acquisition of chromosomal DNA from other strains of Streptococcus Generally via DNA mediated transformation Slowing the Emergence and Spread of Antimicrobial Resistance 1. Responsibilities of Providers: must work to identify microbe and prescribe suitable antimicrobials, must educate patients 2. Responsibilities of Patients: need to carefully follow instructions Slowing the emergence and spread of antimicrobial resistance 3. Educate Public: must understand appropriateness and limitations of antibiotics; antibiotics not effective against viruses 4. Global Impacts: organism that is resistant can quickly travel to another country - in some countries antibiotics available on non-prescription basis - antibiotics fed to animals can select for drug- resistant organisms Current major antibiotic resistance problems: community infections Respiratory tract: penicillin resistance in pneumococcus increasing Gastrointestinal: quinolone resistance in Campylobacter Sexually transmitted: penicillin, quinolone resistance in gonococcus Urinary tract: beta lactam resistance in E coli MRSA and MDRTB Tropical: multidrug resistance in Salmonella typhi, Shigella spp, malaria So, The Criteria of the Ideal Antibiotic: Selectively toxic to microbe but nontoxic to host. Soluble in body- tissue distribution – BBB. Remains in body long enough to be effective - resists excretion and breakdown. Shelf life. Does not lead to resistance. Cost not excessive. Hypoallergenic. Microbiocidal rather than microbiostatic. Doesn’t suppress normal flora - antibiotic associated colitis with Clostridium difficule and it’s toxins or Candida albicans.  Unfortunately, no such antibiotic exists Mechanisms of action of Antibacterial Drugs 1. Inhibit cell wall synthesis 2. Inhibit protein synthesis 3. Inhibit nucleic acid synthesis Cellular targets of antimicrobial drugs Penicillins Cephalosporins Novobiocin Vancomycin Nalidixic acid Bacitracin Rifampin Erythromycin Chloramphenicol Tetracyclines Aminoglycosides (Streptomycin, Kanamycin, Gentamicin) Polymyxins 1. Cell Wall Inhibitors Bacteria cell wall unique in construction Contains peptidoglycan Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell These drugs have very high therapeutic index Low toxicity with high effectiveness 2.Protein Synthesis Inhibitors Most interfere with ribosomes By preventing ribosome function, polypeptide synthesis is inhibited Compounds Aminoglycosides (e.g., streptomycin) Incorrect amino acid is incorporated into polypeptide Tetracyclines No tRNA binding 2. Protein Synthesis Inhibitors 2. Protein Synthesis Inhibitors Others Macrolides - initiation complex, translocation Azalides - initiation complex, translocation Ketolides - initiation complex, translocation Lincomycins - initiation complex, translocation Glycylcyclines - Tet analogs; bind with higher affinity Chloramphenicol - Inhibits peptidyl transferase Streptogramins - Irreversible binding to 50S subunit; unknown mechanism Oxazolidinones (zyvox)- Inhibit fMet tRNA binding to P site 3.Nucleic Acid Synthesis Inhibitors Types DNA/RNA polymerase inhibitors Rifampin Prevents RNA synthesis Quinolones - inhibit bacterial DNA gyrase Sulfonamides Inhibit folic acid synthesis Back to the basics…………… Does the patient need an antibiotic and if so, which one???? Determine if possible… Is there an infection? Identification of infection (CBC) What is it? Culture information (gm+; gm-, cocci; bacillus, other)- etiologic organism What will kill it? Susceptibility determination Is there an infection? Evaluation of the CBC WBC’s 4,000-11,000 wbc/mm3 neutrophils lymphocytes Confer cell mediated immunity monocytes eosinophils basophils 48 Neutrophils “polys”, “segs”, or “PMNs” neutrophils account for 50-70% of circulating leukocytes “Bands” are immature neutrophils and account for 3-5% of circulated leukocytes “Shift to the left” 49 Obtaining and Interpreting Cultures Collection Timing Common culture sites Urine, sputum, wounds Blood, CSF, peritoneal/pleural fluid Colonization, contamination & infection What should be there vs what should not Quantitative culture (the # of organisms) Look for confirmatory evidence 51 Identifying the organism Where’s the culture?  Identifying organism by gram stain Gram Stain color Gram + Strep, Staph Listeria E faecalis Gram – Neisseria meningitides, gonorrhea E coli salmonella shigella 53  Identifying organism by Bacterial Cell Shapes  Bacteria can have several different shapes, but the primary shapes we will be observing are: 1. Spherical or round cells – cocci (plural) or coccus (singular) 2. Rod shaped – bacilli (plural) or bacillus (singular) 3. Spiral shaped – spirilla 54 Put color and shape together… Gram-positive cocci Gram-positive rods Gram-negative cocci Gram-negative rods 55  Gram + cocci Staph, strep enterococci Gram + bacilli Anthrax, clostridium dificile, listeria (tend to be aerobic, above the waist)  Gram - cocci Neisseria gonorrhea, meningitides Gram – bacilli E coli salmonella shigella (tend to be anaerobic, below the waist) Determining Susceptibility of Bacterial to Antimicrobial Drug Conventional disc diffusion method Kirby-Bauer disc diffusion routinely used to qualitatively determine susceptibility Standard concentration of strain uniformly spread of standard media Discs impregnated with specific concentration of antibiotic placed on plate and incubated –Clear zone of inhibition around disc reflects susceptibility Based on size of zone, organism can be described as susceptible or resistant Determining Susceptibility of Bacteria to Antimicrobial Drug Susceptibility of organism to specific antimicrobials is unpredictable Often drug after drug tried until favorable response observed If serious infection, several drugs are prescribed at one time with hope that one was effective Better approach Determine susceptibility Prescribe drug that acts against offending organism Best to choose one that affects as few others as possible Determining Susceptibility of Bacteria to Antimicrobial Drug MIC - Minimum Inhibitory Concentration The smallest quantity of antibiotic in the serum required to “inhibit” the growth of a bacteria Determined by examining bacteria’s ability to grow in broth containing different concentrations of test drug Determining Susceptibility of Bacterial to Antimicrobial Drug MIC is determined by producing serial dilutions with decreasing concentrations of test drug Known concentration of organism is added to each test tube Tubes are incubated and examined for growth Growth determined by turbidity of growth medium Lowest concentration to prevent growth is MIC Susceptibility Determination Which is best? Susceptibility Determination MIC When comparing antibiotics, the lowest MIC is usually indicative of the most “potent” agent Though 2 different drugs might work against the organism, the drug with the lowest MIC is the most potent. 64  Sensitive – organism inhibited by usual dosage of drug Intermediate – organism inhibited by maximum dosage of drug Resistant – organisms resistant to the usually achievable serum drug levels Antibiotic Choice Other factors besides susceptibility and resistance Location of infection (lipid soluble vs. water soluble drugs) Drugs excreted by kidney reach much higher bladder levels than serum levels Gram + vs gram neg  Remember Selective toxicity Spectrum of activity Antimicrobial action Adverse effects Resistance Antimicrobial Classes 1.Sulfonamides 7.Aminoglycosides 2.Penicillins 8.Fluoroquinolones 3.Cephalosporins 9.-Nitroimidazoles 4.Tetracyclines 10. Other 5.Macrolides 6. Glycopeptides 1. Sulfonamides First group of antibiotics. In 1932 a red dye was found to kill strep in rats General action Bacteriostatic effect Inhibits folic acid synthesis Broad spectrum  Sulfonamides contraindicated in what trimester of pregnancy?  Prescribe antibiotics as indicated and for as brief a time as possible If treating an infection in the first trimester Sulfonamides and nitrofurantoin in the first trimester of pregnancy can be used if no other alternatives are available If treating an infection in the second or third trimester Sulfonamides and nitrofurantoins may be used as first- line medications Pregnant women should not be denied appropriate therapy due to serious risks to both mother and fetus Sulfonamides: Therapeutic Uses Active against wide range of gram neg and positives but not strep group A and pseudomonas Cop 7 - 73 Urinary tract infections Otitis media Some respiratory infections  Sulfasalazine lacks significant antimicrobial activity and is poorly absorbed but useful in ulcerative colitis (Why?) Silver sulfadiazine used topically for burns Sulfonamides: Adverse Effects Hemolytic anemia if G6PD deficiency Rash, fever, GI disturbance most common Potentiates warfarin, phenytoin, some hypoglycemic agents and methotrexate 2. Penicillins Part of a large group of chemically related antibiotics Derived from fungus or mold 7 - 76 Penicillins: Action Inhibits synthesis of the bacterial cell wall Most effective on newly forming and actively growing cell walls 7 - 77 Action of penicillin on bacteria (from Medicines and You, U.S. Department of Health and Human Services) Broad-Spectrum Penicillins PCN, (& cephalosporins) ampicillin and amoxicillin – very effective against non-β-lactamase-producing gram+ bacteria. Because they diffuse readily into Gram- bacteria, also very active against many strains of E. coli, H. influenzae, and Salmonella typhimurium. Ineffective against penicillinase-producing bacteria (e.g., S. aureus, 50% of E. coli strains, and up to 15 % of H. influenzae strains.)  Some bacteria produce -lactamase, an enzyme that breaks the critical -lactam ring making the antibiotic ineffective Many bacterial β-lactamases are inhibited by clavulaic acid ± amoxicillin (co-amoxiclav) → antibiotic is effective against penicillinase- producing organisms. co-amoxiclav (Augmentin) indicated in resp and UTI infections, which could be resistant to amoxicillin. 3.Cephalosporins Chemically and pharmacologically related to penicillins Action: prevent bacterial cell wall synthesis but bind to different proteins All are bactericidal Classes of Cephalosporin Include several generations: First: good gram-positive coverage Second: good gram-positive coverage; some gram- negative coverage M Third: less gram-positive coverage; more gram- negative coverage Fourth: good gram-negative coverage, pseudomonas Fifth: MRSA Cephalosporins have no activity against LAME Listeria Atypicals (including mycoplasma & chlamydia) MRSA (except 5th generation) Enterococci Treatment with Cephalosporins Treat infections of: Skin Bone Heart Blood Respiratory tract Gastrointestinal tract Urinary tract  Look at what you are treating and what coverage does the disease/organism need? Pick lowest generation possible.  Strep tonsillitis Is it gram + or gram Neg? Is there any chance of it being gram neg? Pick a cephalosporin….. PNA in an elderly alcoholic pt. Is it gram + or gram neg? Could it be both? What generation cephalosporin would you pick? May → allergic rxn and cross-reactivity to PCN  Penicillin allergy and cross-sensitivity with cephalosporins – Cross sensitivity between Penicillins and Cephalosporins has been over-reported and is probably in the region of 2 – 3% for 3rd generation cephalosporins, but closer to 10% for first generation Cephalosporins.  Cephalosporins should NOT be used in those with known severe Penicillin allergy ( anaphylaxis, angioedema , wheezing ,acute urticaria, severe generalised skin reactions skin reactions , haemolytic anaemia ,interstitial nephritis ,hepatitis) unless skin tests are negative and oral challenge testing is negative. 4. Tetracyclines doxycycline, minocycline Action: inhibit protein synthesis in the bacterial cell; bacteriostatic Broad spectrum Bacteria: gram – and gram + Effective against: protozoa, Mycoplasma, Rickettsia, Chlamydia, syphilis, Lyme disease 4. Tetracyclines. TCNs bind to Ca in growing bones and teeth → can discolor teeth. So, should be avoided in children < 8 yrs old. Antibacterial Drugs that Inhibit Protein Synthesis 5. Macrolides and Ketolides (both are structural analogues of erythromycin) Erythromycin Azithromycin Clarithromycin 5.Macrolides Action Bacteriostatic: inhibits protein synthesis in the bacterial cell Very effective against the organism that typically causes CAP, also some atypicals like mycoplasma, chlamydia Treats both Gm + and some Gm negatives Can be used as an alternative in pcn-sensitive patients, esp in infections caused by streptococci, staphylococci, pneumococci, and clostridia. 5.Macrolides/Ketolides Very safe drugs. Usually given orally. Don’t cross the BBB – ineffective against meningitis. Broader spectrum than EES, less GI upset, qd dosing Azithromycin – very long t1/2 (~40-60 hr) and a single dose was as effective in treating chlamydial urethritis as doxycycline admin over 7-14 days but……………… Resistance has become an issue and single dose azithromycin treatment for GC and Chlamydia no longer recommended Macrolides: Adverse Effects Hypersensitivity Gastrointestinal effects Hepatotoxicity Jaundice Ketek Only ketolide on market –telithromycin Can be used for respiratory infections – in particular those that are macrolide resistant Initial safety concerns ignored and fraudulent research found it safe Multiple cases of severe liver injury and hepatotoxicity and death 6.Vancomycin – glycopeptides Bactericidal Not well absorbed orally. Inhibits peptidoglycan formation. Active against most gram+ organisms. I.V. treatment for septicemia or endocarditis caused by MRSA severe infections Po form for c. dificile (why not much else?) Inhibits cell wall synthesis Other glycopeptides Oritavancin Dalabavancin 6.Aminoglycosides Against many gram- and some gram+. Bactericidal: inhibit cell wall protein synthesis Narrow TI – potentially very toxic. Most important adverse side-effect: VIIIth cranial n. (ototoxicity) and kidney damage. 7.Aminoglycosides Gentamicin – used for acute, life-threatening gram- infections. Has synergism with pen and van and combo. Amikacin – used for bact that are gent-resistant. Neomycin – too toxic for parenteral use. Used for topically for skin infections and orally for sterilizing bowel before surgery. Streptomycin – active against Mycobacterium tuberculosis. But bc of its ototoxicity, rifampin replaced 8. Fluoroquinolones: Action Bactericidal: alter DNA Broad spectrum: effective against gram- negative organisms and some gram-positive 7 organisms 8.Fluoroquinolones Well-absorbed both Levofloxacin orally and i.v. (Levaquin)- qd Ofloxacin Ciprofloxacin- BID Moxifloxacin (Avelox)-qd (not renally excreted- no dosage adjustment in renal dysfx) Gemifloxacin 108 You wouldn’t choose Moxifloxacin to treat___________________? 8.Fluoroquinolones Treat infections of: Lower respiratory tract Bone and joint 7 - 109 Infectious diarrhea Urinary tract Skin But…………… Quinolones have significant drug-drug interactions Increase effects of theophylline, warfarin, propranolol Antacids sucralfate, magnesium, iron, calcium all decrease absorption Prolong QT interval Use with steroids (and without) increases risk of tendonitis and rupture, older adults, < 16 yo 9. 5-Nitroimidazoles Anti anaerobic Agents Wide-spectrum - bactericidal Metronidazole – against anaerobic bacteria and protozoan infections. Tinidazole – longer duration of action. inhibit DNA synthesis and/or damage DNA. 10. Other - Rifampin Inhibits DNA dependent RNA Active against gram + cocci and moderately active against some gram – , MRSA Still active against M tuberculosis, used in combination for synergistic effect and to decreases resistance SE headache, N & V, fever Body fluids turn orange Increases clearance of antiarrhythmics, azoles, clarithromycin, estrogen, warfarin, statins 10. Other - Nitrofurantoin Structurally similar to quinolones Used only for preventing and treating UTIs (why?) Serum concentrations will be very low so not for treatment of complicated UTIs or sepsis Renal excretion so don’t use in those with renal insufficiency  Nine Factors to Consider When Selecting an Antibiotic 1. Spectrum of coverage 2. Patterns of resistance 3. Evidence or track record for the specified infection 4. Achievable serum, tissue, or body fluid concentration (e.g. cerebrospinal fluid, urine) 5. Allergy 6. Toxicity 7. Formulation (IV vs. PO); if PO assess bioavailability 8. Adherence/convenience (e.g. 2x/day vs. 6x/day) 9. Cost  Principles of Antibiotic Therapy Empiric Therapy (85%) Directed Therapy (15%) Infection not well defined Infection well defined (“best guess”) Narrow spectrum Broad spectrum One, seldom two drugs Multiple drugs Evidence usually More adverse reactions stronger More expensive Less adverse reactions Less expensive  Why So Much Empiric Therapy? Need for prompt therapy with certain infections Life or limb threatening infection Mortality increases with delay in these cases Cultures might be difficult to do (i.e. pneumonia, sinusitis, cellulitis) Negative cultures (is it really negative?) Provider Beliefs Fear of error or missing something “Patient is really sick, they should have ‘more’ antibiotics” “They got better on drug X, Y, and Z so I will just continue those” Therapy for Outpatients: Define the infection 3 ways Anatomically, microbiologically, pathophysiologically Obtain cultures before starting antibiotics Often difficult in outpatients (acute otitis media, sinusitis, community-acquired pneumonia) Narrow therapy often with good supporting evidence Amoxicillin or amoxicillin/clavulanate for AOM, sinusitis Penicillin for Group A Streptococcal pharyngitis 1st generation cephalosporin or clindamycin for simple cellulitis (don’t forget MRSA) Trimethoprim/sulfamethoxazole or nitrofurantoin for simple cystitis  Tenet 1: Treat Bacterial Infection, not Colonization Many patients become colonized with potentially pathogenic bacteria but are not infected Asymptomatic bacteriuria or foley catheter colonization Tracheostomy colonization in chronic respiratory failure Chronic wounds and decubiti Lower extremity stasis ulcers Chronic bronchitis Can be difficult to differentiate Presence of WBCs not always indicative of infection Fever may be due to another reason, not the positive culture Tenet 2: Treat patient, not the xray Example: community-acquired pneumonia (CAP) CAP: often a difficult diagnosis X-rays can be difficult to interpret. Infiltrates may be due to non-infectious causes. Examples: Atelectasis Malignancy Hemorrhage Pulmonary edema Community-Acquired Pneumonia (CAP) Pneumonia is not present in up to 30% of patients treated Do not treat abnormal x-rays with antibiotics if the patient does not have systemic evidence of inflammation (fever, wbc, sputum production, etc) Discontinue antibiotics initially started for pneumonia if alternative diagnosis revealed  Tenet 3: Do not Treat Viral Infections with Antibiotics Acute bronchitis Common colds Sinusitis with symptoms less than 7 days Sinusitis not localized to the maxillary sinuses Pharyngitis not due to Group A Streptococcus Tenet 4: Limit Duration of Antibiotic Therapy to the Appropriate Length Most community-acquired pneumonia: 5 days Cystitis: 3 days Pyelonephritis: 7 days if fluoroquinolone used Intra-abdominal with source control: 4-7 days Cellulitis: 5-7 days Other Tenets of Antibiotic Stewardship Re-evaluate, de-escalate or stop therapy at 48-72 hours based on diagnosis and microbiologic results Do not give 2 antibiotics with overlapping activity Other Tenets of Antibiotic Stewardship Use rapid diagnostics if available (e.g. respiratory viral PCR, but know their limitations) Solicit expert opinion if needed Prevent infection Use good hand hygiene and infection control practices  Sensitivity Specificity Negative test rules it Positive test rules it out in SNout SPin