Antimicrobials MW Rev 2024.pdf

Antimicrobials Michael Weber PA-C, MPA Antimicrobial Therapy…What’s Important? • Selective toxicity • the drug should attack the microbe…not the host! • Safety profile • Spectrum • which bugs does this drug kill? • Tissue penetration • where will the antibiotic reach? • Resistance patterns • Co...

Antimicrobials Michael Weber PA-C, MPA Antimicrobial Therapy…What’s Important? • Selective toxicity • the drug should attack the microbe…not the host! • Safety profile • Spectrum • which bugs does this drug kill? • Tissue penetration • where will the antibiotic reach? • Resistance patterns • Cost Spectrum • Gives a general idea of which microbes the antibiotic will target • Guides empiric treatment • Begun before a specific microbe has been identified as the source of infection • Based on the presumption of likely pathogen, as well as consideration that infection requires immediate treatment • Prior to beginning treatment, should obtain any cultures Tissue Penetration • Depends on the properties of the antibiotic and the tissue • Molecule size • Lipophillic vs lipophobic • Presence of blood supply, inflammation, etc… Antibiotic Resistance • Can occur via a variety of mechanisms • Changes in enzymes, binding sites, cell membrane proteins • Some bacteria have natural resistance to antibiotics • i.e. Gram negatives contain a protective outer membrane • Acquired resistance • Vertical gene transfer • a mutation is transferred to a bacteria’s offspring • Horizontal gene transfer • passed to other bacteria Is Antimicrobial Therapy Warranted? • Surge in resistance 2/2 overprescribing • Limited options for severe, life threatening infections Is Antimicrobial Therapy Warranted? • Does the clinical picture indicate there is need for antimicrobial treatment? • Have/will cultures be obtained? • What are the likely etiologic agents? • Will antimicrobial treatment benefit the patient? Cost So…What makes an antibiotic effective? • BacterioSTATIC vs. BacteriCIDAL • BacterioSTATIC drugs • inhibit bacterial growth. • They rely on the host defenses to kill the bacteria • BacterioCIDAL drugs • KILL the microbes What is sensitivity? • Minimal Inhibitory Concentration (MIC)• lowest drug concentration that INHIBITS a microbe’s growth • Minimal Bactericidal Concentration (MBC)dose that KILLS an organism • Bacteriocidal drugs have MICs similar to their MBC • Bacteriostatic drugs have MBCs much higher than their MIC How to choose an Antimicrobial Based on the above • As well as patient factors • Patient medical history • Immunosuppression, CKD, liver disease • • • • Drug reactions/allergies Patient age Pregnancy/lactation status Epidemiologic exposure How Do Antibiotics Work? • Inhibition of cell wall synthesis • PCN’s, ceph’s, monobactams, vanco • Inhibition of protein synthesis • Tetracyclines, macrolides, aminoglycosides, Clinda, Zyvox • Inhibition of nucleic acid synthesis • Quinolones, Flagyl, Macrobid • Alteration of cell membrane function • Polymyxin, daptomycin, INH • Antimetabolites • Alterations in folic acid metabolism • Sulfonamides, trimethoprim Beta- Lactam Antibiotics • • • • Penicillins Cephalosporins Carbapenems Monobactams •Inhibit cell wall synthesis •All are bacterioCIDAL Penicillins (PCN) • Alexander Fleming (1928) • Derived from mold extract • Four Groups: • • • • Natural Penicillins Aminopenicillins Penicillinase-Resistant Penicillins Antipseudomonal Penicillins MOA • Beta-lactams • BacteriCIDAL • Inhibits binding of peptidoglycan polymers and binds penicillin-binding proteins (PBPs) • Thereby, inhibits cell wall synthesis→cell lysis Natural Penicillins • Penicillin G • Always parenterally • Penicillin V • Given orally • Activity: • Gram positive organisms (staph, GA strep, GB strep, E. faecalis, L. monocytogenes) • Anaerobes (Bacteroides, Fusobacterium) • Some gram negatives (E. coli, H. flu, N. gonorrhoeae. T. pallidum, some pseudomonas) • Uses: • Throat infections (strep pharyngitis = treatment of choice) • Treatment of choice in syphilis • URI/LRI, skin, GU infections Resistance  • Beta-lactamases • Aka penicillinases • Enzymes that hydrolyze the beta lactam ring • Found in most staphylococci & many gram-negatives • Altered Binding Sites • I.e. MRSA Overcoming Resistance • Altering penicillin structure • Such as the Penicillinase-Resistant Penicillins Penicillinase-Resistant Penicillins • Nafcillin & oxacillin • parenteral • Dicloxacillin • oral • Activity: • Useful against lactamase producing staph • Skin infections (mastitis) • No useful against MRSA Antipseudomonal Penicillins • • • • AKA extended-spectrum penicillins Piperacillin, Ticarcillin Carbenicillin Activity: • Improved Gm- coverage • Pseudomonas • H. flu, Serratia, Klebsiella • Useful in moderate-severe infections Combining Penicillins with other drugs • Beta Lactamase Inhibitors! • Clavulanic acid, sulbactam, tazobactam • • • • Amoxicillin/clavulanate→ Augmentin Ticarcillin/clavulanate→ Timentin Ampicillin/sulbactam→ Unasyn Piperacillin/tazobactam→ Zosyn • Active against H. flu, M. cat, S. aureus beta lactamases • Hospital acquired PNA, anaerobes PCN’s- Adverse Effects • Most commonly, gastrointestinal side effects • C.Diff • Allergic reactions • Mild rash, urticaria, rarely serious reactions; serum sickness, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Beta-Lactam Cross Reactivity • In those with + skin test to PCN, 11% have reaction to ceph’s. • However, more recent observational studies have found crossreactivity rates of between 0.17% and 0.7%. • In 1 prospective study, the rate of cross-reactivity among subjects with a positive penicillin skin test was 6%. • Cross reactivity is more prominent in early-generation cephalosporins. • Carbapenems have even less risk of cross reactivity <1% • Always ask the patient what their reaction is! Cephalosporins • Developed from fungus Cephalosporium acremonium • Same MOA as penicillins (inhibit cell wall synthesis via blocking linkage of peptidoglycans) • Same mechanisms of drug resistance • There are 5 “generations”, each with different coverage • First Generations • Most active against gram-positive cocci • Second Generations • More gram-negative coverage • Third Generations • Have the most activity against gram-negatives • Less gram-positive cocci coverage • Fourth Generation • Cefepime • Good gram-positive and gram-negative coverage • Fifth Generation • Ceftaroline First Generation Cephalosporins • Most commonly used for skin infections caused by S. aureus and Streptococcus • Also, E. coli, some H. flu and Klebsiella • Very little gram-negative coverage • No MRSA coverage • Cefazolin (Ancef)- IV/IM • Pre-op prophylaxis • Cephalexin (Keflex)- PO • Cefadroxil (Duricef)- PO Second Generation Cephalosporins • Mostly used for respiratory tract infections • Better against H. flu • Gram-negatives like M. cat, Neisseria, Salmonella, Shigella • True cephalosporins • Cefprozil (Cefzil), cefuroxime (Ceftin) • Cephamycins • Cefoxitin, cefotetan • More anaerobic coverage • Cefotetan used prior to GI surgery (appendicitis) Third Generation Cephalosporins • Used for more severe community-acquired respiratory infections, resistant/nosocomial infections • Meningitis (Ceftriaxone penetrates CSF well) • Neisseria, M. cat, Klebsiella • Ceftriaxone (Rocephin), cefotaxime • Cefpodoxime (Vantin), cefixime (Suprax), cefdinir (Omnicef) • Ceftazidine has pseudomonal coverage Third Generation Cephalosporins • The most common etiologic agents for Community Acquired Pneumonia are? Tx: 3rd Generation Cephalosporin PLUS a macrolide Fourth Generation Cephalosporins • Cefepime • Gram-positive and gram-negative coverage including Psuedomonas and Enterobacteriaceae • Intra-abdominal, respiratory tract, and skin infections • Nosocomial pneumonia • Empiric treatment for febrile neutropenia Fifth Generation Cephalosporin • Ceftaroline- Teflaro • Improved efficacy in CAP as compared to Ceftriaxone with similar safety profile • ALSO has MRSA coverage! • 1st Ceph with MRSA coverage • 1st impt FDA-approved drug for CAP since levofloxacin ☺ Adverse Effects • GI upset • Thrombophlebitis (with IV use) • Allergic reaction • Rash, fever, urticaria • Disulfiram-like reaction (cefotetan) • Cholelithiasis (ceftriaxone) Carbapenams • Useful for many multi-drug resistant organisms • Wide spectrum of action including grampositives, gram-negatives including many aerobic and anaerobic gram-negative bacilli • Not useful against intracellular pathogens • Resistant to many beta-lactamases • Parenteral dosing • Meropenam • Gm +, Gm-, Enterobacteriae • Skin infections, intra-abdominal infections, meningitis • Greater activity against gram-negatives • Imipenam (+cilastin) and Ertapenam (Invanz) • UTI’s, pneumonia, intra-abdominal infections, skin infections • Very broad spectrum including gram-positive cocci (Invanz covers MRSA) and anaerobes like Bacteroides • Primaxin (Imipenam + Cilastin) inhibits the kidney enzymes that metabolize imipenem, protecting the kidney from drug toxicity • Doripenem • Newer agent • Pseudomonas Side Effects • GI upset, phlebitis, increased LFT’s, leukopenia • Seizures in epileptic patients • Cross reactive with penicillins Monobactams • Aztreonam (Azactam) • Primarily used against gram-negative aerobes (Pseudomonas and Klebsiella) • Pneumonia, soft tissue infections, intra-abdominal infections, UTI’s, septicemia • Synergistic with aminoglycosides against Pseudomonas • Useful in Cystic Fibrosis patients • Resistant to most beta-lactamases • Side Effects- increased LFT’s, transient eosinophilia, allergic rashes, bone marrow toxicity • Generally safe in PCN allergic patients Vancomycin • Useful in Gm + organisms • Given PO and IV • Is not absorbed in GIT→ increased concentration in stool makes it a good treatment for C. diff • Adverse Effects (when given IV): • Hearing loss (rare) • RED MAN SYNDROME: erythematous pruritic rash on torso after rapid IV infusion due to histamine release (non-immunologic mechanism) • SLOW THE INFUSSION RATE • Trough level of 5-20 • Uses: • All Gm + including MRSA, Enterococcus, MDR S epi, Strep pneumo, Clostridia, B. anthracis Dalvance (dalbavancin) • Similar to Vanco in that it is a glycopeptide antibiotic • Inhibits CW synthesis • Approved May 2014 for Skin & Skin Structure Infections (SSSI) caused by resistant Gm + bacteria • Strep pyogenes, Staph (MSSA & MRSA) • Two-dose regimen: • 1000mg IV then 500mg IV one week later • Low incidence of side effects • Contraindication- hypersensitivity to dalbavancin • Appears to be no cross-reactivity to other glycopeptide antibiotics Orbactiv (oritavancin) • Another glycopeptide approved recently • Same indication as dalbavancin • First & only antibiotic approved for single dosage in SSSIs • 1,200mg IV infusion once Protein Synthesis Inhibitors • 30S Drugs: Binds to the 30s ribosomal subunit, inhibiting protein synthesis • Aminoglycosides • Tetracyclines • 50S Drugs • Macrolides • Clindamycin • Other • Mupirocin • Linezolid Aminoglycosides (30S) • Bactericidal • Aerobic gram-negative bacilli • Klebsiella, Pseudomonas, Enterobacter • UTIs, RTIs, SSTIs, sepsis • Tobramycin→ most active against Pseudomonas • Inhalation solution used in Cystic Fibrosis patients • Gentamicin→ E. coli, Klebsiella • Gent + a penicillin→ endocarditis from enterococcal, staph, strep viridans • Most commonly used aminoglycoside, also used for meningitis in infants Aminoglycosides (30S) • Amikacin→ less resistance • Neomycin→ taken PO as bowel decontaminant, used topically • Streptomycin→ • Yersinia pestis, tularemia, TB Side Effects • Nephrotoxicity • ATN and glomerular toxicity lead to increased plasma levels potentiating toxicity • Monitor renal function and plasma levels! • Ototoxicity • Vestibular…vertigo, n/v, postural/balance problems, nystagmus • Cochlear…tinnitus and hearing impairment • Neuromuscular blockade… (may aggrevate muscle weakness in myasthenia and parkinson’s) 30S Drugs continued… • Tetracyclines • • • • • Tetracycline, doxycycline, minocycline BacterioSTATIC All should not be taken with bismuth or iron Tetracycline should not be taken with dairy Take 1 hour before or 3 hours after meals Spectrum… • Gram-positive, gram-negative, aerobic & anaerobic coverage • Acne (minocycline & doxy) • MRSA • Spirochetes and atypical bacteria • Chlamydia, Mycoplasma, Borrrelia burgdorferi Rocky Mountain Spotted Fever • Treatment of choice • And other rickettsial infections And…. • Brucellosis, ehrlichiosis • Can shorten the course of cholera • H. pylori What’s not to love? • Nausea, vomitting, diarrhea • Dental discoloration, enamel hypoplasia • Don’t use in children under 8 years old (Except in RMSF) • • • • Photosensitivity (especially doxy) Minocycline- vertigo/HA DO NOT use in pregnant patients Decrease efficacy of OCP’s 50S Drugs • Macrolides- bacterioSTATIC • • • • Erythromycin (original) Azithromycin (Zithromax) Clarithromycin (Biaxin) Fidaxomicin (Dificid) Macrolides continued • Indications • URI’s (bronchitis, sinusitis, OM, pharyngitis) and pneumonia • Cover Strep (not so well anymore), H. flu, M. cat., Mycoplasma, Chlamydia • In addition, cover Legionella, pertussis, diphtheria • Azithromycin used single dose for chlamydial urethritis (no longer preferred) • Can be used for strep pharyngitis in PCN allergic patients • Clarithromycin used in combo regimen for H. pylori • Fidaxomycin non-absorbable used in C. Diff colitis Adverse Effects • Erythromycin • Abdominal cramping, n/v/d • Ototoxicity in large IV doses • Clarithromycin • GI upset, dysguesia, dyspepsia • Allergic reactions are rare • CYP450 metabolized • Theophylline, anti-epileptics, warfarin, OCPs • Keep in mind, prolongation of QT interval • CCB’s (verapamil, diltiazem) • Azoles, nafazodone, protease inhibitors • Azithromycin has been associated with a small increase in cardiovascular deaths in those with pre-existing cardiac disease 50S Drugs continued… • Clindamycin • Unrelated to other antibiotics • BacterioSTATIC • Gram positive cocci • Including MRSA, penicillin resistant strep (including necrotizing fasciitis) • Gram negatives • B. fragilis, C. perfringens (gas gangrene) • • • • Topically for acne and Bacterial Vaginosis Toxoplasma (with pyrimethamine) strep pyogenes and staph aureus TSS Risk of C. diff colitis and pseudomembranous colitis Other Mupirocin (Bactroban) • protein synthesis inhibitors • Staph and Strep • Used topically for impetigo • Used intranasally for MRSA (to eradicate colonization) Linezolid (Zyvox) • Oxazolidinedione antibiotic • Staph pneumonia • Methicillin sensitive and resistant (MRSA) • • • • • Vanco resistant E. faecium (VRE) SSTIs caused by staph, Strep pyogenes, Strep agalactiae Healthcare associated pneumonia (not H. flu) Clostridium perfringes, Listeria monocytogenes Can cause thrombocytopenia, serotonin toxicity Drugs that Alter Bacterial DNA Synthesis • Fluoroquinolones • Cipro/Levaquin • Antifolate Drugs • Sulfonamides • Trimethoprim • Silver sulfadiazine Fluoroquinolones • BacterioCIDAL • Inhibit bacterial DNA synthesis via inhibition of DNA topoisomerases • DNA gyrase is generally the target in most Gram negative bacteria • DNA topoisomerase IV in Gram positive bacteria Quinolones • Generally given orally as they are well absorbed • can be given IV • Absorption decreased antacids or iron supplements! Spectrum of Activity • Gram negative • Gram positive • acid fast bacilli • Original (Cipro) • has better activity against gram negative bacteria • UTI’s, prostatitis, PID • Bacterial gastroenteritis/Traveler’s diarrhea • Campylobacter, Salmonella, Shigella, Vibro, E. coli • Anthrax • Including post exposure prophylaxis Respiratory Quinolones Levofloxacin (Levaquin), Moxifloxacin (Avelox), Gemifloxacin (Factive) • Sinusitis, bronchitis, community acquired pneumonia • Also UTI’s and intraabdominal infections • Gram negative coverage + pneumococci • Also cover atypicals • Mycoplasma • MAC & drug resistant TB • Opthalmic solutions available • Conjunctivitis, bacterial corneal ulcers Adverse Effects • Generally safe and well tolerated • Most commonly GI upset • Tendonitis and tendon rupture (m/c Achilles) • Not recommended in pregnant patients as they may damage fetal cartilage • • • • Hypo and hyperglycemia Prolonged QT interval Super infections (C. diff) Cipro- inhibits GABA (may cause seizures in patients with predisposition or renal insufficiency) Daptomycin • Cyclic lipopeptide antibiotic • Uses: Gm+ resistant to methicillin and vanco • Complicated SSTIs • MRSA, VRE, strep agalactiae • Adverse Effects: • GI upset • HA, insomnia • Myopathy (monitor CK) Antifolate Drugs • Two Groups • Sulfonamides • Folate reductase inhibitors • Trimethoprim Sulfonamides • Sulfonamides • Primarily used to prevent and treat UTI’s • Include Sulfamethoxazole & Sulfacetamide • Silver Sulfadiazine • used to prevent or treat burn infections • NEVER USE ON THE FACE • Sulfacetamide used in ocular infections • Conjunctivitis/blepharitis Bactrim (TMP/SMX) • Trimethoprim-Sulfamethoxazole (Bactrim, Septra) • UTI’s and prostate infections • E. coli, Klebsiella, Proteus, Enterobacter • Not active against Pseudomonas  • Drug of Choice in Pneumocystis jiroveci pneumonia • Also used in OM, sinusitis, bronchitis, MRSA • Active against respiratory pathogens like Haemophilus influenzae and Moraxella catarrhalis Side effects • TMP-SMX continued… • Adverse Effects • Skin rashes (mild to Stevens-Johnson syndrome) • Crystalluria • SMX metabolites precipitate in the kidneys…stay hydrated! • Hemolytic anemia in patients with G6PD deficiency • Photosensitivity • New study suggests increased risk of sudden death in the elderly when used concurrently with ACE-I or ARBs • May cause hyperkalemia • found in other common medications! • Thiazide diuretics, sulfonylureas, acetazolamide • Watch for sulfa allergy! Anti-Tuberculous Drugs • Isoniazid (oral, IM, IV) • can induce pyridoxine deficiency (vit B6) causing pellagra manifested by peripheral neuritis, rash, anemia • Need to supplemt with B6 • Rifampin (oral) • Adverse effects: asymptomatic jaundice, elevated LFTs, urine sweat and tears turn red-orange color • Uses: • TB and leprosy • prophylaxis for exposure N. meningiditis • Induces P450 decreasing half life coumadin, BCP, oral hypoglycemics, corticosteroids, dilantin Anti-Tuberculous Drugs • Pyrazinamide (analogue nicotinamide) • Adverse effects: hepatotoxic!!! • Gout by inhibiting UA secretion • Ethambutol • Crosses BBB • Adverse Effects: • Dose related bilateral ocular toxicity usually reversible • Decreased visual acuity, color vision loss, central vision loss (central scotoma) • Uses: TB **only first line drug that is bacterioSTATIC Anti-Tuberculous Drugs • Streptomycin (30S) • IM/IV • Vestibular and otoxic • Contraindicated in pregnancy Amebicides Metronidazole (Flagyl) • Uses: • • • • • • Entamoeba histolytica Giardia lamblia Trichomonas vaginialis Anaerobes: Bacteroides C. diff psuedomembranous colitis Also used in brain abscesses caused by these organisms • Adverse effects: GI, rarely vertigo, paresthesias, numbness • NO ETOH • Tinidazole• newer, use similar to metro but can be used for a shorter course Paromomycin • Luminal amebicides • Can treat ASx carriers of E. histolytica, but not those with dysentery or liver abscess Chloroquine • Malaria is believed to be responsible for more deaths worldwide than any other infectious disease. • Systemic amebicide • Replaced quinine for treatment of malaria after WWII • Used in systemic E. histolytica infections ANITFUNGAL AGENTS • Antifungals are divided into 6 major groups based on mechanism of action Antifungal agents • Polyenes : bind to ergosterol, the main sterol in the fungal cell membrane, and cause depolarization of the membrane • Antimetabolite: inhibits DNA and RNA synthesis • Azoles: inhibit the synthesis of the sterol components of the fungal membrane • Glucan synthesis inhibitors • Allylamines: inhibit ergosterol biosynthesis Antifungal agents ◼ Polyene: ◼ Amphoteracin B (IV) ◼ Systemic fungal infections, not for CSF ◼ Flucytosine ◼ PO ◼ penetrates CSF (also fluconazole IV for cryptococcus) ◼ Azoles: Clotrimazole, fluconazole, itraconazole, voriconazole and posaconazole, Ketaconazole and imidazole ◼ Miconazole and Clotrimazole (Imidazoles) ◼ Topicals, for tinea, candida, dermatophytosis ◼ Oral trouches for thrush, vaginal suppositories Antifungal Agents CONT AZOLES • Itraconazole and Fluconazole (Triazoles) • Oral and IV - metabolized via liver • Adverse effects: • • n/v, rash, pruritis, anorexia, photophobia, hepatotoxic, inhibits CYP450 resulting in decreased androgen and testosterone synthesis causing; • gynecomastia, impotence, decreased libido and decreased sperm production. Antifungal Agents ◼ Allylamines ◼ Terbinafine: (Lamisil): good for dermatophytosis ◼ Others: ◼ Griseofulvin ◼Adverse effects: HA, n/v, photosensitivity and mental confusion, bone marrow suppression ◼Therapeutic Uses: Dermatophytosis skin, hair and nails ◼ Nystatin: oral for thrush and candida esophagitis ◼ Topical for Cutaneous (Dipper rash)