Anti-Infectives Exam II Study Guide.docx

Exam Date: June 26, 2023 Topics: Lectures 9-12 (Beta-Lactams, Gram-Positive Agents) Lecture 9 & 10: Beta-Lactams (6/7-6/12/23) Antibiotics bind to key components of bacteria to impair their function Enters the bacteria through the cell wall and membrane Reach suitable concentrations at the site...

Exam Date: June 26, 2023 Topics: Lectures 9-12 (Beta-Lactams, Gram-Positive Agents) Lecture 9 & 10: Beta-Lactams (6/7-6/12/23) Antibiotics bind to key components of bacteria to impair their function Enters the bacteria through the cell wall and membrane Reach suitable concentrations at the site of action Evade mechanisms of resistance Bind to the target site Cell membrane: selectively permeable Cell wall (peptidoglycan layer): large molecule barrier Gram-positive: thick peptidoglycan layer Gram-negative: thin peptidoglycan layer Atypical: lack cell wall Outer membrane (lipopolysaccharide layer) Component of Gram-negative bacteria Contains porins to allow for small molecules and nutrients to pass through Houses endotoxins Periplasmic space: area between cytoplasmic membrane and outer membrane Cell wall: beta-lactams, vancomycin DNA/RNA synthesis: fluoroquinolones, rifamycins Folate synthesis: trimethoprim, sulfonamides Cell membrane: daptomycin Protein synthesis: linezolid, tetracyclines, macrolides, aminoglycosides Gram-positive structure Thick peptidoglycan layer No lipopolysaccharide layer Retention of crystal violet Gram negative structure Thin peptidoglycan layer Larger lipopolysaccharide layer Structure results in color wash,requires counter stain Multiple mechanisms of resistance Clinically significant Gram-positive aerobic bacteria Clusters: Staphylococcus spp. Coagulase (+): S. aureus Coagulase (-): S. epidermidis, S. saprophyticus, S. haemolyticus, S. hominis, S. capitis Cocci: Streptococcus spp. And Enterococcus spp. Alpha haemolytic: S. pneumonia, S. viridans Beta haemolytic: Groups A, B, C, F, G E. faecalis and E. faecium Rods: Listeria spp. And Nocardia sp. Pathogen Human Source Infection Type Staphylococcus aureus Skin, nasopharynx Bacteremia, cellulitis, pneumonia nosocomial infections, bone and joint infections Coagulase (-) staphylococcus (S. epidermidis, S. saprophyticus, S. haemolyticus, S. hominis, S. capitis) Skin Bone and joint infections, catheter associated infections, UTIs (S. saprophyticus) Streptococcus pneumoniae Respiratory Tract Pneumonia, meningitis Group A, C, D, F Streptococcus Skin Cellulitis Group B Streptococcus Female GU Tract Neonatal sepsis, UTIs Viridans Group Streptococcus Oral Cavity Dental infections, endocarditis Enterococcus spp. GI/GU tract Intra-abdominal infections, UTIs Clinically Significant Gram-positive Anaerobic bacteria Cocci: Peptostreptococcus Rods Clostridium spp. (spore forming) Propionibacterium Actinomyces Clinically Significant Gram-negative Aerobic bacteria Bacilli Lactose Fermenting (Enterobacterales): E. coli, Klebsiella spp., Proteus spp., Enterobacter spp., Salmonella spp. Non-Lactose Fermenting: P. aeruginosa, acinetobacter baumannii, Stenotrophomonas maltophilia Cocci: Neisseria meningitidis, Neisseria gonorrhoeae, Moraxella Catarrhalis Clinically Significant Gram-negative Anaerobic bacteria Bacilli: Bacteroides spp., Fusobacterium spp., Prevotella spp. Pathogen Human Source Infection Type Enterobacterales GI/GU tract Intra-abdominal infections, UTIs Non-fermenting organisms Nosocomial Respiratory Hospital acquired pneumonia, bloodstream infections, surgical infections M. Catarrhalis, H. influenzae Respiratory tract Pneumonia, meningitis, eye and ear infections Neisseria meningitidis Nasopharynx Meningitis Gram-negative anaerobes Oral cavity, GI tract Diverticulitis, necrotic soft tissue infections Clinically significant atypical bacteria Chlamydia spp: C. pneumonia, C. trachomatis Mycoplasma spp: M. pneumonia, M. genitalium Legionella spp: L. pneumophila Beta-lactams: divided into Penicillins, Cephalosporins, Carbapenems, and Monobactam Penicillins are divided into: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, and penicillin beta-lactamase inhibitor combinations Cephalosporins are divided into: first generation, second generation, third generation, fourth generation, fifth generation, and cephalosporin beta-lactamase inhibitor combinations Carbapenems are divided into non-pseudomonal, carbapenem beta-lactamase inhibitor combinations, and anti-pseudomonal Monobactams are monobactam beta-lactamase inhibitor combination Penicillins Structure: Beta-lactam, first discovered in 1928 by Sir Alexander Flemming Mechanism: bind penicillin binding proteins (PBPs) inhibiting cell wall synthesis Resistance: Beta-lactamase enzymes: antimicrobial degradation (common in gram-negative) Efflux pumps: diminished intracellular concentrations (common in gram negative) Decreased outer membrane penetration: diminished intracellular concentrations (common in gram-negative) Alteration of binding site (gram-positive) Class features: incomplete oral bioavailability, short-half lives, hydrophilic, adverse reactions (GI, anaphylaxis), lack activity against atypical bacteria Natural Penicillins Penicillin G (IV), Benzathine Penicillin (IM), and Penicillin V Potassium (PO) PK: Oral bioavailability 60-73% Distribution: 80% protein bound Metabolism: some hepatic, eliminated unchanged Elimination: T ½ = 30-60 minutes, primarily renal elimination Gram-positive aerobes activity: treatment of choice for susceptible Streptococcus spp., good activity against enterococcus faecalis, little to no activity against staphylococcus aureus Susceptible streptococcus spp.: Group A (strep pyogenes), Group B (Strep agalactiae), Group C, F, G, streptococcus pneumoniae, viridans streptococcus Gram negative aerobes activity: minimal activity, some against Neisseria meningitidis Atypical activity: none Anaerobic Gram positive activity: actinomyces spp, peptostreptococcus, and propionibacterium, treatment of choice against Clostridium perfringens, treatment of choice for treponema pallidum Anaerobic Gram negative activity: considered resistant ADRs: CNS (seizures), neutropenia, hypersensitivity, acute interstitial nephritis Drug-interactions: OAT ⅓ interactions (pretomanid, teriflunomide, fexinidazole) and Probenecid (inhibits renal tubular secretion and extends half-life) Penicillinase-resistant penicillins Nafcillin (IV), oxacillin (IV), and dicloxacillin (PO) Widespread use of penicillin resulted in resistance through the blaZ gene (penicillinase) Kinetic Nafcillin Oxacillin Dicloxacillin Absorption N/A N/A 50% Distribution Protein Binding: 90% Widely distributed (CNS) Protein Binding: 95% Widely distributed (CNS) Protein binding: 95-99% Low CSF concentrations Metabolism Limited Limited Limited Elimination Primary through feces No renal dose adjustment Primary through feces No renal dose adjustment Primary through feces No renal dose adjustment Gram-positive activity: Treatment of choice for methicillin-susceptible Staphylococcus aureus (MSSA), no activity against methicillin-resistant S. aureus (MRSA), good activity against penicillin-susceptible streptococcus spp., no activity against Enterococcus faecalis Lacks activity against gram-negative, aerobic, or atypical activity ADRs: hepatic toxicity, neutropenia, acute interstitial nephritis, renal tubular disease, injection site reaction/phlebitis, GI (dicloxacillin) Drug interactions: Nafcillin is a CYP3A4 inducer (azole antifungals, statins, anti-epileptic, transplant medications), Dicloxacillin is a moderate 2C19 inducer (phenytoin and omeprazole), weak 2C9 inducer, and a 3A4 inducer (transplant medications and anti-epileptics) Aminopenicillins Ampicillin (IV), Amoxicillin (PO) Third generation penicillins developed due to resistance issues, thought to have expanded gram-negative activity which is now limited by resistance, high affinity for LMW PBPs Absorption: 75% bioavailability Distribution: 30% protein binding (amoxicillin), 10-18% protein binding (ampicillin) Metabolism: multiple mechanisms of hepatic metabolism Elimination: renal elimination, primarily unchanged drug, t ½ = 2 hours (amoxicillin) or 1-1.5 hours for (ampicillin) Gram-positive aerobic activity: treatment of choice for Enterococcus faecalis, treatment of choice for listeria monocytogenes, limited to no activity against staphylococcus aureus, streptococcus spp. Coverage is the same as penicillin Gram-negative aerobic activity: true gram-negative activity is limited, maintained activity against non-beta lactamase producing strains of E. coli, P. mirabilis, H. influenzae, M. cattarhalis, no activity of klebsiella spp. No atypical activity Gram-positive anaerobes activity: good activity against gram-positive anaerobes (actinomyces, peptostreptococcus, propionibacterium acnes) Gram negative anaerobes: generally resistant Effectively equivalent to natural penicillins ADRs Amoxicillin: abdominal pain, diarrhea, nausea, liver injury Ampicillin: erythema multiforme, exfoliative dermatitis, skin rash (common in patient receiving allopurinol or infected with mononucleosis), neutropenia, leukopenia, anemia, eosinophilia, acute interstitial nephritis Penicillin + Beta-lactamase inhibitors Ampicillin/Sulbactam (IV), Amoxicillin/Clavulanate (PO), Piperacillin/Tazobactam (IV) Gram-positive aerobic activity: Enterococcal and Streptococcal coverage are similar to aminopenicillins, expanded staphylococcal activity to include methicillin-susceptible isolates Gram-negative aerobic activity: Amox/Clav Amp/Sulb Pip/Taz E. coli Klebsiella pneumoniae Proteus Mirabilis Haemophilus influenzae* Moraxella catarrhalis* Pasteurella multocida* Capnocytophaga spp.* E. coli Klebsiella pneumoniae Proteus Mirabilis Haemophilus influenzae* Moraxella catarrhalis* Pasteurella multocida* Capnocytophaga spp. * Acinetobacter baumannii * More activity against all gram negatives, including more resistant E. coli, Klebsiella, and Proteus spp. Pseudomonas aeruginosa Gram-positive anaerobic activity (treatment of choice): Actinomyces spp., Peptostreptococcus, and Propionibacterium acnes Gram-negative anaerobes (treatment of choice): bacteroides fragilis, prevotella spp., and fusobacterium necrophorum Class Important Spectrum Clinical Application Natural Penicillins Streptococci Syphilis Oral anaerobes Streptococci infections (strep throat, strep endocarditis, nonpurulent cellulitis) Syphilis Very narrow, often a de-escalation Penicillinase-resistant penicillins MSSA Gold standard for monomicrobial MSSA Toxicities limit use to more severe infections (endocarditis, CNS, and bacteremia) Aminopenicillins Enterococci Narrow gram-negative Infections caused by E. faecalis or streptococci Community acquired pneumonia or oropharyngeal infections with known susceptibility Beta-lactam/Beta-lactamase inhibitors (BL/BLI) Streptococci Anaerobes Enterobacterales Pseudomonas (Pip/Taz only) Community acquired pneumonia Coverage of polymicrobial soft tissue infections (diabetic foot infections) Coverage of intra-abdominal infections with known susceptibility Cephalosporins Chemical structure: Beta-lactams, more stable against beta-lactamases and have longer half lives compared to penicillins, low allergy cross-reactivity Classes are defined by generation (1-5 + advanced generation), with expanding gram negative coverage as generation increases First Generation Cefazolin (IV), Cefalexin (PO), Cefdroxil (PO) Gram Positive aerobic activity: not effective against enterococcus, *treatment of choice for methicillin susceptible staphylococcus aureus, excellent coverage of streptococcus spp. (Group A- pyogenes, B- agalactiae, C, F, G, streptococcus pneumoniae, viridans streptococcus) Gram Negative aerobic activity: limited to E. coli, K. pneumoniae, and P. mirabilis, different MIC (16) for UTIs compared to other infections here. No activity against non-fermenting organisms (acinetobacter baumannii, pseudomonas aeruginosa, stenotrophomonas maltophilia) Gram Positive Anaerobic activity: P. acnes and Peptostreptococcus Gram negative Anaerobic activity: none Atypical activity: none Second Generation Cefuroxime (IV/PO), Cefprozil (PO), Cefaclor (PO), Cefotetan (IV), Cefoxitin (IV) Gram Positive Aerobic activity: lack activity against enterococcus, less activity against methicillin susceptible staphylococcus aureus than first generation, excellent coverage of streptococcus spp. Gram Negative Aerobic activity: improved activity against E. coli, K. pneumoniae, and P. mirabilis compared to first generation, activity against H. influenzae and M. catarrhalis, no activity against non-fermenting organisms (acinetobacter baumannii, pseudomonas aeruginosa, and stenotrophomonas maltophilia) Gram Positive Anaerobic activity: maintain activity against P. acnes and Peptostreptococcus Gram Negative Anaerobic activity: a subgroup of the second generation called cephamycins (cefotetan and cefoxitin) have expanded coverage of Bacteroides spp., Fusobacterium spp., and Prevotella spp. Atypical activity: none Third Generation Ceftriaxone (IV), Cefotaxime (IV), Ceftazidime (IV), Cefdinir (PO), Cefditoren (PO), Cefixime (PO), Cefpodoxime (PO), Ceftibuten (PO) Gram Positive Aerobic Activity: lack activity against Enterococcus spp as mono therapy (can be combined with ampicillin), limited activity against methicillin susceptible staphylococcus aureus, great coverage against Streptococcus spp (ceftriaxone is treatment of choice here) Gram Negative Aerobic Activity: More active compared to first and second generations, first line therapy for E. coli, K. pneumoniae, H. influenzae, and salmonella spp., Ceftazidime has activity against non-fermenting organisms (Pseudomonas aeruginosa, Acinetobacter baumannii, stenotrophomonas maltophilia, but resistance is common in acinetobacter spp. And stenotrophomonas spp.) Gram Positive Anaerobic bacteria: P. acnes and Peptostreptococcus Gram Negative Anaerobic bacteria: None Atypical Activity: None Fourth Generation Cefepime Gram Positive Aerobic Activity: lack activity against Enterococcus spp., good activity against methicillin susceptible staphylococcus aureus (but not better than 1st generation), great coverage of Streptococcus spp. Gram Negative Aerobic Activity: broad gram negative activity, extensive coverage of E. coli, K. pneumoniae, H. influenzae, and salmonella spp. (not usually first line), stable in the presence of “AmpC” beta-lactamases (inducible beta-lactamases seen in some gram negative bacteria: Enterobacter cloacae, Citrobacter Freundii, and Klebsiella aerogenes * first line for these), treatment of choice for Pseudomonas aeruginosa Gram Positive Anaerobic activity: P. acnes and Peptostreptococcus Gram Negative Anaerobic Activity: none Atypical activity: none Fifth Generation Ceftaroline Gram Positive Aerobic activity: broadest activity of all cephalosporins, lack activity against Enterococcus spp., best coverage of any beta lactam of methicillin susceptible staphylococcus aureus and methicillin resistant staphylococcus aureus (reserved for severe MRSA infections), great coverage of Streptococcus spp. Gram Negative Aerobic Activity: limited, active against E. coli, K. pneumoniae, and P. mirabilis and H. influenzae and M. catarrhalis, no activity against non-fermenters Gram Positive Anaerobic activity: P. acnes and Peptostreptococcus spp. Gram Negative Anaerobic activity: none Atypical activity: none Advanced Generation Cefiderocol, Ceftazidime-avibactam, Ceftolozane-tazobactam Their place in therapy is used in multi-drug resistant gram-negative organisms, not used in gram positive infections Very broad gram-negative coverage All are active against extended spectrum beta-lactamase (ESBL) producing organisms Ceftazidime-avibactam is active against carbapenemase-producing organisms (commonly via KPC enzyme) Ceftolozane-tazobactam has coverage of muti-drug resistant Pseudomonas aeruginosa Cefiderocol has activity against carbapenemase-producing organisms, pseudomonas aeruginosa, and Actinobacter, MBL producing organisms Limited anaerobic activity (Ceftazidime-avibactam and Ceftolozane-tazobactam have activity against P. acnes and Peptostreptococcus) Absorption: Cephalexin, cefadroxil, cefaclor, and cefprozil have high bioavailability (80-95%) Distribution: variable between agents, most are around 20% protein bound, oral agents have low penetration into the CNS Cefuroxime, ceftriaxone, cefotaxime, ceftazidime, and cefepime all penetrate the BBB well Metabolism/Elimination: limited metabolism, primary route of elimination is the kidneys, t ½ = 1-2 hours, ceftriaxone does not require renal dosing adjustments ADRs: diarrhea, biliary sludging (Cefriaxone only, cannot be given to neonates), LFT elevations, immune mediated hepatitis, encephalopathy, seizures, hypersensitivity, rash, serum sickness, anaphylaxis Class Important Spectrum Clinical Application/Notes 1st generation MSSA Streptococcus First line for MSSA infections Non-purulent soft tissue infections Surgical prophylaxis 2nd generation Haemophilus Moraxella Anaerobes (Cephamycin) Commonly acquired pneumonia (pediatrics) Intra-abdominal infections and prophylaxis 3rd generation Enterobacteriales Streptococcus (Ceftriaxone) Community acquired pneumonia Urinary Tract Infections Intra-abdominal infections 4th generation Enterobacteriales AmpC producing organisms Pseudomonas Empiric covering of septic shock Febrile neutropenia Hospital acquired pneumonia Coverage of Pseudomonas and AmpC producing organisms 5th generation MRSA Salvage therapy for invasive MRSA infections Advanced Generation Carbapenem-resistant Enterobacteriales (ceftazidime-avibactam) MDR pseudomonas Treatment of highly resistant Gram-negative infections Carbapenems Chemical Structure: Beta-lactam, highly stable in the presence of beta-lactamases, negligible cross reactivity with penicillins Non-pseudomonal: ertapenem Pseudomonal: imipenem, meropenem Carbapenem + beta-lactamase inhibitor: meropenem-vaborbactam, imipenem-relebactam Gram Positive Aerobic Activity: Meropenem and Imipenem have activity against E. faecalis, has activity against methicillin susceptible staphylococcus aureus, active against all Streptococcus spp. Gram Negative Aerobic Activity: active against E. coli, K. pneumoniae, and P. mirabilis, including the ESBL producing strains, first line against ESBL producing Enterobacteriales, Meropenem and imipenem have activity against Pseudomonas aeruginosa and Acinetobacter baumannii (unlike ertapenem), none are active against Stenotrophomonas maltophilia Carbapenem-BLI combinations have exceptionally broad gram negative coverage Developed to treat MDR infections Active against ESBL and carbapenemase-producing organisms Slightly expanded activity with Acinetobacter spp. And Pseudomonas spp. No activity against Stenotrophomonas maltophilia Atypical activity: None Anaerobic activity: Great activity against both gram positive and gram negative anaerobes, can be used for polymicrobial infections that includes anaerobes Metabolism/Elimination: Imipenem is subject to degradation by DHP-1 (formulated with a DHP-1 antagonist) High volume of distribution, well distributed into tissues Imipenem and meropenem are used to treat CNS infections’ T ½ for meropenem and imipenem = 1 hour (dosed every 6-8 hours) T ½ for ertapenem = 4 hours (dosed every 24 hours) Extensive renal elimination and require renal dose adjustments ADRs: nausea, vomiting, diarrhea, headache, seizures (imipenem > meropenem > ertapenem), hypersensitivity Drug Interactions: Valproic acid (carbapenems decrease valproic acid concentrations leading to breakthrough seizures, cannot be overcome by dose, avoid combination) and Probenecid (increases plasma levels of carbapenems and should be avoided due to increased risk of seizures) Monobactam- Aztreonam MOA: binds to penicillin binding proteins (PBPs), specifically PBP3 and inhibits cross-linking of peptidoglycan in the cell wall, leading to autolysis and cell death Gram Positive activity: none Anaerobes activity: none Atypical activity: none Gram Negative activity: broad gram negative activity, active against E. coli, K. pneumoniae, and P. mirabilis (active against MBLs but not ESBL or KPC), active against pseudomonas aeruginosa and is considered the treatment of choice in beta-lactam intolerant/allergic patients, no activity against non-fermenters (stenotrophomonas maltophilia and acinetobacter baumannii) Metabolism/Elimination Not extensively metabolized, IV only Protein binding 56%, distributed well through the body and into the CNS Half life is 1.7 hours, extended with renal impairment, dose adjustment required ADRs: nausea, vomiting, diarrhea, rash No significant interactions Lecture 11 & 12: Gram Positive Agents (6/14-6/21) Two systems of immunity: Innate (non-specific) and adaptive (specific) Innate- physical barriers, phagocytes (neutrophils, macrophages), proteins strategically pre deployed and prepositioned to prevent or quickly neutralize the infection Exterior defenses include skin, mucus, cilia, normal flora, saliva, low pH of the stomach, skin, and GU tract Time to response: hours Soluble factors: lysozymes, complement, C-reactive protein, and interferons Cells include neutrophils, monocytes, macrophages, NKCs, and eosinophils Adaptive- evolves and adapts against invading pathogens, divided into humoral (B lymphocytes) and cellular (T lymphocytes) Time to response: days Soluble factors: antibodies, cytokines Barriers to Entry into the body The skin and lining of the respiratory, UG tract, GI tract have epithelial cells that have tight junctions to form barriers against an outside environment Immune response is dictated by the nature of the pathogen and the route of infection Efficient elimination of the pathogen requires complex coordination between epithelial and innate immune cells and local and systemic action Skin: physical an immunologic barrier Dryness, salinity, and mild acidity combined with natural skin flora make it inhospitable Sebum coats hair and skin and has natural antimicrobial properties Mucous membranes: most pathogens enter through mucosal surfaces of respiratory, GI, and UG tracts Mucus is formed by mucins and carriers immune cells, antimicrobial factors, bacteria, nutrients, and waste Respiratory Tract: trachea, bronchi, and bronchioles are ciliated to propel mucus upwards Infection from inhaled microorganisms can occur if the pathogen is not eliminated quickly Gastrointestinal Tract: acidic pH of the stomach and the antibacterial effect of the pancreatic enzymes, bile, and intestinal secretions are effective, non-specific antimicrobial defenses Small intestine mucus limited the number of bacteria that can reach other parts of the GI tract Large intestine inner mucus is relatively free of bacteria and the outer layer of the mucus hosts commensal bacteria Genitourinary tract: Lactobacillus spp. Creates a low vaginal pH that restricts growth of organisms The lower urinary tract is rinsed with urine eliminating potential pathogens Uromodulin prevents E. coli from attaching to the cellular lining of the urinary tract Eye: tears are an effective means of protection, foreign substances are diluted and washed away Cells of Innate Immunity: White Blood Cells and Neutrophils White Blood Cells (WBCs): major role is defense against invading organisms, elevated during an infection Divided into Granulocytes and Agranulocytes Granulocytes are Neutrophils, Basophils, and Eosinophils Agranulocytes are Lymphocytes and Macrophages (Monocytes) Neutrophils (70% of WBCs): enter tissues to phagocytize pathogens Segs (segmented nucleus): mature neutrophils Bands (lack segments): immature neutrophils Left shift refers to an increased number of bands (> 5%) during an infection due to the production of new neutrophils Macrophage: antigen presenting cell, surveillance of antigens Neutrophils: defense against bacteria and fungi Eosinophils: defense against parasites, response against allergic reactions Basophils: allergic response B lymphocytes: antibody production, antigen presenting cell T lymphocyte: cellular immunity against virus and tumors, regulation of the immune system Gram Positive Antibiotics: three subsets Glycopeptides & Lipopeptides: vancomycin, daptomycin, telavancin, dalbavancin, oritavancin Oxazolidinones: linezolid, tedizolid Misc: Clindamycin, Lefamulin Vancomycin MOA: inhibition of late cell wall synthesis, forms complexes with the carboxyl-terminal D-alanine residues of peptidoglycan precursors Binding at this step block the incorporation of disaccharide pentapeptide subunits into the nascent peptidoglycan and likely inhibits transpeptidation Gram Positive Aerobic Activity: broad, treatment of choice for methicillin resistant staphylococcus aureus (MRSA) and coagulase-negative staphylococcus, can cover methicillin susceptible staphylococcus aureus but is associated with worse outcomes compared to beta-lactams, covers all Streptococcus spp. (can be used in combination with S. pneumoniae meningitis or if the patient is resistant/intolerant to beta-lactams) Patients with MSSA should receive nafcillin or cefazolin as soon as the infection is identified, NOT vancomycin Gram Positive Anaerobic activity: very good coverage, treatment of choice for Clostridioides difficile infection, can also cover peptostreptococcus and propionibacterium acnes Gram Negative Aerobic activity: none Gram negative Anaerobic activity: none Atypical activity: none Absorption: can be administered via any route except IM, poor absorption when given orally so it is not given orally except for C. dif infections because it reaches high fecal concentrations Distribution: Wide range of distribution dependent on patient factors, penetrates well into the kidney, liver, spleen, heart tissue Does not penetrate CNS without meningeal inflammation Does not penetrate the lungs well Elimination: excreted unchanged in the kidneys, t ½ = 4-6 hours Dosing Target goal AUC/MIC = 400-600 Or Trough goal 10-15 ADRs: nephrotoxicity, infusion related reaction, hematologic effects, delayed hypersensitivity reactions Vancomycin associated Nephrotoxicity (VAN): reported early is use due to impurities, primarily occurred due to oxidative effect on the cells of the proximal renal tubule (causes ischemia), usually reversible, usually occurs with long term use (over 7 days), risk factors: troughs over 15, doses over 4 g/day, duration over 7 days, obesity, pre-existing renal impairment, age over 65, critically ill patients, or concomitant use of other nephrotoxic agents like aminoglycosides, piperacillin-tazobactam, etc Infusion-related reaction: most common side effect, rapid onset of rash due to histamine release from degranulation of mast cells, premedication with diphenhydramine and slowing the infusion rate will help Hematologic effects: neutropenia, pancytopenia, thrombocytopenia (rare), leukocytoclastic vasculitis (rare) Delayed hypersensitivity reactions: very severe! Discontinue if these occur! Daptomycin MOA: lipopeptide that has calcium-dependent insertion of lipophilic tail into the cytoplasmic membrane, causes oligomerization and disruption of the cell membrane, in addition to release of intracellular ions and cell death Gram Positive Aerobic activity: broad, treatment of choice for vancomycin resistant Enterococci (VRE), covers MSSA and MRSA (used only as salvage therapy), covers most streptococci species (except S. anginosus and viridans streptococci) Cross-resistance: exposure to vancomycin causes MRSA to increase the cell wall thickness, which require the MICs for both vancomycin and daptomycin to increase Causes Oxacillin MIC to decrease Gram Positive Anaerobic activity: good coverage, includes peptostreptococcus and propionibacterium acnes Gram Negative Aerobic activity: None Gram Negative Anaerobic activity: None Atypical activity: none Distribution: long terminal half life (dosed every 1-2 days), distributed mainly into plasma and interstitial fluid, CNS penetration is poor, inactivated by surfactant in the lungs so cannot be used for pneumonia Elimination: excreted primarily in the kidneys and feces, t ½ = 8-9 hours ADRs: CPK elevations (muscle toxicities, risk factors include concomitant statin use, obesity, critically ill patients, higher doses, and severe renal impairment), eosinophilic pneumonia (long-term therapy), LFT elevations, vomiting, abdominal pain, diarrhea Lipoglycopeptides: telavancin, Dalbavancin, and Oritavancin MOA: presence of a lipophilic side chain that binds to the cell wall and blocks crosslinking of peptidoglycans Creates structural rigidity that locks the binding pocket into place and anchors the antibacterial into the membrane Gram-Positive Aerobic activity: broad, have coverage against E. faecalis, MSSA, and MRSA, Coverage against VRE (oritavancin), coverage of streptococci spp. (except S. pneumoniae for oritavancin and dalbavancin) Gram Positive Anaerobic Activity: Very good, not active against Actinomyces spp., covers peptostreptococcus and propionibacterium acnes Gram Negative Aerobic activity: none Gram Negative Anaerobic activity: none Atypical activity: none Distribution Telavancin: low volume of distribution Dalbavancin: most protein bound Oritavancin: highest volume of distribution Elimination: mostly in the urine, telavancin has the shortest half life (7-10 hours), dalbavancin and oritavancin have extremely long half lives and are given IV, 1-2 doses ADRs: headache, dizziness, eosinophilia, anemia, new onset or worsening renal impairment (monitor renal function prior to, during, and after therapy), vomiting, diarrhea, nausea, metallic taste (33%), injection site reaction Linezolid MOA: protein synthesis inhibitor (binds to the V-domain of the 23S RNA component of the 50S ribosomal subunit), bacteriostatic, manipulation of the A & B ring are important for activity Gram Positive Aerobic activity: active against enterococcus spp. (treatment of choice depending on location, high penetration into bone), often a step-down therapy from daptomycin, active against MSSA and MRSA (great oral option), active against Streptococcus spp., used in polymicrobial infections (intra abdominal or SSTI) when coverage of Enterococci and MSRA need to be covered in addition to Streptococcus Gram Positive Bacillus activity: gram-positive rods, listeria monocytes (treatment of choice is ampicillin + gentamicin, but can be used in meningitis in neonates, bacteremia during pregnancy, bacteremia or endocarditis in immunocompromised patients), Nocardia spp (treatment is usually trimethoprim-sulfamethoxazole, but can be used with brain abscess or pneumonia) Gram Positive Anaerobic activity: broad activity, actinomyces, propionibacterium, and peptostreptococcus, active against Clostridium (not C. diff), some activity of prevotella and fusobacterium Gram Negative Anaerobic activity: limited from the GI tract (B. fragilis) Gram Negative Aerobic activity: none Atypical activity: none Other organisms Some activity against Mycobacteria, including M. tuberculosis (treatment option for drug-resistant TB) Also active against Mycobacterium abscessus (multidrug resistant) and Mycobacterium avium complex (MAC) Metabolism/Excretion: bioavailability is 100%, 31% protein bound, great distribution into the tissues (high concentration in epithelial lining, bone, joint, and CNS), metabolized in the liver, t ½ = 5 hours, some renal excretion but no dose adjustment needed Drug interactions Monoamine Oxidase Inhibition: linezolid is a reversible, non-selective monoamine oxidase inhibitor, use is associated with serotonin syndrome (fever, agitation, mental status changes, tremors) due to increased serotonin levels. Occurs with concurrent use of serotonergic agents. Recommended wash-out period, but that cannot always occur clinically Tedizolid MOA: protein synthesis inhibitor (binds to the V-domain of the 23S RNA component of the 50S ribosomal subunit), bacteriostatic, contains a hydroxymethyl group which allows the activity to be upheld against linezolid-resistant organisms (resistance caused by the cfr gene) Favorable MIC is associated with the C and D ring of the structure Gram Positive Aerobic Activity: broad, tedizolid is 2-8 times more potent than linezolid (may not reflect clinically), Enterococcus spp. Including E. faecalis and vancomycin resistant E. faecium (VRE), MSSA, MSRA, all streptococcus spp. Gram Positive Bacillus activity: MIC values several fold lower (compared to linezolid) for Arcanobacter spp., C. jeikeium, L. monocytogenes, with the exception of Nocardia nova and Nocardia brasiliensis (where activity is comparable) Gram Positive Anaerobic activity: broad, same in vitro superiority compared to linezolid but not clinically tested Gram Negative Anaerobic activity: none Gram Negative Aerobic activity: none Atypical activity: none Other organisms Mycobacteria- good activity, in vitro appears to be better than linezolid but clinically untested Metabolism/Excretion: prodrug converted by plasma phosphatases following oral & IV administration, bioavailability 91%, protein binding 70-90%, t ½ = 12 hours (once daily dosing, good for outpatient use), primarily metabolized by the liver, no renal dosing adjustment needed Drug Interactions Monoamine Oxidase Inhibitor: weak, reversible monoamine oxidase inhibition so it does not cause serotonin syndrome, good option for patients on serotonergic agents Oxazolidinones (Linezolid and Tedizolid) Adverse Reactions Diarrhea, Hepatic (increased LFTs), hematologic toxicity including myelosuppression, pancytopenia, thrombocytopenia (increased risk in linezolid), neuropathy including dysesthesias and optic neuropathy (increased risk in linezolid) Clindamycin MOA: lincosamide antibiotic, protein synthesis inhibitor (binds reversibly to 50S subunit of the ribosome), suppresses endotoxin production (alpha toxins, TSST-1, PVL, and enterotoxins) Gram Positive Aerobic Activity: no enterococcal coverage, staphylococcal coverage limited by resistance (may be active against MSSA or MRSA depending on local resistance patterns, must utilize D-test to determine if it’s susceptible before use), resistance-limited use in streptococci spp. (used in combination with penicillin for Group A Streptococcal toxic shock syndrome) Gram Positive Anaerobic activity: treatment of choice* for gram-positive anaerobes, use is limited due to resistance and high risk of C. difficile infections, alternative for penicillin in patients with allergy and oropharyngeal infections Gram Negative Anaerobic activity: limited due to resistance (B. fragilis) Gram Negative Aerobic activity: none Atypical activity: none Other organisms Toxoplasmosis: in vitro activity against Toxoplasma gondii and is used in combination with pyrimethamine to treat toxoplasmosis Pneumocystis Pneumonia (PJP): activity against pneumocystis and is used as an alternative (in combination with Primaquine) Malaria: activity against Plasmodium falciparum and is an alternative agent for malaria in pregnancy Metabolism/Excretion: bioavailability 90%, good penetration into most tissues especially bone (with the exception of CSF), most of the drug is metabolized by the liver (CYP3A4 substrate!), t ½ = 2.4 hours, extended in severe renal impairment and severe liver disease Drug interactions: CYP3A4 inducers/inhibitors ADRs Diarrhea, C. difficile infection, dermatologic, hepatic (increased LFTs) Lefamulin MOA: pleuromutilin antibiotic, protein synthesis inhibitor (interference with peptidyl transferase to subsequently inhibit peptide synthesis and chain elongation) Gram Positive Aerobic Activity: broad coverage, some activity against E. faecium but not E. faecalis, active against staphylococcus (MSSA and MRSA), streptococcus (including susceptible and resistant S. pneumoniae), active against beta and alpha hemolytic streptococci Gram Negative Aerobic activity: no activity against Enterobacteriales (E. coli, K. pneumoniae, Enterbacter spp., Proteus spp., etc), no activity against non-fermenting gram negatives (A. baumannii, pseudomonas aeruginosa, stenotrophomonas), good activity against gram negative organisms associated with community acquired pneumonia (H. influenzae and M. catarrhalis) Gram Positive Anaerobic activity: activity against C. acnes, C. perfringens, Fusobacterium, Peptostreptococcus, and prevotella but no FDA breakpoints Gram Negative Anaerobic activity: lack coverage against C. difficiles and B. fragilis Atypical activity: Great activity against C. pneumoniae, M. pneumoniae, and L. pneumoniae Metabolism/Excretion: absorption is decreased by food, 95-97% protein bound, high levels in the lungs, skeletal muscle, and adipose tissue, both a substrate and an inhibitor of CYP3A4 and Pgp, dose reduce in hepatic impairment Lots of drug interactions Monitor, adjust dosage Avoid co-administration Contraindicated Alprazolam (increased concentrations of alprazolam) Diltiazem (increased concentrations of diltiazem) Simvastatin (increased concentrations of simvastatin) Vardenafil (increased concentrations of vardenafil) Verapamil (increased concentrations of verapamil) Amiodarone (increased concentrations of amiodarone and QTc interval) Antipsychotics (increased QTc interval) Fluoroquinolone (increased QTc interval) Ketoconazole (increased lefamulin concentrations) Macrolides (increased QTc interval) Midazolam, PO (increased concentrations of midazolam) Procainamide (increased QTc interval) Quinidine (increased quinidine concentration and QTc interval) Rifampin (decreased concentration of lefamulin) Sotalol (increased QTc) Tricyclic antidepressants (increased QTc) Pimozide (increased pimozide and QTc interval) ADRs: diarrhea, nausea, vomiting, prolonged QTc (most drug interactions here!), insomnia, headache, anxiety, drowsiness, anemia, thrombocytopenia, infusion site pain, injection site phlebitis, injection site reaction