Pharmacology Antimicrobials Overview
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Bacteria by Site of Infection
- Mouth: Peptococcus, Peptostreptococcus, Actinomyces
- Skin/Soft Tissue: S. aureus, S. pyogenes, S. epidermidis, Pasteurella
- Bone and Joint: S. aureus, S. epidermidis, Streptococci, N. gonorrhoeae, Gram-negative rods
- Abdomen: E. coli, Proteus, Klebsiella, Enterococcus, Bacteroides sp.
- Urinary Tract: E. coli, Proteus, Klebsiella, Enterococcus, Staph saprophyticus
- Upper Respiratory: S. pneumoniae, H. influenzae, M. catarrhalis, S. pyogenes
- Lower Respiratory Community: S. pneumoniae, H. influenzae, K. Pneumoniae, Legionella pneumophila, Mycoplasma, Chlamydia
- Lower Respiratory Hospital: K. pneumoniae, P. aeruginosa, Enterobacter sp., Serratia sp., S. Aureus
- Meningitis: S. pneumoniae, N. meningitidis, H. influenza, Group B Strep, E. coli, Listeria
Minimum Inhibitory Concentration (MIC)
- Lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism
- Used as a laboratory measurement of the activity of an antimicrobial agent against an organism
- Each drug has at least one MIC breakpoint
- Value used to separate “susceptible” from “resistant”
- MIC > breakpoint = resistant, and vice versa
- Some drugs have >1 breakpoint (different values for different bacteria)
Bactericidal vs Bacteriostatic
- Bacteria Killing vs Bacteria Inhibiting
- Bactericidal activity is not an invariable property of an antibiotic; it can depend upon the organism and the growth conditions
A period of time after complete removal of an antibiotic during which there is no growth of the target organism
Classes of Antimicrobials
- Penicillins and Cephalosporins are β-Lactams
- Penicillins: Penicillin, Anti-staphylococcal, Aminopenicillins, Extended spectrum (anti-pseudomonal)
- Cephalosporins: 1st to 4th (5th) generation
B-lactams (Penicillins & Cephalosporins) Pharmacology
- MOA: Bactericidal. Cell wall synthesis inhibitors. Bind to penicillin-binding proteins (PBPs) in bacterial cell walls which leads to inhibition of peptidoglycan synthesis.
- Absorption: Oral B-lactams are variably absorbed. Food can delay the rate and extent of absorption. Pen VK absorbed better than oral Pen G. Amoxicillin absorbed better than ampicillin
- Distribution: Widely distributed into tissues and fluids
- Elimination: Most eliminated primarily by the kidney
- Elimination exceptions: nafcillin, oxacillin, ceftriaxone, and cefoperazone are eliminated primarily by the liver; piperacillin also undergoes some hepatic elimination
- Many B-lactams have short elimination half-lives (< 2º), except for a few cephalosporins (ceftriaxone)
- Often require frequent dosing.
B-Lactams Adverse Effects
- Penicillins and Cephalosporins
- Need to distinguish adverse rxn from allergic rxn!
- Hypersensitivity: 3-10%
- Allergic reactions: rash to anaphylaxis and death.
- Cross-reactivity exists among all penicillins and even other B-lactams
- Desensitization is possible. Necessary for treatment of Syphilis.
- 90% persons with penicillin hypersensitivity are ok on cephalosporins.
- Neurologic: especially with penicillins and carbapenems (imipenem). More of a concern in patients receiving high doses in the presence of renal insufficiency. Irritability, jerking, confusion, seizures.
- Hematologic: Leukopenia, neutropenia, thrombocytopenia
- GI: Increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (C. difficile diarrhea)
- Interstitial Nephritis: Cellular infiltration in renal tubules (Type IV hypersensitivity reaction; characterized by abrupt increase in serum creatinine); can lead to renal failure. Especially with methicillin or nafcillin.
- Cephalosporin-specific: MTT side chain - cefamandole, cefotetan, cefmetazole, cefoperazone, moxalactam. Hypoprothrombinemia due to reduction in vitamin K-producing bacteria in GI tract. Ethanol intolerance.
- Others: phlebitis, hypokalemia, Na overload
Penicillins Overview of Agents
- Natural (“plain” penicillin): Penicillin G (iv), Penicillin VK (po)
- Penicillinase - Resistant or “Anti-Staphylococcal” Penicillins: Nafcillin (iv), Oxacillin (iv),
- Dicloxacillin (po), Cloxacillin (po), “Methicillin”
- Aminopenicillins: Ampicillin (iv/po), Ampicillin + Sulbactam (Unasyn, iv), Amoxicillin (po), Amox + Clavulanic acid (po) (Augmentin)
- Extended Spectrum (all iv) or “Anti-Pseudomonal” Penicillins: Carboxypenicillins, Ticarcillin + Clavulanic acid (Timentin, iv), Acylureidopenicillins, Piperacillin + Tazobactam (Zosyn, iv)
β-Lactam Antibiotic Resistance
- Steric hindrance prevents enzyme from reaching β-lactam ring. Enzymatic destruction of drug is most important characteristic of drug resistant bacteria.
- Change in the drug target penicillin binding protein (PBP); MRSA, Altered PBP 2A
- Alteration in outer membrane permeability (gram negative bacteria).
- Production of deactivating enzymes or beta-lactamases
- Most clinically important factor in mediating resistance to beta-lactam antibiotics
Penicillin G (Na or K) IV / Penicillin VK po (natural penicillin)
- Activity: Streptococci (S. pneu, viridans, Gp A), Enterococcus, Listeria, Clostridia, Treponema pallidum
- NO Staphylococcal Activity.
- Not resistant to beta-lactamases.
- Uses: Streptococcal infections (pharyngitis, endocarditis, pneumonia), Syphilis
Penicillin G and VK)
- Gram-positive: pen-susc S. aureus (rare), pen-susc S. pneumoniae, Group streptococci, viridans streptococci, Enterococcus
- Gram-negative: Neisseria sp.
- Anaerobes: Above the diaphragm, Clostridium sp.
- Other: Treponema pallidum (syphilis)
- Very limited use.
- Benzathine penicillin (IM): Long acting, low serum levels in body
- Uses: Syphilis, Strep. Throat
- Procaine penicillin (IM): Intermediate acting, higher serum levels than benzathine
- Uses: pneumococcal pneumonia
Penicillinase Resistant Penicillins
- Anti-staphylococcal Penicillins: nafcillin, oxacillin, dicloxacillin, cloxacillin
- Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins
- Gram-positive: methicillin-susceptible S. aureus (MSSA), Group streptococci, viridans streptococci
Dicloxacillin/Cloxacillin (po), Nafcillin/Oxacillin (iv)
- Penicillinase Resistant Penicillins
- Methicillin is not used due to a higher incidence of interstitial nephritis
- NO adjustment for renal dysfunction
- Uses: MSSA infections, Skin and skin structure infections, Acute cellulitis (not caused by CA-MRSA), Impetigo, Furuncles and Carbuncles, Erysipelas
Penicillins - Aminopenicillins
- Ampicillin & Ampicillin-Sulbactam (Unasyn)
- Amoxicillin & Amox-Clavulanate (Augmentin)
- Sulbactam & clavulante are beta-lactamase inhibitors
- Amp/Amox: Gram (+) & (-), Strep, E. coli, Proteus, Listeria, some anaerobes
- Amp + Sulb / Amox + Clav: Increased gram (+) activity, including beta lactamase (+) Staph. aureus, increased Gram (-) & anaerobe activity, Listeria, “animal bites”
- Uses: UTIs, respiratory infections, skin and skin structure infections….
Aminopenicillins (ampicillin, amoxicillin)
- Gram-Positive: pen-susc S. aureus, Group streptococci, viridans streptococci, Enterococcus sp., Listeria monocytogene
- Gram-Negative: Proteus mirabilis, Salmonella, Shigella, some E. coli, L- H. influenzae
Extended Spectrum Penicillins: Anti-Pseudomonal Penicillins
- Piperacillin, Ticarcillin, Mezlocillin
- NOT resistant to beta-lactamase
- Activity: Gram (-) including Pseudomonas aeruginosa, Gram (+), Streptococcal, good anaerobe activity.
- Weaker Staphylococcal activity
- No MRSA
- Rarely used
- Ticarcillin/Clavulanic acid (Timentin)
- Piperacillin/Tazobactam (Zosyn)
- Clavulanic acid & Tazobactam are beta-lactamase inhibitors
- Activity is enhanced vs beta-lactamase producing organisms e.g. S. aureus, gram negatives, anaerobes
- Pip/Tazo more active against Pseudomonas
- Uses: UTIs, abdominal infections, nosocomial infections
-Lactamase Inhibitor Combos (Unasyn, Augmentin, Timentin, Zosyn)
- Gram-positive: S. aureus
- Anaerobes: Bacteroides sp.
- Gram-negative: H. influenzae, E. coli, Proteus sp., Klebsiella sp., Neisseria gonorrhoeae, Moraxella catarrhalis
Classification and Spectrum of Activity of Cephalosporins
- Divided into 4 or 5 major groups referred to as “Generations”
- Generations based on Development timeline, Antimicrobial activity, Resistance to beta-lactamase
- Variability exists between and within “generations”
1st Gen Cephalosporins
- Best activity against gram-positive aerobes, with limited activity against a few gram-negative aerobes.
- Gram-positive: meth-susc S. aureus, pen-susc S. pneumoniae, Group streptococci, viridans streptococci
- Gram-negative: E. coli, K. pneumoniae, P. mirabilis
2nd Gen Cephalosporins
- In general, slightly less active against gram-positive aerobes, but more active against gram-negative aerobes.
- 2 Subgroups: Cephamycins (Activity against ‘anaerobes’), Carbacephems
2nd Gen Cephalosporins Spectrum of Activity
- Gram-positive: meth-susc S. aureus, pen-susc S. pneumoniae, Group streptococci, viridans streptococci
- Gram-negative: E. coli, K. pneumoniae, P. mirabilis, H. influenzae, M. catarrhalis, Neisseria sp.
- The cephamycins (cefoxitin, cefotetan, and cefmetazole) are the only 2nd generation cephalosporins that have activity against anaerobes: Bacteroides fragilis, Bacteroides fragilis group
3rd Gen Cephalosporins Spectrum of Activity
- “Generally” are less active against gram-positive aerobes, but have greater activity against gram-negative aerobes.
- Ceftriaxone/Rocephin and Cefotaxime have the best activity against gram-positive aerobes, including pen-resistant S. pneumoniae.
- Ceftazidime has the ‘best’ activity against P. aeruginosa in this class.
- Gram-negative aerobes: E. coli, K. pneumoniae, P. mirabilis, H. influenzae, M. catarrhalis, N. gonorrhoeae (including beta-lactamase producing); N. meningitidis, Citrobacter sp., Enterobacter sp., Acinetobacter sp., Morganella morganii, Serratia marcescens, Providencia, Pseudomonas aeruginosa (ceftazidime)
4th Gen Cephalosporins
- Limited role. Hospital only.
- Extended spectrum of activity
- Gram-positives: similar to ceftriaxone, cefotaxime
- Gram-negatives: similar to ceftazidime. Including Pseudomonas aeruginosa; also covers B-lactamase producing Enterobacter sp.
- Stability against B-lactamases: poor inducer of extended-spectrum B-lactamases
- Only cefepime is currently available in U.S.
5th Gen Cephalosporin
- Ceftobiprole (iv) is the first approved broad-spectrum anti-MRSA antibiotic belonging to the cephalosporin class.
- Ceftobiprole has demonstrated broad-spectrum activity against a wide range of difficult-to-treat Gram-positive and Gram-negative hospital and community-acquired infections including MRSA.
1st Gen Cephalosporins
- Cefazolin (Ancef, Kefzol) iv: Commonly used in surgical prophylaxis, cellulitis (SSTIs), UTIs
- Activity: Gram (+); Staph., Strep., NO MRSA or Enterococcus , UTIs , some gram (-); E. coli, Proteus, No anaerobes
- Has some stability to beta-lactamases
- Shortcomings: Inactive against Pseudomonas aeruginosa, weaker gram negative drugs, Inactive against Enterococcus and MRSA, Inactive against Bacteroides fragilis, weaker anaerobic drugs, Poor CNS penetration
- Therapeutic Uses: Skin & Skin Structure (Soft-Tissue) Infections, cellulitis, impetigo, UTIs, cystitis, pyelonephritis, Surgical Antibiotic Prophylaxis
2nd Gen Cephalosporins
- Generally improved beta-lactamase stability
- Activity: Generally less active vs. Staph., and Strep., Slightly more active vs. certain gram (-) bacilli, Some with anti-anaerobic activity
- No MRSA or Enterococcus activity
- Cefamandole (Mandol): Good biliary exc., poor CSF, bleeding
- Cefoxitin (Mefoxin): Good anaerobe activity (B. Fragilis)
- Cefuroxime (Zinacef): Community acq. Pneumonia
- Cefotetan (Cefotan): Good anaerobic activity
- Cefonicid (Monocid): Long half-life, No CSF penetration
- Cefmetazole (Zefazone)
- Shortcomings: Inactive against Pseudomonas aeruginosa. Inactive against Enterococcus, MRSA. Weak and variable activity vs many more ‘resistant’ gram negative organisms. Variable activity vs. B. fragilis and other anaerobes, except for cefoxitin, cefotetan mainly. Lack of appreciable activity vs H. influenzae (except cefuroxime and newer oral cephs). Not optimal CSF penetration
Oral 2nd Gen Cephalosporins
- Cefuroxime axetil (Ceftin)
- Oral equivalent of iv cefuroxime
- Uses: Community Acquired Pneumonia (CAP), Lower Respiratory Tract Infections (LRI), Urinary Tract Infections (UTI), skin & soft tissue infections
- Cefaclor (Ceclor): URI infections mainly, UTIs, Skin & Structure Infections
- Cefprozil (Cefzil): Respiratory infections, otitis media, skin & skin structure infections, possibly UTI’s.
- Cefpodoxime proxetil (Vantin): Indications for Pharyngitis/tonsillitis, otitis media, bronchitis, community acquired pneumonia, skin & skin structure infections and uncomp UTIs. Has activity vs Neisseria gonorrhoeae (similar to cefixime).
- Loracarbef (Lorabid): Indications for Pharyngitis/tonsillitis, otitis media, bronchitis, sinusitis, CAP, skin & skin structure infections and uncomp UTIs including pyelonephritis. Similar to cephalosporins but chemically is a carbacephem.
3rd Gen Cephalosporins
- More resistant to beta-lactamases
- Activity (general): Excellent gram (-), poorer gram (+) activity, no anaerobes, MRSA, Enterococcus
- Ceftazidime has excellent Pseudomonas activity
- Shortcomings: Inactive vs. Enterococcus, MRSA. Variable activity vs. S. aureus that is generally less than 1st gen. Variable activity vs. P. aeruginosa and Serratia (except ceftazidime). Weaker anaerobe activity.
3rd Gen Cephalosporins - IV
- Cefotaxime (Claforan): Good gram (+), good vs H. flu, excellent CSF penetration
- Cefoperazone (Cefobid): MTT side chain, some Pseudomonas activity
- Ceftizoxime (Cefizox)
- Ceftriaxone (Rocephin): Once a day, except for meningitis. No dose adjustment for renal dysfunction. Commonly used in community acquired pneumonia & meningitis.
- Ceftazidime (Fortaz): Excellent gram (-) activity, esp Ps. aeruginosa
3rd Gen Cephalosporins - Oral
- Cefixime (Suprax): Indicated for uncomplicated UTIs, 0titis media, pharyngitis/tonsillitis, acute bronchitis and exacerbations of chronic, Uncomplicated gonorrhea caused by N. gonorrhoeae.
- Ceftibuten (Cedax): Indicated for acute exacerbations of chronic bronchitis, Acute bacterial otitis media except caused by S. pneumonia, Pharyngitis and tonsillitis, Once daily dosing, take on a empty stomach, Bottom Line… no real advantages or benefits
- Cefdinir (Onmicef): Approved for acute sinusitis, otitis media, AECB, pharyngitis, CAP, and skin infections. Activity is similar to cefpodoxime. Do not take with Al or Mg antacids or iron or food. Bottom line... older, less expensive drugs are preferred; this offers no real advantage at this time.
- Cefditoren (Spectracef): Approved for AECB, Pharyngitis, Tonsillitis, Uncomplicated Skin & Soft Tissue Infections. Bottom Line... Offers no advantage over cefdinir or cefpodoxime except cost. Not a first line agent.
Oral Cephalosporin Therapeutic Use
- Upper respiratory tract infections
- Otitis media
- Lower respiratory tract
- Mild-moderate community-acquired pneumonia
- Skin-skin structure infections
- Urinary tract infections
- 1st Gen: Cephalexin, cefadroxil. Cephalexin dosed qid vs bid for cefadroxil
- 2nd Gen: Cefaclor, cefuroxime axetil, cefprozil. Improved activity against H. influenzae compared with the 1st generation oral cephalosporins. May be useful in treating otitis, sinusitis, and respiratory tract infections.
- 3rd Gen: Cefixime, cefpodoxime, ceftibuten, cefdinir, cefditoren. Active against streptococci, H. influenzae and M. catarrhalis. More active than the other oral cephalosporins against enteric gram-negative bacilli, including E. coli, P. mirabilis, and Klebsiella
- Cefixime and ceftibuten have little activity against staphylococci but cefpodoxime proxetil and cefdinir have more activity.
4th Gen Cephalosporins
- Cefepime (Maxipime) IV: Gram (+) activity of cefotaxime, Gram (-) activity of ceftazidime
- May retain activity vs. some organisms resistant to 3rd gen. cephalosporins
- Clinical efficacy in LRTI, UTIs, skin & skin structure inf., intraabdominal & gynecologic inf., bacteremia/sepsis, febrile neutropenia, pediatric CF & meningitis
Cephalosporin Activity Comparison
- 1st Gen: Gram + (excellent), Gram – (fair), Anaerobes (weak), Other (Gram – urinary pathogens)
- 2nd Gen: Gram + (good), Gram – (weak), Anaerobes (good to excellent), Other (many oral options)
- 3rd Gen: Gram + (fair), Gram – (weak), Anaerobes (fair), Other (pseudomonas activity, Ceftazidime)
- 4th Gen: Gram + (good to excellent), Gram – (excellent), Anaerobes (fair), Other (may maintain activity vs 3rd gen resistant Gram –‘s)
- Use: Febrile neutropenia, consolidation therapy, resistant infections, pancreatitis, intraabdominal conditions.
- Do not want to overuse.
- Imipenem/cilastatin (Primaxin)
- Meropenem (Merram)
- Ertapenem (Invanz)
- Doripenem (Doribax)
Carbapenem, Imipenem/Cilastatin (Primaxin)
- MOA: inhibits cell wall synthesis
- Cilastatin prevents the breakdown of imipenem by renal dihydropeptidases thereby increasing renal recovery and prevention of a toxic metabolite.
- Highly stable to beta-lactamases.
- Cross reactivity with penicillins & cephalosporins.
- Adverse effects: GI, nausea, CNS (seizures)
- Activity: GORILLACILLIN or Cepha-kill-em-all, Broad spectrum single agent, Gram (+), (-) & anaerobes
Carbapenem, Meropenem (Merram)
- Similar to imipenem however may be less active vs. gram (+) bacteria and more active vs. gram (-) bacteria.
- Less seizure potential than imipenem.
Carbapenem, Ertapenem (Invanz)
- Newer agent with no significant advantage over Imipenem or Meropenam except that is it dosed once/day.
- NO Pseudomonas or Acinetobacter activity
- Bottom Line, an alternative for outpatient therapy for certain infections.
Carbapenem, Doripenem (Doribax)
- Newest agent.
- Possible enhances activity vs P. auruginosa compared to other carbapenems.
- Indicated for complicated intra-abdominal infections and urinary tract infections.
Monobactam, Aztreonam (Azactam)
- MOA: Inhibits cell wall synthesis
- Adverse reactions: local, rash (generally well tolerated)
- No cross reactivity with penicillins/cephalosporins
- Little to no activity against gram-positives or anaerobes; stable to beta-lactamases
- Uses: Infections caused by gram negative organisms resistant to first-line agents or in patients with hypersensitivity to beta-lactams.
- Broad spectrum of activity
- Improved kinetic properties
- Excellent oral absorption, tissue penetration, prolonged half-lives
- Overall good safety profile
- MOA: Inhibit bacterial topoisomerases which are necessary for DNA synthesis.
- DNA gyrase – removes excess positive supercoiling in the DNA helix. Primary target in gram-negative bacteria
- Topoisomerase IV – essential for separation of interlinked daughter DNA molecules. Primary target for many gram-positive bacteria.
- FQs display concentration-dependent bactericidal activity.
- Adverse Effects: GI, Nausea, vomiting, diarrhea, dyspepsia, CNS (headache, agitation, insomnia, dizziness, rarely, hallucinations and seizures in elderly), Hepatotoxicity, LFT elevation (led to withdrawal of trovafloxacin) , Phototoxicity (uncommon with current FQs. More common with older FQs -halogen at position 8), Cardiac (Variable prolongation in QTc interval.), Articular Damage (arthropathy including articular cartilage damage, arthralgias, and joint swelling.)
- Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity
- Contraindications: pediatric patients and pregnant or breastfeeding women
FQs Gram + Activity
- Older agents with poor activity; newer FQs with enhanced potency.
- Methicillin-susceptible Staphylococcus aureus
- Streptococcus pneumoniae (including PRSP)
- Group and viridans streptococci – limited activity
- Enterococcus sp. – limited activity
- Not primary antistreptococcal drug.
FQs Gram – Spectrum of Activity
- All FQs have excellent activity (cipro = levo > moxi).
- Enterobacteriaceae – including E. coli, Klebsiella sp, Enterobacter sp, Proteus sp, Salmonella, Shigella, Serratia marcescens, etc.
- H. influenzae, M. catarrhalis, Neisseria sp.
- P. aeruginosa – significant resistance has emerged; ciprofloxacin and levofloxacin with best activity
FQs Anaerobe Spectrum of Activity
- Anaerobe: Trovafloxacin
- Atypical Bacteria: All have excellent activity against atypical bacteria including; Legionella pneumophila , Chlamydia sp., Mycoplasma sp., Ureaplasma urealyticum
- Other Bacteria: Mycobacterium tuberculosis, Bacillus anthracis
FQs Drug Interactions
- Divalent and trivalent cations: Zinc, Iron, Calcium, Aluminum, Magnesium, Antacids, Sucralfate, ddI, enteral feedings.
- Impair oral absorption of orally-administered FQs – may lead to CLINICAL FAILURE.
- Administer doses 2 to 4 hours apart; FQ first on empty stomach.
- Theophylline and Cyclosporine – cipro: inhibition of metabolism, ↑ levels, ↑ toxicity
- Warfarin: idiosyncratic, all FQs
- 2nd Gen FQ
- Best activity vs Pseudomonas aeruginosa
- Uses: Lower RTI, UTIs, bone, joint & skin structure infections, gonococcal infections & infectious diarrhea
FQ, Ofloxacin (Floxin)
- 2nd Gen FQ
- Best activity vs chlamydia
- Uses: Lower RTI, skin structure infections, UTIs, gonococcal & chlamydial infections, prostatitis
- 3rd Gen FQ
- Active stereoisomer of ofloxacin
- Uses: CAP, acute exacerbations of chronic bronchitis, sinusitis, skin & skin structure infections & complicated UTI’s
- 3rd Gen FQ
- Uses: CAP, AECB, Sinusitis, Some anaerobe activity.
- Not for UTIs. Doesn’t get into urine.
- More active vs. Strep pneumo than Levofloxacin.
- 3rd Gen FQ
- Activity: S. pneumoniae, H. flu., M. cat., K. pneumoniae
- Uses: Mild to moderate community-acquired pneumonia
- Acute exacerbations of chronic bronchitis
- No advantage over Moxifloxacin.
- Gentamicin, Tobramycin, Amikacin
- Protein synthesis inhibitors
- Gram-negative activity mainly
- Often used in combination with beta-lactams for gram (+) organisms
- No anaerobe activity
- Rarely used alone, except in UTIs
- Toxicity: Renal and ototoxicity
- Erythromycin (stimulated gastric motility)
- Newer agents: Broader spectrum of activity, Improved kinetic properties, Better bioavailability, tissue penetration, prolonged half-lives, Improved tolerability
- MOA: Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit
- Adverse Effects: GI, Nausea, vomiting, diarrhea, dyspepsia, Most common with erythro; less with new agents, Thrombophlebitis – IV Erythro and Azithro (Dilution of dose; slow administration)
- Other: ototoxicity (high dose erythro in patients with RI); QTc prolongation; allergy
- Rarely used
- Oral formulations, Various “salt” forms
- IV formulation available
2nd Generation Macrolides
- General: Improved absorption compared to erythromycin, Longer T½ allowing qd or bid dosing, Less GI side-effects, Short duration of therapy for azithromycin (5 days), Single dose for Chylamdia trachomatis (Azith.), Broader spectrum of activity including H. flu, Mycobacterium avium
- 2nd Gen Macrolide
- highly active against organisms sens. to erythromycin
- Use: sinusitis, pharyngitis/tonsillitis, otitis, bronchitis, CAP, uncomp. skin & skin structure inf., MAI treatment/prophyaxis
- 2nd Gen Macrolide
- iv formulation available
- Use: Single 1 gm po dose for chlamydial infections, pharyngitis, bronchitis, CAP, skin & skin structure inf., MAI treatment/prophylaxis
- Less food/drug interactions
- 2nd Gen Macrolide
- Generally less active than other macrolides against most organisms except Campylobacter jejuni & Borrelia burgdorferi
- Inactive against H. influenzae
- Drug interaction profile similar to azithromycin
- Indicated for acute exhaberations of chronic bronchitis, pharyngitis, tonsillitis (S. pyogenes) & skin and skin structure infections
Macrolide Spectrum of Activity
- Anaerobes: activity against upper airway anaerobes
- Atypical Bacteria: all macrolides have excellent activity against atypical bacteria including
- Legionella pneumophila – DOC, Chlamydia sp., Mycoplasma sp., Ureaplasma urealyticum
- Other Bacteria: Mycobacterium avium complex (MAC – only A and C), Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella, Pasteurella
Macrolide Drug Interactions
Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of: Theophylline, Digoxin, Disopyramide, Carbamazepine, Valproic acid, Cyclosporine, Terfenadine, Astemizole, Phenytoin, Cisapride, Warfarin, Ergot alkaloids
- Telithromycin - Ketek
- Sub-class of the macrolide-lincosamide-streptogramin group
- MOA: is similar to macrolides
- Activity/Indications: CAP (activity vs macrolide resistant streptococci), 10 day therapy
- Pharyngitis, tonsillitis, sinusitis, AECB (5-day therapy)
- AE: GI, QT interval prolongation
- Contraindication: patients w/myasthenia gravis
- Reports of acute hepatic failure and death
- MOA: Inhibits protein synthesis
- Activity: MSSA, Streptococcus pneumoniae (only PSSP), Group and viridans streptococci
- Anaerobes: above the diaphragm anaerobes
- Other Bacteria: Pneumocystis jiroveci, Toxoplasmosis gondii, Malaria
- Uses: Infections caused by some gram-positive and anaerobic organisms, Skin and skin structure infections, CA-MRSA
- Adverse Effects: GI 3-4%, Nausea, vomiting, diarrhea, dyspepsia, C. difficile colitis (one of worst offenders), Mild to severe diarrhea, Requires treatment with metronidazole, Hepatotoxicity (rare), Elevated transaminase
- Oral/IV agent used mainly for anaerobes, parasites and C. difficile colitis
- Adverse Effects: GI, nausea, vomiting, stomatitis, metallic taste, CNS peripheral neuropathy, seizures, encephalopathy, Potential for drug interactions
Chloramphenicol Sodium Succinate (Chloromycetin)
- Activity: gram (+) & (-), rickettsia, salmonella, anaerobes, H. flu, Neisseria
- Adverse effects: Hematologic, rare idiosyncratic aplastic anemia (< 1:40,000)
- Uses: RMSF
Tetracyclines, Doxycycline (Vibramycin)
- Activity: Rickettsia, gram-positive and gram-negative bacteria
- Atypical pathogens: Borrelia spp, Coxiella burnetii, Treponema spp, Chlamydophila and Chlamydia spp, Mycoplasma pneumoniae, Plasmodium spp, Vibrio cholerae, Vibrio vulnificus, Brucella spp, Calymmatobacterium granulomatis, Leptospira, Borrelia burgdorferi, Borrelia recurrentis, Burkholderia pseudomallei, Mycobacterium marinum, and Entamoeba histolytica
- Adverse effects: GI, rash, hepatic, “photosensitivity”
- AVOID in children
- Uses: RMSF, Lyme disease, CAMRSA skin infections
Trimethoprim/Sulfamethoxazole (Septra, Bactrim)
- Activity: Gram (-) urinary pathogens, protozoa, Pneumocystis pneumonia, some gram (+), no anaerobes
- Dose: “Double Strength” (DS) tablets bid for most indications
- Adverse effects: Allergic (rash) most common, GI, Hematologic, Renal hyperkalemia possible, CNS
- Uses: UTIs, Resp. tract, CAMRSA skin infections
- Widely used antibiotic for resistant gram-positive organisms
- 1st line for Gram + and suspected staphylococcal
- Activity: Gram-positive bacteria, MRSA, MSSA, coagulase-negative staphylococci, Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus
- Enterococcus sp.
- 1st or 2nd line for Clostridium sp. (including C. difficile), Peptococcus, Peptostreptococcus
- No activity against gram-negative aerobes or anaerobes
- Clinical Use: Infections due to MRSA, Bacteremia, empyema, endocarditis, peritonitis, pneumonia, skin and soft tissue infections, osteomyelitis, Serious gram-positive infections in -lactam allergic patients, Endocarditis or surgical prophylaxis in select cases
- Oral vancomycin for refractory C. difficile colitis
- Adverse Effects: Renal, ototoxicity, infusion related (“red-man” reaction)
- Dose: patient specific
- Blood monitoring needed
- Activity: Gram-positive pathogens: MSSA, MRSA, VRSA, Enterococci/VRE, PRSP
- It is not active against gram-negative pathogens
- Daptomycin should NOT be used to treat pneumonia or CNS disease
- Adverse effects: Myopathy
- Use: Gram positive endocarditis, bacteremia
- Linezolid (Zyvox)
- $ Very expensive
- Developed in response to need for agents with activity against resistant gram-positives (MRSA, GISA, VRE)
- Activity: Gram-Positive Bacteria; MRSA, MSSA AND Vancomycin-Resistant Staph aureus and coagulase-negative staphylococci, Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus, Enterococcus faecium AND faecalis (including VRE)
- Use: Oral or iv agent for infections caused by gram-positive organisms, Pneumonia, skin and skin structure
- Adverse Effects: GI nausea, vomiting, diarrhea, Headache, Thrombocytopenia , Most often with treatment durations of > 2 weeks, Therapy should be discontinued – platelet counts will return to normal
Antifungal Agents for Invasive Fungal Infections
- Polyenes: Amphotericin B deoxycholate, Lipid-based amphotericin (Amphotericin B Lipid Complex ABLC, ABCD Amphotericin B Colloidal Dispersion, Liposomal amphotericin B), “Amphoterrible”
- Azoles: Fluconazole, Itraconazole, Voriconazole, Posaconazole
- Echinocandins: Caspofungin, Micafungin, Anidulafungin
- Others: Flucytosine
Ampho B: Spectrum of Activity
- Aspergillus spp (except A. terreus)
- Candida albicans
- Candida non-albicans (except C. lusitaniae)
- Cryptococcus spp
- Coccidioides spp
- Histoplasma spp
- Fusarium spp (+/-)
Amphotericin B Deoxycholate (AmBd)
- Broadest spectrum antifungal
- No adjustment for renal dysfunction
- Toxicities: Nephrotoxicity (dose-limiting), Infusion-related toxicities (chills, rigors, fever, hypotension)
- Electrolyte imbalances: K wasting, Mg wasting
- GI: Nausea, vomiting
- Hematologic: anemia
Lipid-Based Formulations of Amphotericin B
- Amphotericin B lipid complex (ABLC)
- Liposomal amphotericin B (LAmB)
- Amphotericin B colloidal dispersion (ABCD)
- Less toxicities vs conventional AMB
- More expensive
- Present Place in Therapy
- Cryptococcal meningitis (+ 5FC)
- Zygomycosis (initial management)
- Histoplasmosis (disseminated)
- Refractory invasive fungal infections
- Failure of other antifungal therapies
Amphotericin B: Summary
- Broadest spectrum
- Lacks activity against A terreus, C lusitaniae
- Fungicidal, concentration-dependent activity
- Established efficacy in invasive disease
- Data limited for lipid formulations as primary therapy
- Limited drug interactions
- Intravenous formulation only
- Optimal dose unknown
- Toxicities (aka “ampho-terrible”)
- Nephrotoxicity (reduced with lipid formulations)
- Infusion-related reactions (reduced with liposomal amphotericin B)
- Electrolyte depletion
- Increased cost with lipid formulations
Azoles: Spectrum of Activity
- Fluconazole: C. albicans, C. non-albicans (+/-), Cryptococcus spp, Coccidioides spp, Blastomycetes, Histoplasma
- Itraconazole: Aspergillus spp, C. albicans, C. non-albicans (+/-), Cryptococcus spp, Coccidioides spp, Blastomycetes, Histoplasma spp, Scedosporium (+/-)
- Voriconazole: Aspergillus spp, C. albicans, C. non-albicans, Cryptococcus spp, Coccidioides spp, Histoplasma spp (+/-), Fusarium spp, Scedosporium
- Posaconazole: Aspergillus spp, C. albicans, C. non-albicans, Cryptococcus spp, Coccidioides spp, Histoplasma spp, Fusarium spp, Scedosporium, Zygomycetes
- More effective azole listed first below.
- Aspergillus spp: Itraconazole, Voriconazole, Posaconazole
- C. albicans: Voriconazole, Posaconazole, Fluconazole, Itraconazole
- C. non-albicans: Voriconazole, Posaconazole, Fluconazole (+/-), Itraconazole (+/-)
- Cryptococcus spp: Fluconazole, Itraconazole, Voriconazole, Posaconazole
- Coccidioides spp: Itraconazole, Fluconazole, Voriconazole, Posaconazole
- Blastomycetes: Itraconazole, Fluconazole, Voriconazole, Posaconazole
- Histoplasma spp: Itraconazole, Fluconazole, Posaconazole, Voriconazole (+/-)
- Fusarium spp: Voriconazole, Posaconazole
- Scedosporium: Voriconazole, Posaconazole, Itraconazole (+/-)
- Zygomycetes: Posaconazole
- Potent antifungal with rapid development of resistance (used in combination therapies)
- Toxicities: GI, hematological, rash
- Issues: dose reduction in HIV patients, renal dysfunction, gastrointestinal, hematologic toxicity, need for serum concentration monitoring (toxicity)
- Used almost exclusively in combination with AMB for cryptococcal meningitis
- Spectrum of Activity: Aspergillus spp, C. albicans, C. non-albicans, Coccidioides spp (+/-), Blastomycetes (+/-), Histoplasma spp (+/-)
- Activity: cidal (Candida), static (Aspergillus), activity against mold infections, activity against non-albicans Candida, activity maintained in biofilms, no cross-resistance with other antifungal classes
- Safety: favorable safety profile, reduced potential for drug interactions
- Administration: IV only. Once daily dosing, infrequent infusion reactions (usually mild) related to rapid infusions
- Nystatin: Cream, ointment, powder, suspension, Used for mucocutaneous fungal infections, oral candidiasis, Well tolerated
- Clotrimazole etc: Cream, ointment, spray, powder, liquid, suppository, lozenge (troche). Topical treatment of tinea corporis, tinea pedis, tinea versicolor, and oral and mucocutaneous candidiasis
- Terbinafine: Topical (Lamisil) for Various Tinea infections, Oral for Onychomycosis of the toenail or fingernail due to dermatophytes
- Acyclovir/Valacyclovir: HSV, VZV, EBV
- Famciclovir: HSV, VZV
- Ganciclovir/Valganciclovir: CMV primarily
- Foscarnet: Resistant HSV and CMV
- Cidofovir: CMV primarily
- MOA: Inhibition of viral DNA polymerases
- Activity: HSV 1 & 2, VZV, EBV
- Clinical Use: Herpesvirus treatment and prevention, Varicella-zoster
- Adverse Effects: Renal failure (acyclovir IV @ high doses)
- Well tolerated
- Cross resistance
Acyclovir (IV and po)
- Poor oral absorption
- Use iv for serious infections
Valacyclovir (po) (Valtrex)
- Oral pro-dug of acyclovir
- 3-5x better absorption than acyclovir
- Less frequent dosing than acyclovir
- Oral pro-drug converted to penciclovir
- Alternative to acyclovir, unclear if any advantages
- Less frequent dosing
- MOA: Tri-phosphoralyated to active form, inhibit viral DNA polymerases
- Formulations: Intravenous preparation (ganciclovir), Intraocular implant (ganciclovir), Oral ganciclovir capsules
- Poor absorption (< 10%)
- Valganciclovir – improved absorption, > 90%
- Side effects: Bone marrow suppression, Nephrotoxicity, Can also increase effects of other drugs
- Activity/Clinical Use: CMV infections, Has activity against HSV, EBV
- Toxicity limits use in non-CMV infections
- MOA: Pyrophosphate analog, inhibits viral-specific DNA polymerase
- Does NOT require intracellular phosphorylation
- Adverse Events: Renal impairment- 33%, Headache (26%) and seizures (10%), Less bone marrow toxicity, Electrolyte abnormalities (calcium, phosphorsus, magnesium)
- Activity/Clinical Use (iv only): Ganciclovir resistant CMV, Resistant HSV
Antivirals for Influenza
- Two classes of antiviral drugs are available for the prevention and treatment of influenza
- Amantadine and Rimantadine: Active against influenza A, H1N1 is resistant
- Neuraminidase inhibitors: Zanamivir (Relenza, inh), Oseltamivir (Tamiflu, po), Active against both influenza A and influenza B
- Malaria Acute Attack
- Quinine sulfate
- Fansidar (pyrimethamine/sulfadiazine 25/500)
- Metronidazole (Flagyl)
- Tinidazole (Tindamax)
- Paromomycin (Humatin)
- Iodoquinol (Yodoxin)
- Furazolidone (Furoxone)
Assessment of Therapeutic Failure
- Incorrect drug selection (resistance)
- Unrealistic expectation of rate of response to treatment
- Insufficient drug therapy; Duration of therapy too short, Dose of drug too small, Limited delivery of drug to infected site, Noncompliance
- Overwhelming inoculum
- Sequestered infection site requiring surgical intervention
- Noninfectious cause for symptoms; Other disease states, Adverse drug reaction/interaction
- Antibiotic antagonism
- Immunosuppression / inadequate host defense
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