19 Macrolides, Ketolides, Tetracyclines Cupo Flashcards
What is the MOA of Macrolides?
Reversibly bind the 23S ribosomal RNA in the 50S-subunit of the bacterial ribosome. Interferes with peptide bond formation of the growing peptide chain. Thus, suppress RNA-dependent protein synthesis
What are the mechanisms of acquired resistance to Macrolides?
Target site alteration - encoded by erm A, B, C genes. Alteration in transport (efflux) - encoded by mrsA, mefA, mefE (confers cross-resistance to 14- and 15-membered rings, but not 16-membered
What are the Macrolides?
Erythromycin, Clarithromycin, Azithromycin
How is Erythromycin degraded?
Acid degradation. Erythromycin in acid rapidly converted to anhydroketal and spiroketal derivatives. Result: potent GI stimulatory effects
Which Macrolide required renal adjustment?
Clarithromycin, all others are primarily hepatically cleared
What is the distribution of Macrolides like?
Lipophilic. Extensive penetration to tissues/fluids. Respiratory tract concentrations > serum. Increased concentrations in macrophages, PMNs (highest azithro). Notable exception: not well penetrated to CSF
What is the metabolism/elimination of Erythromycin like?
Biliary excretion of unchanged drug
What is the metabolism/elimination of Calrithromycin like?
Metabolized to 7 metabolites, major active = 14-OH; (renal adjust for CrCl < 30)
What is the metabolism/elimination of Azithromycin like?
Biliary excretion of unchanged drug
What are the Macrolide pharmacodynamics?
Bacteriostatic. Time-dependent. PAE - variable: 2-3 hours
What is the Spectrum of Activity for Erythromycin?
MSSA, S. pyogenes, S. pneumoniae (Pen-S). Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Bordetella pertussis. NOT Enterococci, NOT MRSA
What are the clinical applications of Erythromycin?
āMotilin effectā (GI stimulatory) - 240mg IVPB Q8h. Diabetic gastroparesis. Post-op ileus
What are the ADRs associated with Erythromycin?
N/V/D (main). Abdominal discomfort. Urticaria, rash. Ototoxicity. Increased LFTs. Cholestatic jaundice (esp. estolate). Arrhythmias
What is the structure of Clarithromycin like?
14-membered lactone ring. Replace hydroxyl group at C6 position with methoxyl group (enhanced spectrum of activity, acid stability; may take without regard to meals, decreased GI ADRs, longer t1/2, easier dose and administration
What is the Spectrum of Activity for Clarithromycin?
Gram-positive. Atypicals. Notable additions: H. influenzae (d/t addition effect of 14-OH Clarithro), H. pylori, Mycobacterium avium complex (MAC)
What are the dosage formulations for Clarithromycin?
Available PO only. Biaxim 250mg, 500mg tablets. Biaxin XL 1000mg QD. Prevpac - with Amox 500mg, Prevacid 30mg
What are the clinical applications of Clarithromycin?
ABECB: 250-500mg PO x 7-14 days. H. pylori: (part of triple regimen) x 10-14 days: clarithro, lanso, amox. MAC prophylaxis: 500mg po BID. Sinusitis: 500mg BID x 14 days. Pharyngitis: 250mg BID x 10 days
What are the ADRs associated with Clarithromycin?
Taste perversion (metallic, very common). N/V/D (less than Ery). Dyspepsia. Abdominal pain, Flatulence. HA
What is the structure of Azithromycin like?
15 membered ring. N-methyl group inserted between C9 and C10
What is the Spectrum of Activity for Azithromycin?
Gram (+). Atypicals, M. catarrhalis, H. influenzae. Additionally: N. gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticum
What are the dosage formulations of Azithromycin?
Oral: 250, 500, or 600mg. IV: 500mg. Z-pak: 500mg x 1, 250mg x 4 days. Zithromax Tri-Pak: 500mg QD x 3 days. Zithromax powder (oral suspension): 100 and 200mg/5ml. Zmax ER Powder: 2g/60ml
What are the clinical applications of Azithromycin?
CAP guidelines: 500mg PO/IV + B-lactam. Mild-Moderate ABECB: 500mg daily x 3 or 500mg x 1, 250mg QD x 4. Sinusitis: 500mg PO QD x 3. Gonorrhea: 2g PO x 1. Chlamydia infection: 1g PO x 1. MAC prophylaxis: 1,200mg Qweek
What are the ADRs associated with Azithromycin?
D/V. Abdominal pain. Vomiting (much lower than others)
What unique effects do Macrolides have?
Immunomodulatory effects: maintenance of epithelial barrier. Effects on neutrophils (accumulation and migration, reduce reactive oxygen species). Modification of cytokine production. Suppress bacterial quorum sensing. Mucoregulatory and ciliary effects. Effects on biofilm and decrease bacterial adherence. Macrolides are commonly used in CF for these reasons
What is the DDI between Macrolides and Rifampin like?
Decreased levels of Erythro, Clarithro
What is the caution of Macrolide DDIs causing QT prolongation?
Increased chance when used with Quinidine, Amiodarone, or Sotalol
What pregnancy category are Macrolides?
Pregnancy Category B
What is some Patient Counseling for Macrolides?
Skin rash, hives, itching or difficulty breathing, swelling of the face, throat, lips: contact healthcare professional. For Erythromycin Estolate (Ilosone): severe stomach pain, weakness, or if the skin has a yellow color. Fast or irregular heartbeat (Ery, Clar). Taste disturbances (Clar)
What is Telithromycin (Ketek)?
First in class. Designed to treat macrolide-resistant respiratory tract pathogens
What is the Spectrum of Activity for Telithromycin?
S. aureus, S. pneumoniae (DRSP), H. influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae
What is the therapeutic use of Telithromycin?
Acute bacterial sinusitis. Acute bacterial exacerbations of chronic bronchitis. Mild-to-moderate community-acquired pneumonia
What is the PK of Telithromycin?
BA: 57%. T1/2: 9.8 hours. 37% metabolized by liver. 13% excreted unchanged in urine, 7% excreted unchanged in feces
What is the dosage and administration of Telithromycin like?
800mg/day PO QD. Pregnancy and breastfeeding: use only if benefit outweighs risk to fetus, may be excreted in breast milk
What are the ADRs associated with Telithromycin?
D/N. HA. Dizziness. Vomiting. Loose stools. Dysgeusia
What are some major ADRs with Telithromycin?
Hepatotoxicity!!! QT prolongation. N/V: may take w/o regard to meals
What is the FDA and the Case of Ketek?
Several cases of severe liver injury and a few deaths
What is the Spectrum of Activity of Clindamycin?
Gram (+) cocci, esp. streptococci. MSSA, MSSE, CA-MRSA (pvl +, cross-R, needs D test). Peptococci, Propionibacterium, Actinomyces, Clostridia perfringens. Bacteroides fragilis, Bacteroides spp, Fusobacterium, Prevotella. NOT Enterococci, NOT Gram (-) aerobes
What is the PK of Clindamycin?
90% absorption (not affected by food). T1/2: 2.7 hours. Distribution: bone, pleural fluid, intestinal mucosa, pelvic fluid, PMNs. 90-95% protein binding. Biliary elimination, little renal
What are the ADRs associated with Clindamycin?
N/V/D. Increased LFTs. Pseudomembranous colitis. Dermatologic
What are the therapeutic uses of Clindamycin?
Emperic treatment of skin/soft tissue infection, head/neck in PCN allergy. Endocarditis prophylaxis (PCN-allergy). Surgical prophylaxis - colorectal (PCN-allergy). CA-MRSA (caution, D-test needed d/t inducible-R). Empiric treatment of GI or genitourinary tract infections (in combination with Gram (-) coverage)
What pregnancy category is Clindamycin?
Pregnancy Category B
What are the counseling points for Clindamycin?
Do not begin antidiarrheals if severe, blood diarrhea - call healthcare professional. Inform provider if yellow of skin, discolored urine, or pale stools
What are some general characteristics of Tetracyclines?
Among the first antibiotics to be used. Also have non-bacterial effects: anti-inflammation, immunosuppression, inhibition of lipase and colleganase activity, wound healing
What are the different Tetracycline agents used?
Tetracycline (PO only). Doxycycline (Both IV and PO). Minocycline (Both IV and PO). Demeclocycline (PO only)
What is the general structure of Tetracyclines?
Chemical structure consists of four rings (ātetracyclineā) comprising the backbone. Keto-enol functional groups provide the ability to chelate divalent cations
What is the MOA of Tetracyclines?
Reversibly bind to the 30S ribosome. Inhitibt binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome
What is the mechanism of resistance to Tetracyclines?
4 mechanisms: 1) Efflux Pumps, most common. 2) Ribosomal Protection Proteins (RPPs). 3) Enzymatic inactivation. 4) rRNA mutation. Resistance to one may confer resistance to all (can transfer genes). Often located on plasmids and transposons
What are the pharmacodynamics of the different Tetracyclines?
Bacteriostatic effect. Time-dependent. Peak effect - variable: Tetracycline (2-4hrs), Doxycycline (1.5-4hrs), Minocycline (1-4hrs)
How does the dosing schedule of Tetracyclines compare?
Doxy and Mino: Q12h. Tetra: Q6h
Which Tetracyclines need renal adjustment?
Doxy (40% renal clearance). Mino and Tetra do not need adjustment
What is the Spectrum of Activity of Tetracycline?
Gram (+): some Strep coverage (limited, w/ growing resistance), Propionibacterium acnes, Listeria monocytogenes. Tick borne: Rickettsia spp, Borrelia spp. Protozoa: Plasmodium. H. pylori. Chlamydia trachomatis
What are the clinical applications of Tetracycline?
Acne. Peridontal disease. Rosacea. H. pylori (in combo with Bismuth, Metronidazole, Omeprazole)
What is the Spectrum of Activity of Doxycycline?
Gram (+): Strep (less of GAS and GBS. S. pneumoniae), S. aureus (MSSA - less, CA-MRSA), Listeria, Propionibacterium acnes. Gram (-): Neisseria (meningitidis, gonorrhoeae (+/-)), M. catarrhalis, H. influenzae, Aeromonas, Brucella, Legionella, F. tularensis. Anaerobes (not C. diff). Atypicals (M. pneumoniae, Chlamydia). Tick borne (Rickettsia)
What are the clinical applications of Doxycycline?
CA-MRSA. STDs (Syphilis, Chlamydial infections, Uncomplicated gonorrhea). Acne. Rosacea. Malaria prophylaxis. Rickettsia. Periodontitis
What is the Spectrum of Activity for Minocycline?
Gram (+): Strep (GAS, GBS, S. pneumonia), S. aureus (MSSA, CA-MRSA), Listeria, Propionibacterium acnes, Peptostreptococcus. NOT Enterococci. Gram (-): Neisseria (meningitidis, gonorrhea (+/-)), M. catarrhalis, H. influenzae, Prevotella melaninogenica, Brucella, Legionella. Atypicals (M. pneumoniae, Chlamydia). Tick borne: Rickettsia
What are the clinical applications of Minocycline?
CA-MRSA. Skin and skin structure. Acne
What is Demeclocycline?
Not used to treat infectious processes. Used to treat SIADH via adverse effect ā> nephrogenic diabetes insipidus (possibly replaced by vasopressin receptor antagonists)
What is photosensitivity like for Tetracyclines?
Skin redness or rash after exposure to sunlight. Important counseling point to patients. More common with tetracycline. Not an allergic reaction to the medication
What is Tooth Discoloration like for Tetracyclines?
Greatest concern for growing teeth and bones (children and pregnant women (Pregnancy D). Can lead to inhibition of growth and bone deformities. Caution age < 8 years). Tooth discoloration (dependent upon cumulative dose; permanent). Most common with TCN, less with doxycycline
What are some rare ADRs only associated with Minocycline?
Vertigo. Drug-induced lupus
What are the Gastrointestinal ADRs associated with Tetracyclines?
Nausea, diarrhea, vomiting, abdominal cramps (may be relieved by food; some tetracyclines may have lower absorption with food (tetra, deme))
What are some more serious but less common ADRs associated with Tetracyclines?
Esophagitis. Antibiotic-associated pseudomembranous colitis. Pancreatitis
What is a counseling tip for Tetracyclines and GI issues?
Separate dose from milk, antacids, iron supplements by > 2 hours (absorption decreased by 50%)
What is hepatotoxicity like for Tetracyclines?
Highest risk in patients with pre-existing hepatic impairment
What is renal impairment like for Tetracyclines?
Acute renal failure, azotemia, renal damage reported. Use with caution in patients with renal impairment. Dosage adjustment recommended. Exception: Doxycycline (eliminated hepatically, can be administered with renal failure)
Which tetracycline can be administered with renal failure?
Doxycycline
What are some common DDIs associated with Tetracyclines?
Anticonvulsants. Bile Acid Sequestrants. Oral contraceptives. Warfarin
What type of structure is Tigecycline (Tygacil)?
Glycycline derivative
What is the spectrum of activity for Tigecycline?
Staphylococcus, including MRSA. Streptococcus. Enterococcus (including VRE). Enterobacteriaceae, including ESBL-producing. Acinetobacter (+/-). Bacteroides fragilis. Notable exceptions: Proteus mirabalis, Provedencia, P. auriginosa (Three Pās)
What are the pharmacodynamics of Tigecycline?
Bacteriostatic. PAE ~2-3 hrs. Resistance: overcomes ribosome-based - enhanced binding, Not exported by tet-specific efflux proteins
What is the PK of Tigecycline?
T1/2: 42hrs. 71-89% protein binding. Primarily eliminated in the feces, 22% excreted unchanged in urine
What is the normal dose of Tigecycline
100mg load, maintenance dose of 50mg Q12h. Infuse over 30-60 minutes
When does Tigecycline need dose adjustment?
Severe hepatic impairment: decrease maintenance dose to 25mg for Child-Pugh C
What are the ADRs of Tigecycline?
Most common: N/V/D (extremely hard to tolerate at 100mg dose). Injection-site reactions. Infection-related. Fever. Abdominal pain. HA
What is a DDI associated with Tigecycline?
Coumadin: monitor INR
What are the clinical applications of Tigecycline?
Complicated skin and skin structure (cSSSIs). Complicated intraabdominal infections (cIAIs)
What did the FDA update Tigecycline with?
Labeling change to include increased risk of mortality. This is a last line drug, not used much
