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Renal 16 Antibiotics
Bridges: Antibiotics - Protein synthesis inhibitors
| Question | Answer |
|---|---|
| Inhibit bacterial cell wall synthesis | Beta-lactams Vancomycin Bacitracin |
| Anti-metabolic activity | Sulfonamides Trimethoprim |
| Inhibition of bacterial protein synthesis. | Aminoglycosides Tetracyclins Chloramphenicol Macrolides |
| Inhibit bacterial nucleic acid syntheses | Fluoroquinolones |
| Which drug classes target the bacterial ribosome? | Aminoglycosides Tetracyclins Macrolides Chloramphenicol |
| This class is of protein synthesis inhibitors are bacteriocidal | Aminoglycosides |
| Classes that work on the 50s unit | Macrolides Streptogramins Chloramphenicol Lincosamides Oxazolidinones |
| Classes that work on the 30s unit | Aminoglycosides Tetracyclins |
| Animoglycoside that is topically OTC | Neomycin |
| Aminoglycosides are frequently used in | Serious infxn from aerobic G- |
| Use is limited due to | Toxicity |
| Used in combination with... | Beta-lactams Vancomycin |
| Why does it work best in aerobics G-? | Uptake of the drug requires O2 dependent transport system |
| Frequently used for infxns due to... | PEPS Pseudomonas (DoC) Enterobacter Proteus Serratia |
| Can also be used to treat | Invasive enterococcal infxn Serious staph. infxn Y. pestis and Francisella tularenis |
| Clinical applications of aminoglycosides | -Serious infxns- Septicemia Nosocomial RTI Complicated UTI Osteomyelitis |
| When are aminoglycosides discontinued? | Once the organism is identified and susceptibility is known |
| Aminoglycoside MoA | Irreversibly binds to 30s ribosome 1. interferes with initiation complex formation 2. Causes misreading of mRNA 3. Restricts polysome formation |
| What contributes to the bacteriocidal nature? | Concentration-dependent killing Long PAE |
| AG uptake into G- | Diffuse across the outer membrane via porin channels Cross the inner membrance via O2 dependent active transport Inner membrane potential drives transport |
| What can block the transport of AG? | Anaerobic environment Low extracellular pH |
| Aminoglycoside resistance | Inactivation of drug by microbial enzymes (aminoglycoside modifying enzymes) |
| Aminoglycoside kinetics | Very polar compounds Don't cross the membrane well |
| Aminoglycoside pharmacokinetics | Concentrated in the proximal tubular cells Largely eliminated by GF |
| What must you do in renal compromised pts? | Adjust the dose/dosing frequency Blood levels are very important Must adjust dose relative to creatintine clearance |
| Advantages of consolidated therapy | Comparable efficacy Decreased nephrotoxicity Long PAE |
| Toxicity is dependent on | Concentration and time above threshold |
| Consolidation therapy is not recommended for what situations? | Pregnant pts Osteomyelitis Infective endocarditis Pts recieving concurrent ototoxins Pts undergoing solid organ transplantation |
| Aminoglycosides therapeutic index | Narrow |
| Primary toxicities of aminoglycosides | Nephrotoxicity Ototoxicity Neuromuscular blockade |
| Which of these are reversible/irreversible? | -Reversible- Nephrotoxicity Neuromuscular blockade -Irreversible- Ototoxicity |
| Makes nephrotoxicity and ototoxicity more likely | Therapy > 5 days In elderly pts In pts with renal dysfunction Tox incidence related to drug concentration |
| Nephrotoxicity | Reversible Involves an acute tubular necrosis |
| The most important result of nephrotoxicity | Decreased AG excretion -Increased AG plasma levels -Predisposes to ototoxicity |
| AGs accumulate and are retained in.. | Proximal tubular cells |
| Results of AG accumulation | Impairs renal concentrating ability Mild proteinuria Appearance of hyalin and granular casts GFR decreases |
| 2 drugs that are nephrotoxic | Amphotericin B Cyclosporine |
| Why is ototoxicity is difficult to determine? | May occur after drug is stopped |
| Where do AGs accumulate in the ear? | Perilymph and endolymph in the inner ear |
| Ototoxicity manifestations | Tinnitus High freq. hearing loss Vestibular damage |
| What is special about ototoxicity? | Irreversible Damage accumulates with repeat courses |
| This class of drugs may enhance ototoxicity. | Loop diuretics |
| Absolute contraindication for AG use | Pts with Myasthenia gravis |
| What may be seen with neuromuscular blockade? | Acute respiratory paralysis May enhance effects skeletal muscle relaxants |
| Mechanism of NM blockade | May inhibit prejunctional relase of acetylcholine Reduce postsynaptic sensitivity |
| Streptomycin use | Limited by resistance and advent of newer AGs |
| Streptomycin used alone to treat... | Tularemia and plague (DoC) |
| Streptomycin used in combination to treat | Tuberculosis Brucellosis (DoC with doxy) Endocarditis (w/ cillin) |
| Gentamycin | One of the most frequently used Generally chosen first |
| Gentamycin used in combination for... | (used with cillin) Pseudomonas (DoC) Enterococcal (DoC) |
| Amakacin primarily used for | Pseudomonas Other serious infxns caused by *organisms resistant to other AGs* |
| Amikacin has | The broadest spectrum Resistance to inactivating enzymes |
| What makes amikacin more effective than other AGs? | There is only one site susceptible to enzyme anabolism |
| Neomycin is... | Not used systemically Used topically The most toxic AG |
| Only time Neomycin is used orally/systemically | To sterilize the gut When organisms are resistant to other agents |
| Tetracycline (class) spectrum | G+, G-, aerobic, anaerobic Intracellular bacteria -Chlamydia, Rickettsia, Mycoplasm p.) |
| Doxycycline and minocycline | 2 of the most widely prescribed drugs |
| Doxycycline | One of the most active and clinically used Preferred in pts with poor renal fxn |
| Minocycline | Meningococcal carrier state Crosses the blood-brain-barrier |
| Tetracyclines are Docs or alternatives for | Mycoplasma p Chlamydia Rickettsiae Lyme Dz Plague, tularemia, brucellosis, malaria prophylaxis |
| Tetracycline (group) MoA | Reversibly binds to 30s Prevents tRNA binding to acceptor site Prevents addition of amino acids to growing peptide |
| How does it get into the cell? | Passive diffusion (porin Om in G-) Active transport (plasma membrane) |
| Why are tetracyclins and penicillina antagonistic? | Tetra's stop bacterial growth Penicillions need bacterial growth |
| Primary mechanism of resistance to tetras | Efflux pumps *Ribosome protection* -Proteins interfere with binding and dislodge drug form ribosome |
| This provides a cross-resistance among tetracyclines except for | Tigrecyclin |
| Tetracycline pharmacokinetics | GI absorption is variable For stable chelates with cations |
| DD interactions | Milk Antacids Pepto-Bismol |
| Tetracycline that gets into the CSF | Minocycline |
| Chelates with Ca effecting | Bones and teeth |
| Don't give to which patient population? | Pregnant women |
| Tetracycline elimination | Eliminated by the kidneys |
| Which 3 tetras are less dependent on the kidneys for excretion? | Doxy, mino, and Tige Excreted by the bile |
| Tigecycline spectrum of action | Very broad spectrum antibiotic Effective in resistant organisms (MRSA, Staph epi, PRSP, VRE) |
| What makes tigecycline so useful? | Not susceptible to efflux pumps and ribosome protection |
| Tigecyclin route of administration and excretion | IV Poor oral absorption Biliary excretion |
| Tigecycline uses | Complicated skin and skin structure infxn Intraabdominal infxn Community-acquired pneumonia |
| Tetracycline adverse effects | GI Boney structures and teeth Liver tox Local Tissus Tox Photosensitivity Vestibular reactions |
| Tetracycline AE: GI | Oral dosing can cause GI distress NVD |
| Tetracycline AE: Bone | Bind Ca, esp. in newly formed bone of young kids Kids may develop permanent brown discoloration |
| What increases the risk of permanent brown discoloration? | Use in the last half of pregnancy and up to 8 y/o Crosses the placenta and accumulates in fetus |
| Tetracycline AE: Liver Tox | Rare but fatal Occurs more commonly with tetra and mino |
| Tetracycline AE: Local tissue tox | Directly irritating to tissues IV: thromboplebitis IM: painful |
| Tetracycline AE: Photosensitivity | Fair skin pts ate major risk |
| Tetracycline AE: Vestibular Rxn | May be produced by Mino Ataxia Dizziness NV |
| Tetracycline AE: Superinfections | Pseudomembranous colitis |
| Precautions with Tetracyclines | Don't give to: Pregnant pts kids <8 Discard unused drugs as it may cause Fanconi syndrome |
| Drug classes that act on the 50s | Chloramphenicol Macrolides Lincosamides Streptogramins Oxazolidinones |
| Chloramphenicol | Rarely used Serious toxicity limits use Reserved for life-threatening infxn due to resistance or allergies to safer drugs |
| Chloramphenicol occasionally used for | Rickettsial infxn Menengitis Anaerobic infxn |
| Chloramphenicol spectrum and MoA | Broad spectrum -Aerobic, anaerobic, G+, G- Reversibly binds to inhibit peptidyl transferase (Peptide bond formation) |
| Chloramphenicol Toxicity | Hematological Toxicity Bone marrow suppression -anemia, leukocytopenia, thrombocytopenia Dose dependent and reversible |
| Chloramphenicol: Idiosyncratic response | Serious and fatal Aplastic anemia-> fatal pancytopenia Rare; does NOT containdicate |
| Chloramphenicol: Idiosyncratic drug reaction | Abnormal Rare and unpredictable Occurs sporadically Not related to dose |
| Chloramphenicol: Adverse Effects | Gray syndrome/gray baby syndrome -Gray color, shock, hypothermia, vomiting, flaccidity Can be fatal in 2 days |
| Gray baby syndrome: Mechanism | Lack of glucuronyl transferare activity |
| Macrolides | Good substitute for penicillins G+ activity |
| Clarithromycin and Azrithromycin: Spectrum | G+ and some G- Camylobacter jejuni H. pylori Shingella spp E. Coli Meisseria gonorrhoeae |
| Macrolides are DoC for | Kids and pregnant women Pts allergic to penicillin Preferred for community-acquired RTIs |
| Restrictions for macrolide use in CAP | Uncomplicated pneumonia not requiring hospitalization No sig. comorbidities No ABx use in past 3 mo. No sig. macrolide-resistant strains locally |
| Macrolides also DoC for... | Mycoplasma p Chlamydia Bordetella Campylobacter Mycobacterium avian complex (MAC) |
| Macrolides: Mechanism of Action | Bacteriostatic Inhibits peptide chain elongation (translocation or peptidyl tRNA from A to P site is inhibited |
| Macrolides: Resistance | Efflux pumps Ribosome modification -Alters macrolide binding site on the bacterial ribosome |
| Macrolides: Pharmacokinetics | New macrolides are more acid-stable Clarithro: less freq dosing Azithro has 1/2 life ~70hrs |
| Macrolides: Drug interactions | **Inhibit CYP3A4** P450 inhibition |
| Macrolides: Toxicity (Primarily seen with Erythromycin) | GI -Anorexia, NVD -Epigastric distress Cholestatic hepatitis -Fever, jaundice, impaired liver fxn |
| Lincosamides Clindamycin: Spectrum and Clinical use | Anaerobic, strept, staph infxns DoC for C. perfringens Aerobic G- bacilli are intrinsically resistant |
| Lincosamides Clindamycin: Mechanism of Action | Binds close to erythromycin and chloramphenicol binding sites Inhibits peptide bond formation |
| Lincosamides Clindamycin: Resistance | Alterations of ribosomal binding site -Cross resistance with erythro Metabolism of drug G- intrinsic resistance |
| Lincosamides Clindamycin: Pharmacokinetics | Does not cross BBB Penetrates into bone (high levels) Actively transported into PMN leukocytes and macrophages (high levels) |
| Lincosamides Clindamycin: Adverse effects | Severe diarrhea -May cause antibiotic associated diarrhea |
| Lincosamides Clindamycin and pseudomembranous colitis | Clindamycin classically assoc. with this disorder |
| Streptogramins Quinupristin + Dalfopristin: Spectrum | G+ bacteria -Staph resistant to: Methacillin, quinolones, vanc -Strept. pneumonia resistant to Pens Vanc-resistant E. farcium |
| Streptogramins Quinupristin + Dalfopristin: Principle Clinical Use | Drug resistant G+ cocci infxn -Skin and soft tissue Serious or life-threatening VRE Complicated skin infxn -MSSA and S. pyrogenes |
| Streptogramins Quinupristin + Dalfopristin: Mechanism of Action | Q: binds same site as macrolides D: directly interferes with polypeptide chain formation Binds near Q, enhances binding of Q Bactericidal |
| Streptogramins Quinupristin + Dalfopristin: Resistance | D: enzymatic inactivation, efflux pumps Q: binding site mods by methylase, enzymatic inactivation |
| Streptogramins Quinupristin + Dalfopristin: Drug Interactions | **POTENT CYP3A4 inhibitor** |
| Streptogramins Quinupristin + Dalfopristin: Adverse Effects | Pain and phlebitis at infusion site Severe arthalgias and myalgias |
| Oxazolidinones Linezolid: Spectrum | Similar to quinupristin+dalfopristin (G+) plus e. faecalis Should be reserved for MDR G+ |
| Oxazolidinones Linezolid: Clinical Use | Hospital and community AP -Strep pneumoniae Tx of skin and soft tissue -Complicated/uncomplicated -MRSA & MSSA VR enterococcus |
| Oxazolidinones Linezolid: Mechanism of Action | Block formation of initiation complex Mostly bacteriostatic -Cidal to strep. |
| Oxazolidinones Linezolid: Resistance and Pharmacokinetics | R: mutation or rRNA binding site P: MAO inhibitor Weak, reversible Tyramine rich foods can cause sudden and severe high BP |
| Oxazolidinones Linezolid: Adverse Effects | Myelosuppression -Thrombocytopenia (most common effect) Anemia, Leukopenia |
Created by:
bcriss
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