Antimicrobials 2 Flashcards
What are Carbapenems?
Imipenem, Meropenem
Antimicrobials that are synthetic B-lactam antibiotics therefore contain B-lactam ring and bind to the PBP.
These are broad spectrum antibiotics that are resistant to hydrolysis by most B-lactamases. They are mainly active against penicillinase-producing Gram positive and negative organisms, aerobes and anaerobes as well as P. aeruginosa. They are not active agaisnt carbapenemase producing organisms (certain enterobacteriaceae and klebsiella species). They are not active against MRSA.
Administered parenterally only and restricted to empiric therapy of serious infections.
**Drug of choice for enterobacter infections and extended-spectrum B-lactamase producing gram negative
What are the AE of imipenem and Meropenem?
These are carbapenems
Imipenem - nephrotoxic (therefore combine with cilastatin), GI distress, rash, CNS toxicity (seizures at high doses), partial cross-reactivity to PCN so possible allergic reactions
Meropenem - GI distress, rash, partial cross-reactivity to PCN so possible allergic reactions
What is the drug of choice for enterobacter infections and extended-spectrum B-lactamase producing gram negatives?
Carbapenems - imipenem and Meropenem
Aztreonam?
Monobactam category - binds PBP as it has B-lactam structure
They are effective against aerobic gram-negative rods ONLY (including pseudomonas) so there is no activity against gram-positive bacteria or anaerobes. They are resistant to the action of B-lactamases.
Administered IV, IM (parenteral) or via inhalation in CF pts. It can penetrate the CSF when inflamed and is excreted primarily by the urine.
Used to treat… UTIs, lower RTIs, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible gram negative bacteria – these drugs are not the drug of choice for any of these uses, but rather just a possible use if the other drugs are ineffective
AE - relatively non-toxic but there is little cross-HSN with other B-lactam antibiotics
Vancomycin?
Glycopeptide antimicrobial that is bactericidal. It binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptides inhibiting bacterial cell wall synthesis and peptidoglycan polymerization. Resistance needs to be watched as it is due to modifications of D-Ala-D-Ala binding site where D-Ala is replaced by D-lactate.
It is active against gram positive bacteria only and is resistant to pretty much all gram negative organisms. Vancomycin is effective against multi-drug resistant organisms such as MRSA, enterococci and PRSP.
Tx - Serious infections caused by resistant Gram positive organisms. Treatment of severely penicillin-allergic patients. C.difficile.
AE - Nephrotoxicity (drug accumulation), Ototoxicity (drug accumulation), Red man syndrome (infusion related flushing over face and upper torss)
There is poor oral absorption therefore requires slow IV infusion (60-90 minutes) and penetrates the CSF when inflamed. 90-100% is excreted by the kidneys therefore can cause nephrotoxicty if it accumulates int he kidney.
What is the drug of choice for empirical tx of infective endocarditis?
Vancomycin + aminoglycoside
Daptomycin?
Bacterial glycopeptide antimicrobial that acts as a bactericidal. It binds to cell membrane via calcium-dependent insertion of lipid tail resulting in depolarization of cell membrane with K+ efflux leading to cell death. This is the novel mechanism of action as it is useful against mutli-drug resistant bacteria.
Effective against GRAM POSITIVE ONLY (MRSA, enterococci, VRE, VRSA). Inactive against gram-negative bacteria and NOT effective in tx against pneumonia b/c it gets inactivated when it mixes with surfactant.
Recommended for tx of severe infections caused by MRSA or VRA or complicated skin/structure infections caused by susceptible S. aureus.
Administration via IV only and can accumulate in the kidney in renal insufficiency.
AE - constipation, nausea, headache, insomnia, ELEVATED CREATININE PHOSPHOKINASE (similar to statin AE), myopathy and rhabdomyolysis
Bacitracin?
Anti-microbial that interferes with LATE STAGE CELL WALL SYNTHESIS. It is effective against gram-positive organisms and is unique in that it has no cross resistance even though it binds to PBP. It is mainly used as topical as it has marked nephrotoxicity.
Fosfomycin?
Anti-microbial that inhibits cytoplasmic enzyme enolpyrvate transferase in EARLY STAGE of cell wall synthesis. It is effective against gram-positive and negative organisms [broad spectrum abx]
Used in tx of uncomplicated lower UTIs.
Administered orally.
MOA of tetracycline?
Doxycycline, Minocycline, Tetracycline
Broad spectrum - Activity against aerobic and anaerobic gram-positive and gram-negative organisms [resistance is massive as they have been overused and is primarily plasmid mediated]
Bacteriostatic - therefore do not give with another Abx that requires actively replicating cells (ex. PCN)
Tetracyclines enter via passive diffusion and energy-dependent transport unique to bacterial inner cytoplasmic membrane. The bacteria that are susceptible allows or drugs to concentrate intracellularly. Once they concentrate in the cell, they bind reversibly to 30S subunit to ribosomes, preventing attachment of aminoacyl tRNA.
- Most common use - severe acne and roseacea
- Empiric therapy - community-acquired pneumonia
- DRUG OF CHOICE [chlamydia, mycoplasma pneumonia, lyme disease, cholera, anthrax prophylaxis, rickettsia]
- Also used to tx - respiratory tract infections, sinuses, middle ear, urinary tract, intestinal infections, and SYPHILIS in pts allergic to PCN
Used in combination for H. pylori eradication, malaria prophylaxis and tx, tx of plaque, tularemia, brucellosis
**TERATOGENIC where all tetracyclines can cross placenta and are excreted into breast milk [FDA category D]
AE - GI Distress, Discoloration and hypoplasia of teeth, Inhibition of bone growth in children (avoid in children younger than 8 yo), Photosensitivity, Superinfections
pharmacokinetics - variable oral absorption that is decreased by divalent and trivalent cations (binding causes molecules to be too large to be absorbed) - drugs concentrate in the liver, kidney, spleen and skin
- Doxycycline is lipid soluble therefore parenteral admin is preferred and a good choice for STDs and prostatitis
- Minocycline is lipid soluble and reaches high concentration in all secretions therefore is useful for eradication of meningococcal carrier state
- excreted in the urine other than doxycycline which is excreted in the bile
MOA of macrolides?
Erythromycin, Clarithromycin, Azithromycin, Telithromycin
- used to tx gram-positive infections
- bacteriostatic (bactericidal at high concentrations)
Macrolides reversibly bind to the 23S rRNA of the 50S subunit inhibiting translocation. The binding site is identical or close to that for clindamycin and chloramphenicol.
Active against most gram-positive bacteria with a wider spectrum than PCNs. Azithromycin, Clarithromycin and Telithromycin have broader spectrum than erythromycin.
- complete cross-resistance b/t erythromycin, azithromycin and clarithromycin
- partial cross-resistance with clindamycin and streptogramins
Used in empiric therapy of community-acquired pneumonia (outpatient and in combination with B-lactam for inpatient), DOC for mycoplasma pneumonia and used to tx upper resp tract infections and soft tissue infections
**common substitute for pt with penicillin allergy
MOA of aminoglycosides?
Amikacin, Gentamicin, Tobramycin, Streptomycin, Neomycin
Bactericidal
Associated with serious toxicity
replaced by safe Abx
Passively diffuse across membrane of GRAM NEGATIVE organisms or it can be actively transmitted across cytoplasmic membrane via O2 dependent process. Once inside the cell it binds to 30S ribosomal subunit prior to ribosome formation leads to a misreading of the mRNA and inhibition of translocation of peptide strand. These Abx are mostly active against gram-negative bacteria as anaerobes lack O2-dependent transport into the cell.
Oral Neomycin is used as treatment for hepatic encephalopathy.
AE- GI Distress, Discoloration of teeth, Inhibition of bone growth in children, Photosensitivity, Superinfections
Aminoglycosides - empiric therapy of infective endocarditis in combination with PCN or vancomycin, streptomycin is drug of choice for Plague
Explain the mechanism of acquired drug resistance.
Tetracyclines…
- impaired influx or increased efflux by active protein pump
- production of proteins that interfere with binding to ribosomes
- enzymatic inactivation
Aminoglycosides…
- plasmid-associated synthesis of enzymes that modify and inactive drug
- decreased accumulation of drug
- receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation
Macrolides (plasmid encoded)…
- reduced membrane permeability or active efflus
- production of esterase that hydrolyzes drug (by enterobacteriaceae)
- modification of ribosomal binding site (by chromosomal mutation or by methylation)
Explain the rational basis for combination therapy with an aminoglycoside and a PCN, cephalosporin or vancomycin.
Aminoglycosides are most commonly used in combination of other Abx. Once an organism is identified aminoglycosides are normally discontinued in favor of less toxic drug.
gentamicin - used in combination with vancomycin for empiric treatment of endocarditis / Serratia (in combination with antipseudomonal penicillin)
Describe the pharmacokinetic property of each class of protein synthesis inhibitor?
Tetracyclines - variable oral absorption that is decreased by divalent and trivalent cations (binding causes molecules to be too large to be absorbed) - drugs concentrate in the liver, kidney, spleen and skin
- Doxycycline is lipid soluble therefore parenteral admin is preferred and a good choice for STDs and prostatitis
- Minocycline is lipid soluble and reaches high concentration in all secretions therefore is useful for eradication of meningococcal carrier state
- excreted in the urine other than doxycycline which is excreted in the bile
glycylcyclines - IV only with good tissue and intracellular penetration, primarily bile and fecal elimination
Aminoglycosides - Parenteral admin only except neomycin which is topical, only needs to be administered once a day as it is well distributed in the body (except CSF and bronchial secretion), 99% is excreted in urine
Macrolides - Clarithromycin, azithromycin, telithromycin have improved oral absorption, a longer half-life and increased bioavailability compared to erythromycin. Azithromycin and telithromycin have greater tissue penetration compared to other macrolides. Erythromycin, clarithromycin and telithromycin cause CYP P450 inhibition (NOT azithromycin)
