Cell wall inhibitors
Vancomycin binds D-ala-D-ala, and blocks cell wall crosslinking by a steric effect. It treats serious gram + infections, notably MRSA. VRE is resistant because D-ala-D-ala becomes D-ala-D-lac.
Beta-lactam antibiotics mimic D-ala-D-ala. The 4-membered beta-lactam ring is critical. Another 5-membered ring in penicillins, carbapenems; 6-membered in cephalosporins; none in monobactams. They are noncompetitive inhibitors of "penicillin binding proteins" in the inner cell membrane. PBPs function in transpeptidation, maintenance of rod shape, and cell division; if you take them out, you get lysis, ovoid cells, or nondividing lengthening filaments.
Physical factors determine beta-lactam susceptibility. If the bacteria are growing slowly, they aren't synthesizing or modifying the cell wall much (example: endocarditis). Therefore treatment regime needs to be longer, so you can catch bacteria when are active. Normally, cell wall protects bacteria from lysing in a hypo-osmotic environment. In the kidney the environment is relatively more hyperosmotic, therefore bacteria are more resistant to beta-lactams.
Gram-negative bacteria are in general less susceptible to penicillins. For one, not all penicillins can get through porins in outer cell membrane. For two, many gram negatives produce beta lactamases that can accumulate in the periplasmic space.
Listeria, in particular, resistant to cephalosporins.
Mechanisms of antibiotic resistance to beta-lactams
Mutation in porin proteins (example: Pseudomonas)
Transduction conferring new PBP (example: MRSA and mec locus)
--> Use Vancomycin
Transformation conferring new PBP (classically, pneumococcus)
--> Resistance occurs stepwise; for partially resistant organisms, use ceftriaxone (they are actually more sensitive at this stage)
Conjugation conferring plasmid-encoded beta-lactamase (Pseudomonas, gram neg enterics)
--> Use ampicillin, amoxicillin, combined with clavulanic acid (remember, not an effective antibiotic by itself, must use in conjunction with penicillin)
--> Ampicillin/amoxicillin HELPS kill enterococci
- Haemophilus
- E. coli
- Listeria monocytogenes
- Proteus mirabilis
- Salmonella
- Enterococci
Quinolones (Fluoroquinolones)
Work by inhibiting bacterial DNA gyrase (topoisomerase II); induce double strand breaks -- that's why it's bactericidal. Ciprofloxacin is representative of the class; active against gram-negative rods of urinary and GI tracts, and is the fluoroquinolone used for Pseudomonas. Respiratory quinolones are more active against gram positive infections of upper and lower respiratory tract (can treat Mycoplasma, which lack a cell wall, whereas penicillins would fail). Quinolones achieve high intracellular concentrations (such as macrophages) and therefore are great for intracellular pathogens like Salmonella and Shigella.
Resistance strategies to quinolones:
Chromosomal (multiple, stepwise changes can confer high-level resistance)
Stepwise changes in DNA gyrase
Porin alterations (decreased uptake)
Efflux pumps
Plasmid-encoded enzymes (affecting gyrase or the drug); in general low-level resistance unless combined with above
Trimethoprim-Sulfamethoxaxole
Sulfamethoxazole and dapsone block first step in tetrahydrofolate synthesis: PABA + pteridine --> dihydropteroic acid, catalyzed by dihydropteroate synthetase.
Trimethoprim blocks dihydrofolate reductase, which gives THF. Folate metabolism is necessary to provide methyl donors for thymidine and therefore DNA synthesis.
Treats community acquired MRSA (good outpatient option since can be taken orally), recurrent UTIs (gram negative), Shigella, Salmonella, Pneumocystis jiroveci (in HIV population). Being phased out for UTIs by fluroquinolones due to increasing resistance.
Resistance: plasmid-acquired metabolic bypass (enzymes that perform same function, but not susceptible to TMP-SMX).
Protein synthesis inhibitors
Target rRNA of 30S or 50S at SEVERAL DIFFERENT sites, so single-step chromosomal mutations are unlikely to confer resistance.
Tetracycline
Bacteriostatic (can't use for endocarditis, meningitis, or in neutropenic patients); acts at 30S; prevents binding of aminoacyl-tRNA. Resistance conferred by plasmid: efflux pump or poorly-characterized "ribosomal protection." Tigecycline is a new tetracycline that circumvents these acquired resistance mechanisms; however, it does not extend the spectrum.
Aminoglycosides
Bactericidal (irreversibly binds ribosome); acts at 30S; prevents formation of initiation complex, causes misreading of mRNA. Resistance conferred by plasmid: enzymes that modify drug. Resistance can be conferred by single chromosomal mutation for streptomycin, the first aminoglycoside (hence, limited utility of this drug). Amikacin has the least number of modifiable side groups, so it's best at resisting bacterial resistance.
Aminoglycosides don't get into mammalian cells well. Used for extracellular infections like UTIs, not intracellular infections. Aminoglycosides require electron transport chain to get into cell. Hence, not effective against anaerobes ("Mean GNATS canNOT kill anaerobes").
Macrolides
Bacteriostatic; acts at 50S, specificially 23S rRNA; prevents translocation. Active against gram-positive cocci (strep infections in patients allergic to penicillin), Mycoplasma, Legionella, Chlamydia, Neisseria. Used for URIs, pneumonias, STDs.
Resistance can be due to efflux. Or to MLS phenotype: cross-resistance to macrolides, lincosamides, and streptogramins due to methylation of 23S rRNA. MLS phenotype also confers resistance to clindamycin. Significance of this is that if MRSA infections are resistance via efflux of macrolides only, you can still use clindamycin; if they are MLS phenotype, you cannot.
Linezolid
Inhibits protein synthesis by poorly understood mechanism. Used for multi-drug resistant gram-positive infections: VRE, MRSA. Can be given orally, so good for outpatients; similar to TMP-SMX in this regard. However, it's very expensive.
