Bacterial DNA is made via folic acid production with p-aminobenzoic acid (PABA) as an intermediate.
Bacterial genome is unwound by DNA gyrase and helicase allowing it to be read.
DNA is transcribed forming mRNA.
mRNA combines with the bacterial 70S ribosome (composed of 50S and 30S components) and translation occurs, forming proteins including cell wall components.
Penicillin-binding proteins (PBPs) catalyze construction of cell wall peptidoglycan including transpeptidase, which binds d-Ala-d-Ala chain of peptidoglycan for cross-linking.
Gram-negative (GN) bacteria have an outer cell wall, whereas gram positive (GP) do not have.
Porins (outer membrane proteins [omps] of different subtypes) allow entry of particular molecules of various sizes, charges, and shapes through the cell wall.
Efflux pumps (with different subtypes) are ATPase pumps that expel molecules from within the cell.
Enzymatic inhibition—modification of the antibacterial material
Beta-lactamase—hydrolysis of beta-lactam—affects penicillins and cephalosporins.
Number one resistance pattern
Many with particular beta-lactamase are coresistance to tetracyclines, sulfonamides, aminoglycosides, even fluoroquinolones (GN only)
Aminoglycoside modifying enzymes reduce affinity for 30S ribosome.
Penicillin-binding proteins (PBPs) modification—changing binding site of beta-lactam, decreasing its affinity for PBP
Low affinity for binding beta-lactam antibiotic requiring clinically unattainable drug concentrations to overcome inhibition.
PBP2a—confers penicillin and cephalosporin resistance via plasmid gene mecA in methicillin-resistant Staphylococcus aureus (MRSA).
Use of d-Ala-d-Lactate instead of d-Ala-d-Ala confers resistance to cephalosporins and vancomycin.
Porin (omp) modification
Decreased porin production—Pseudomonas aeruginosa—decreased susceptibility to beta-lactams
Loss of porin type—may confer particular or multidrug resistance
Efflux pump in GN organisms
Increased production—Escherichia coli—may produce major facilitator tetracycline transporter (tetB) for tetracycline only versus small multidrug resistance (SMR) emrE-gene transport protein which provides resistance against broad range of antibiotics.
Modification of antibiotic target
Ribosome—antibiotic binding site may be altered.
Point gene mutation
Methylation
Cell wall—modification of cell phospholipid bilayer leads to repulsion of daptomycin-calcium molecule.
Mutated DNA gyrase and topoisomerase IV genes confers resistance to fluoroquinolones.
RNA polymerase—rifampicin cannot bind.
Biofilm production—production of extracellular polymeric substance which may account for nine times greater mass than the bacteria itself. Reduced penetration of antibiotic.
Bacteria enter slow growth state.
| Classification | Name | Spectrum | Mechanism of Action | Side Effects |
|---|---|---|---|---|
| Quinolones (bactericidal) | Ciprofloxacin | GN bacilli, Pseudomonas, atypicals, no anaerobic or GP coverage | Inhibit DNA gyrase and bacterial topoisomerase IV that promotes DNA strand breakage | Stevens-Johnson syndrome, QTc prolongation, arthropathy, tendonitis, tendon rupture |
| Levofloxacin | MSSA, Streptococcus sp., GN bacilli, atypicals | |||
| Moxifloxacin | MSSA, Streptococcus sp., anaerobes, atypicals | |||
| Nitrofuran | Nitrofurantoin (bacteriostatic, can be bactericidal at high concentrations) | Broad spectrum—GP and GN: E. coli and S. saprophyticus | Damages bacterial DNA | Pulmonary fibrosis, hemolytic anemia, neuropathies |
| Nitroimidazole (bactericidal) | Metronidazole | Anaerobes, GN—Bacteroides fragilis, C. difficile, protozoa; penetrates blood-brain barrier | Binds to cellular proteins and DNA | Headache, nausea, vaginitis, metallic taste, disulfiram-like reaction with alcohol, peripheral neuropathy |
| Folic acid inhibitors (bactericidal) | Trimethoprim | Broad spectrum—GP and GN: MSSA, CA-MRSA | Inhibits reduction of dihydrofolic acid to tetrahydrofolic acid | Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), urolithiasis, cytopenias, hepatitis, hyperkalemia, increases warfarin levels |
| Sulfonamides (bacteriostatic) | Sulfamethoxazole | Broad spectrum—GP and GN: MRSA | Inhibits enzymatic conversion of pteridine and p-aminobenzoic acid (PABA) to dihydropteroic acid | Nausea, vomiting, diarrhea, hypersensitivity, hematologic effects (anemia, aganulocytosis, thrombocytopenia) |
| Classification | Drug | Spectrum | Mechanism of Action | Side Effects |
|---|---|---|---|---|
| Pseudomonic acid | Mupirocin (bacteriostatic; bactericidal at high concentrations) | Mostly GP | Inhibits RNA and protein synthesis | Contact dermatitis |
| Antimycobacterial (bactericidal) | Rifampin | Broad spectrum—GP + GN: Pseudomonas, Mycobacterium tuberculosis | Blocks RNA transcription | Liver enzymes, rash, discoloration of teeth, urine, saliva, sweat, tears |
| Classification | Drug | Spectrum | Mechanism of Action | Side Effects |
|---|---|---|---|---|
| Macrolides (bacteriostatic) | Broad spectrum: Streptococcus sp., Corynebacterium, Chlamydia sp., Legionella, Moraxella, Helicobacter pylori | Irreversible binding to 50S ribosome to inhibit protein synthesis; prevent continuation of protein synthesis | QTc prolongation, reduces birth-control effectiveness, drug-drug interactions | |
| Erythromycin | Avoid in liver disease, increases GI motility | |||
| Clarithromycin | Haemophilus influenzae | Adjust for CKD | ||
| Azithromycin | Mycoplasma, Mycobacterium avium complex, H. influenzae | Avoid in hepatic disease | ||
| Lincosamide | Clindamycin (bacteriostatic; bactericidal at high concentrations against staphylococci, streptococci, anaerobes such as B. fragilis) | Streptococcus sp., MSSA, CA-MRSA, anaerobes | Irreversible binding to 50S ribosomal subunit | C. difficile infections, adjust with liver dysfunction |
| Oxazolidinone (bactericidal) | Linezolid | Resistant GP organisms | Binds to 50S ribosomal subunit | Cytopenias, serotonin syndrome, altered taste, tongue discoloration, optic neuritis |
| Phenicol (bacteriostatic) | Chloramphenicol | Broad-spectrum—GP + GN: Streptococcus pneumoniae, N. meningitidis, H. influenzae, Enterococcus faecium | Binds 50S subunit | Irreversible aplastic anemia, myelosuppression, neuritis, glossitis, gray baby syndrome |
| Classification | Drug | Spectrum | Mechanism of Action | Side Effects |
|---|---|---|---|---|
| Aminoglycosides (bactericidal) | Listed most to least vestibulotoxic | Aerobic GN bacilli: Pseudomonas, Klebsiella, Serratia, Proteus, Acinetobacter, and Enterobacter | Binds to 30S ribosomal subunit | Vestibulocochlear toxicity (hair cell death in cristae ampullaris, utricle, and saccule; see below) high > low frequency, dose dependent. Mitochondrial susceptibility, reversible nephrotoxicity |
| Streptomycin | ||||
| Gentamicin | Synergy with beta-lactam to treat Enterococcus sp. infections; not as effective against Pseudomonas | |||
| Tobramycin | More active against Pseudomonas | |||
| Amikacin | Reserve for resistant Pseudomonas and Acinetobacter infections | Most cochleotoxic | ||
| Vestibulotoxicity: streptomycin > gentamicin > tobramycin > amikacin—most cochleotoxic | ||||
| Tetracyclines (bacteriostatic) | Broad: GP (MSSA, MRSA), GN, protozoa, spirochetes, mycobacteria, and atypical species | Binds reversibly to 30S ribosomal subunit | Hepatotoxicity, photosensitivity, tinnitus, pseudotumor cerebri, teeth discoloration. Avoid in children, pregnancy. Expired medication can cause Fanconi syndrome. | |
| Doxycycline | ||||
| Tetracycline | Adjust for CKD | |||
| Minocycline | ||||
| Demeclocycline | ||||
| Glycycline | Tigecycline (derivative of minocycline) | Very broad spectrum—reserve for ID or MDR organisms | Binds reversibly to 30S ribosomal subunit to inhibit protein synthesis | Nausea, vomiting, diarrhea, photosensitivity, teeth discoloration, fetal damage |
| Classification | Drug | Spectrum | Mechanism of Action | Side Effects |
|---|---|---|---|---|
| Penicillins (bactericidal) | PCN G, PCN V | GP cocci and rods, GN cocci, most anaerobes; Not GN bacilli | Binds PBPs inhibiting cell-wall synthesis | Interstitial nephritis, cytopenias. Adjust for CKD |
| Antistaphylococcal | Nafcillin, oxacillin, dicloxacillin | MSSA | Nafcillin and oxacillin metabolized by liver | |
| Broad-spectrum, second generation | Ampicillin, amoxicillin | Above plus GN bacilli: E. coli, Proteus mirabilis, Salmonella, Shigella, H. influenzae | 30% incidence of rash in those with infectious mononucleosis (EBV) | |
| Anti-pseudomonal, third generation | Carbenicillin, ticarcillin | GN organisms, indole-positive Proteus, Enterobacter, Pseudomonas | ||
| Fourth generation | Piperacillin | Same as above plus Klebsiella, enterococci, B. fragilis, Pseudomonas | ||
| PCN with beta-lactamase inhibitor | Amoxacillin/clavulanate Ticarcillin/clavulanate | Oxacillin-sensitive S. aureus, H. influenzae, beta-lactamase producing Enterobacteriaceae | Beta-lactamase inhibitors cause increased diarrhea | |
| Ampicillin/sulbactam | Same plus anaerobes (B. fragilis), Acinetobacter baumannii | |||
| Piperacillin/tazobactam | Similar to above | |||
| Cephalosporins (bactericidal) | Binds PBPs inhibiting cell wall synthesis | Cytopenias, anaphylaxis, pseudomembranous colitis, adjust for CKD | ||
| First generation | Cefazolin, cephalexin, cefadroxil | Most GP cocci, E. coli, P. mirabilis, K. pneumoniae | ||
| Second generation | Cefaclor, cefuroxime, cefprozil | Less active against staphylococci; greater activity against GN bacilli – H. influenzae, Moraxella catarrhalis | ||
| Cephamycin subgroup | Cefotetan, cefoxitin | E. coli, P. mirabilis, Klebsiella, Bacteroides | ||
| Third generation | Cefdinir, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefditoren | Therapy of choice for GN meningitis, less active against most GP; E. coli, P. mirabilis, Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter, Neisseria, H. influenzae | ||
| Cefotaxime, ceftriaxone | Usually active against pneumococci with intermediate susceptibility to penicillin; Lyme disease, meningitis due to H. influenzae | |||
| Ceftazidime | Above plus P. aeruginosa; poor GP coverage | |||
| Fourth generation | Cefepime | Pneumococci, MSSA, Neisseria, H. influenzae, Enterobacter, indole-positive Proteus, Citrobacter, Serratia, P. aeruginosa | ||
| Fifth generation | Ceftaroline | Similar to ceftriaxone with improved GP activity: MRSA, VISA | ||
| Beta-lactamase inhibitor combination, new generation | Ceftolozane/tazobactam | Broad spectrum against GN bacilli: P. aeruginosa, most ESBL; limited GP | ||
| Ceftrazidime/avibactam | Broad spectrum: most Enterobacteriaceae, P. aeruginosa, Actinobacter | |||
| Carbapenems (bactericidal) | Broad spectrum: GN, anaerobes (B. fragilis), P. aeruginosa, GP (including MRSA) | Binds PBPs inhibiting cell wall synthesis | C. difficile, seizures in high doses; adjust for CKD | |
| Imipenem/cilastin, meropenem, doripenem | ||||
| Ertapenem | Narrower spectrum: no Pseudomonas, Acinetobacter coverage, MRSA | |||
| Monobactam (bactericidal) | Aztreonam | GN: Pseudomonas, Enterobacter; no anaerobe or GP coverage | Inhibits mucopeptide synthesis of cell wall | Rare: toxic epidermal necrolysis, eosinophilia; adjust for CKD |
| Glycopeptides (bactericidal) | Vancomycin | MSSA, MRSA, MRSE, Streptococcus sp., Corynebacterium, Enterococcus faecalis and faecium; oral: C. difficile | Inhibits late-stage cell wall synthesis | Vancomycin-induced renal failure, red man syndrome; adjust for CKD |
| Lipoglycoprotein (bactericidal) | Telavancin (derivative of vancomycin) | Useful in vancomycin intermediate resistant bacteria | Inhibits late-stage cell wall synthesis and causes cell membrane depolarization | |
| Cyclic peptides | Bacitracin (bacteriostatic, -cidal depending on organism/concentration) | GP | Inhibits peptidoglycan transport | Contact dermatitis |
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