Beta-Lactam Antibiotics: Pharmacology

Antibacterial Pharmacology: Beta-Lactams

• Beta-lactam antibiotics include Monobactams, Carbapenems, Cephalosporins, and Penicillins
• Beta-lactams have a general recognizable structure that includes a Thiazolidine and a Beta-lactam ring
• Beta-lactams inhibit cell wall synthesis by inhibiting cross-linking
• Time above MIC determines the efficacy of Beta-lactams.
• Beta-lactams are generally bactericidal, contrary to the statement that they're bacteriostatic
• They generally have poor CNS penetration, except for ceftriaxone and cefotaxime
• Beta-lactams generally require adjustment in renal insufficiency, except nafcillin, oxacillin, ceftriaxone, And cefoperazone
• Beta-lactams generally have a short half life and require frequent dosing, except ceftriaxone
• The most common mechanism of resistance to beta-lactams is inactivation of antibiotics enzymatically by beta-lactamases
• Drugs that contain beta-lactamase inhibitors include Augmentin (amoxicillin/clavulanic acid), ampicillin/sulbactam, and piperacillin/tazobactam

Cephalosporin Generations

• Ceftazidime: 3rd generation
• Not a correct pairing: Cefepime is not 2nd gen, nor is cefazolin 3rd, and ceftaroline is not 2nd Gen.
• Antimicrobial coverage trends through the generations are less gram-positive and more gram-negative
• Aztreonam has coverage similar to ceftazidime and is reserved for patients with a penicillin allergy
• Desensitization can be done for patients with allergies to antibiotics.

Quinolones

• Quinolones have topoisomerase inhibitors for gram-positive and DNA gyrase for gram-negative bacteria
• Quinolones are bactericidal for susceptible bugs and are not bacteriostatic
• Quinolones can cause arthropathy and tendinopathy, which is important for counseling
• It does require separation from multivitamins because it binds to divalent cations
• Quinolones do cause QT prolongation
• Ranking of quinolones by QT prolongation risk: moxi > Cipro > levo

Macrolides

• The spectrum of activity for macrolides includes Gram +, Gram -, and Atypicals
• The four macrolides are clarithromycin, telithromycin, erythromycin, and azithromycin
• Gram-positive activity ranking: T > C > E > A.
• Gram-negative activity ranking: A > C > E > T

Treatments

• If a patient develops a seizure caused by antibiotics, Benzodiazepines are the preferred treatment, and Keppra may provide some benefit to its ability to modulate the GABA channel
• Neonates are at an increased risk of penicillin induced seizures
• Patients treated for meningitis may be predisposed to seizures
• Carbapenems have a higher incidence than penicillins
• Risk factors include advanced age, high dose, and renal insufficiency

Susceptibility & MIC

• The Number of bacteria, Panel of antibiotics, and Incubation times must be kept constant when determining MIC in the lab
• 10^5 - 10^6 bacterial isolates are generally incubated.
• Macrodilutions provide a specific MIC but take longer as they can test more antibiotic concentration
• Microdilutions only provide an S/I/R rating but are quicker
• Susceptible bacteria will most likely be eradicated with normal doses of the antibiotics

Performing Resistance Testing

• Cidal testing is a reduction by at least 3 logs in conc at 24hrs
• Static testingis a 1.4 to 2.9 reduction in conc. at 24 hrs
• Cidal and static testing does necessarilly involve MOA
• Both E-tests and Kirby-Bauer are diffusion assays, but E-tests give exact MIC's while Kirby-Bauer's get S/I/R readings
• Antibiograms differ per institution
• A specific institution's ED is different than general admitted patients, concerning antibiograms

Antibiotic MOA Summary

• Cell Wall Biosynthesis includes Beta-lactams, Glycopeptides, and Bacitracin.
• Protein Synthesis includes Aminoglycosides, Oxazolidinones, Tetracyclines, Macrolides, Chloramphenicol, Lincosamides, and Streptogramins
• Folate Biosynthesis includes Sulfonamides
• DNA Gyrase includes Fluoroquinolones
• RNA Polymerase includes Rifampicin
• Membrane Integrity includes Cationic peptides and Lipopeptides.

Cell Wall Inhibitors

• Lipid 4, the building block of peptidoglycan polymers, is synthesized in the cell cytoplasm, diffuses across the inner membrane, the attaches to the growing polymer
• A way to avoid beta-lactamase activity is with the addition of a bulky side chain
• Polar groups facilitate passage through porins
• Carbapenems target an additional enzyme of the cell wall biosynthesis, Ld transferase which can bypass the need for Tpase
• Carbapenems have activity against some gram-positive strains, and also have activity against ESBLs
• Ertapenem does not cover pseudomonas
• Unused D-ala D-ala serve as a sponge for vancomycin in VISA (Vancomycin Intermediate S. aureus)
• D-ala D-lactate is coded for by the Van gene in VRSA (Vancomycin-resistant S. aureus)
• Have an abnormal cell wall and are fairly sick in VISA.
• VRSA is more "fit" strain

Specific MOA

• Fosfomycin inhibits MurA, an enzyme involved in lipid II synthesis
• Bacitracin inhibits dephosphorylation of bactoprenol which moves lipid II across the cytoplasmic membrane
• Vancomycin binds tightly to D-ala D-ala residues preventing peptidoglycan polymerization and transpeptidation
• Colistin disrupts the outer membrane by displacing Mg2+ and Ca2+ ions and inner membrane by acting as a detergent
• Dalbavancin binds proteins very tightly and can be given once a week

Protein Synthesis Inhibitors

• Antibiotics that act upon the large ribosomal subunit inhibit peptide bond formation or the growth of the nascent peptide chain.
• Antibiotics that bind to the small subunit interfere with tRNA binding or the accuracy of protein synthesis.
• Bacterial rRNA genes are redundant; several identical genes in genomes of bacteria code for rRNA so less resistance to random mutations
• Macrolides bind to the large ribosomal subunits in the nascent peptide tunnel
• Macrolides completely block the exit tunnel and inhibit synthesis of all proteins - only proteins with MAMs
• Macrolides interact primarily or exclusively with rRNA, specifically the contact of desosamine with A2058
• Methylation of A2058 is very important and is the main target of the resistance mechanisms
• Erm - a methyltransferase that methylates A2058, dimethylation of A2058 displaces a critical molecule of water required for macrolide binding
• MsrE - ribosome protection, removes macrolide from the ribosome
• TolC - multidrug efflux pumps
• Mef - macrolide-specific efflux pumps
• Linezolid doesn't cover primary gram-negative pathogens but can be used as an oxazolidinone
• Linezolid binds to the large ribosomal subunit but not to a small one.
• Reversible myelosuppression is a side effect of Linezolid
• A spontaneous mutation of one copy of 23S rRNA is enough to confer resistance to oxazolidinones
• Tedizolid lacks an acetamindomethly chain, making its smaller side chain compatible with the resistance found in A2503
• Streptogramins are most appropriately used for VRE (Vancomycin-resistant Enterococcus faecium)
• Dalfopristin of streptogramins binds to the catalytic center, and Quinupristin binds to the exit tunnel
• Steptogramin A is Dalfopristin and Streptogramin B is Quinupristin
• The mechanism of action for retapamulin is it binds to the peptidyl transferase center in the large ribosomal subunit
• Aminoglycosides flip out two guanines in the large subunit rRNA which incorrectly matches mRNA and tRNA
• Aminoglycosides effect can be self-promoted due to the uptake.
• Aminoglycosides are not selective and affect both bacterial and eukaryotic ribosomes
• Resistance includes N-acetylation O-phosphorylation, and O-adenylation
• Possible side effects of aminoglycoside therapy are nephrotoxicity and ototoxicity
• Aminoglycosides are not bacteriostatic but are bactericidal
• Tetracyclines bind to the small ribosomal subunit, which blocks binding of aminoacyl-tRNA to the ribosome
• Tigecycline is more potent than doxycycline

RNA/DNA/Folate Biosynthesis Drugs

• Rifampicin is an inhibitor of bacterial RNA polymerase
• An adverse effect of rifampicin is red urine, sweat, and tears
• Trimethoprim inhibits dihydrofolate reductase, and Sulfonamides inhibit dihydropteroate synthase by competing with PABA
• Bactrim does cover gram-positive pathogens and gram-negative pathogens
• Daptomycin and Novobiocin are not quinolones
• Gram - Bacteria is the target: DNA gyrase
• Gram + Bacteria is the target: Topoisomerase 4
• Quinolones bind to subunit A and not the catalytic subunit B, also subunit B is ATPase that provides energy for the reaction
• It is False about quinolones: Quinolones bind to the catalytic subunit B. binds to subunit A, subunit B is ATPase that provide energy for the reaction
• Modifications of lipopolysaccharides is not a mechanism for quinolone resistance

Antibiotic Class Structures

• Clarithromycin is a macrolide
• Linezolid is a Oxazolidinone
• Amoxicillin is a Beta lactam
• Dalfopristin is Streptogramin
• Retapamulin is Pleuromutilin
• Tigecycline is Tetracycline
• Aztreonam is Monobactam
• Lincomycin is Lincosamide
• Vancomycin is Glycopeptide
• Gentamicin is Aminoglycoside
• Levofloxacin is Fluoroquinolone
• Sulfamethoxazole is Sulfonamide
• Trimethoprim is Trimethoprim

Microbiomes

• Microbiomes are comprised of prokaryotes, eukaryotes, and viruses, but bacteria is the most common element
• The microbiome in the gut is significantly less varied than other sites
• Proteobacteria, actinobacteria, firmicutes, and bacteriodetes make up 93.5% of the microbiome
• The microbiome helps produce production of beneficial metabolites ( Short chain fatty acids, Secondary bile acids, Neurotransmitters, Choline derived metabolites), Vitamin synthesis, Resistance against invading pathogens, and Maturation of mucosal immune system and immune cells
• Fidaxomicin and Rifaximin don't cause alterations in microbiome composition, compared to the other antibiotics on the list
• Antibiotic exposure in the first year of life increases the risk of being classified in the AW
• modifiable risk factors for initial Clostridium difficile infection include PPIs and Broad spectrum antibiotics
• C. Diff is likely to recur in 1/4 of patients
• Risk factors for recurrent CDI include Antibiotics
• Donor-feces infusion following vancomycin 500 mg PO QID is the best treatment for recurrent C. diff
• A setting that would not require an IND for a FMT is a 20 year-old woman with recurrent C. diff

Probiotics and Prebiotics

• Probiotics are bacteria, and prebiotics are carbohydrates, food for your microbiome
• Recommended dose of a probiotic post antibiotic: 10-15 billion units per day
• Some adverse effects of probiotics are GI upset
• Probiotic metabolite pairs include: Lactobacillus and Lactic acid, Bifidobacterium and Acetic acid

• Lactobacillus and Lactic acid Bifidobacterium and Acetic acid

Explore the pharmacology of beta-lactam antibiotics, including penicillins, cephalosporins, carbapenems and monobactams. Learn about their mechanism of action, which involves inhibiting cell wall synthesis by blocking cross-linking. Discover factors influencing their efficacy, resistance mechanisms, and special considerations for renal insufficiency and CNS penetration.