Drugs That Weaken the Bacterial Cell Wall - Penicillin

‭Beta-Lactam Antibiotics‬ ‭‬ P ● ‭ enicillins‬ ‭●‬ ‭Cephalosporins‬ ‭‬ C ● ‭ arbapenems‬ ‭●‬ ‭Aztreonam‬ ‭MRSA Resistance‬ ‭Production of PBPs to which the penicillinase-resistant penicillins cannot bind‬ ‭●‬ ‭Penicillin‬ ‭●‬ ‭Methicillin‬ ‭●‬ ‭All but one cephalosporin‬ ‭Effective Drugs Against HA-MRSA‬ ‭‬ V ● ‭ ancomycin‬ ‭●‬ ‭Linezolid‬ ‭●‬ ‭Daptomycin‬ ‭‬ T ● ‭ elavancin‬ ‭●‬ ‭Dlynamycin‬ ‭●‬ ‭Ceftaroline‬ ‭Effective Drugs Against CA-MRSA‬ ‭Does not respond to beta-lactam antibiotics except ceftaroline‬ ‭●‬ ‭Thimethoprim/sulfamethoxazole‬ ‭●‬ ‭Clindamycin‬ ‭●‬ ‭Minocycline‬ ‭●‬ ‭Ceftaroline‬ ‭●‬ ‭Doxycycline‬ ‭Reserved for Severe Infections‬ ‭●‬ ‭Vancomycin‬ ‭●‬ ‭Daptomycin‬ ‭●‬ ‭Linezolid‬ ‭Penicillins‬ ‭Mechanism of Action‬ 1‭ .‬ I‭ nhibition of transpeptidases‬ ‭2.‬ ‭Disinhibition of autolysins‬ ‭Mechanisms of Bacterial Resistance‬ 1‭ .‬ I‭ nability of penicillins to reach target PBPs‬ ‭2.‬ ‭Inactivation of penicillins by bacterial enzymes‬ ‭3.‬ ‭Production of PBPs that have a low affinity for penicillins‬ ‭Clinically Useful Antimicrobial Spectrum‬ ‭Resistant Bacteria‬ ‭Streptococcus‬‭species,‬‭Neisseria‬‭species,‬ ‭many anaerobes, spirochetes, others‬ ‭ enicillin G:‬‭Penicillinase-producing‬ P ‭staphylococci (gram-positive), gram-negative‬ ‭bacilli (few exceptions)‬ ‭Penicillin G:‬‭Most gram-positive bacteria,‬ g‭ ram-negative cocci (‬‭Neisseria meningitidis‬ ‭and non-penicillinase-producing strains of‬‭N‭.‬‬ ‭gonorrhoeae‬‭), anaerobic bacteria, spirochetes‬ ‭(‭T ‬ reponema pallidum‬‭)‬ ‭Penicillinase-producing strains of‬ ‭staphylococci‬‭(ex.‬‭S. aureus‬‭,‬‭S. epidermidis‬‭,‬ ‭most staphylococci)‬ ‭Non-penicillinase-producing‬‭staphylococci‬ ‭(less active than penicillin G), MRSA‬ ‭ ame as penicillin G plus certain‬ S ‭gram-negative bacilli (‬‭Haemophilus influenza‬‭,‬ ‭Esherichia coli‬‭,‬‭Salmonella‬‭,‬‭Shigella‬‭),‬ ‭Proteus mirabiliis‬‭, enterococci,‬‭Neisseria‬ ‭gonorrhoeae‬ ‭Most infections caused by‬‭S‬‭.‬‭aureus‬ ‭ mpicillin:‬‭Enterococcus faecalis‬‭,‬‭Proteus‬ A ‭mirabilis‬‭,‬‭E‬‭.‬‭coli‬‭,‬‭Salmonella‬‭,‬‭Shigella‬‭,‬‭H‬‭.‬ ‭influenzae‬ ‭Same as broad spectrum penicillins plus‬ ‭ seudomonas aeruginosa‬‭,‬‭Enterobacter‬ P ‭species,‬‭Proteus‬‭(indole positive),‬‭Bacteroides‬ ‭fragilis‬‭, many Klebsiella‬ ‭Most strains of‬‭S‬‭.‬‭aureus‬ ‭Penicillin G (Benzylpenicillin)‬ ‭Pharmacokinetics: Absorption‬ ‭●‬ ‭Repository preparations are useful against highly sensitive organisms (ex.‬‭T‭.‬‬‭pallidum‬‭)‬ ‭Salt Type‬ ‭Administration‬ ‭Absorption‬ ‭Potassium‬ ‭IM‬ ‭Rapid (15 mins)‬ ‭Sodium‬ ‭IM‬ ‭Rapid (15 mins)‬ ‭Procaine‬ ‭IM (Never IV)‬ ‭Slowly (repository)‬ ‭Benzathine‬ ‭IM (Never IV)‬ ‭Slowly (repository)‬ ‭Pharmacokinetics: Distribution‬ ‭●‬ ‭In absence of inflammation, poor distribution to‬ ‭the meninges, fluids of joints, and eyes‬ ‭●‬ ‭In presence of inflammation, entry into CSF,‬ ‭joints, and eyes is enhanced‬ ‭Pharmacokinetics: Metabolism and Excretion‬ ‭●‬ ‭Minimal metabolism; eliminated mostly‬ ‭unchanged‬ ‭●‬ ‭Renal excretion (mostly active tubular secretion)‬ ‭●‬ ‭Half-life: 30 minutes for older children and adults‬ ‭○‬ ‭Renal impairment → dramatic increase,‬ ‭reduction in dosage‬ ‭Side Effects and Toxicities‬ ‭●‬ ‭Least toxic of all antibiotics, among safest of all medications‬ ‭●‬ ‭Pain at IM injection site‬ ‭●‬ ‭Prolonged sensory and motor dysfunction if injected into peripheral nerve‬ ‭●‬ ‭Neurotoxicity with high blood levels (seizures, confusions, hallucinations)‬ ‭●‬ ‭Gangrene, necrosis, and sloughing of tissue with intraarterial injection‬ ‭●‬ ‭Caution with sodium penicillin G with sodium restriction‬ ‭Penicillin V/VK‬ ‭‬ S ● ‭ table in gastric acid, unlike penicillin G‬ ‭●‬ ‭Replaced penicillin G for oral therapy‬ ‭Narrow Spectrum, Penicillinase-Resistant Penicillins‬ ‭‬ H ● ‭ ighly resistant to inactivation by beta-lactamases‬ ‭●‬ ‭Drug of choice for most staphylococcal infections, as most produce penicillinase‬ ‭Broad-Spectrum Penicillins (Aminopenicillins)‬ ‭ ‬ I‭ ncreased ability to penetrate the gram-negative cell envelope‬ ● ‭●‬ ‭Readily inactivated by beta-lactamases → ineffective against‬‭S‬‭.‬‭aureus‬ ‭Ampicillin‬ ‭●‬ ‭Side Effects‬ ‭○‬ ‭Rash and diarrhea‬ ‭○‬ ‭More frequently than any other penicillin‬ ‭●‬ ‭Oral or IV administration‬ ‭Amoxicillin‬ ‭●‬ ‭More acid stable than ampicillin → greater serum levels PO‬ ‭●‬ ‭Preferred for oral therapy‬ ‭○‬ ‭Requires dosage reduction for renal impairment‬ ‭●‬ ‭One of the msot frequently prescribed antibiotics‬ ‭Extended-Spectrum Penicillin (Antipseudomonal Penicillin)‬ ‭‬ S ● ‭ usceptible to beta-lactamases → ineffective against‬‭S‬‭. aureus‬ ‭●‬ ‭An antipseudomonal aminoglycoside (gentamicin, tobramycin, amikacin, netilmicin) can‬ ‭be added to increase bactericidality to‬‭Pseudomonas‬ ‭○‬ ‭Should not be mixed in the same IV solution‬ ‭Penicillin Allergy‬ ‭‬ C ● ‭ ross sensitivity:‬‭Cephalosporins and carbapenems‬ ‭●‬ ‭Safe alternatives:‬‭Vancomycin, erythromycin, and clindamycin‬ ‭Reaction Types‬ ‭●‬ ‭Immediate:‬‭2-30 minutes after administration‬ ‭●‬ ‭Accelerated:‬‭1-72 hours after administration‬ ‭●‬ ‭Delayed:‬‭Days to weeks after administration‬ ‭●‬ ‭Anaphylaxis:‬‭Laryngeal edema, bronchoconstriction,‬‭severe hypotension‬ ‭○‬ ‭Epinephrine and respiratory support‬ ‭Drug-Drug Interactions‬ ‭Aminoglycosides‬ ‭●‬ ‭Weakens the cell wall and facilitates intracellular access of the aminoglycoside (ex.‬ ‭gentamicin) to increase bactericidal effects‬ ‭●‬ ‭High concentrations of penicillin → inactivation of aminoglycosides‬ ‭●‬ ‭Should not be mixed in the same IV solution; separate administration‬ ‭Beta-Lactamase Inhibitors‬ ‭●‬ ‭Combined with penicillinase-sensitive penicillins to extend the antimicrobial spectrum‬ ‭●‬ ‭Sulbactam, tazobactam, relebactam, and clavulanic acid (clavulanate)‬ ‭●‬ ‭Only in fixed doses with penicillin; minimal toxicity itself‬ ‭●‬ ‭Unasyn: Ampicillin/sulbactam‬ ‭●‬ ‭Augmentin, Clavulin: Amoxicillin/clavulanate‬ ‭●‬ ‭Zosyn, Tazocin: Piperacillin/tazobactam‬