Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Скачать

Заказать новую работу

Внимание! Если размещение файла нарушает Ваши авторские права, то обязательно сообщите нам

Antibacterial Agents

1

Learning Objectives

Apply the principles of antimicrobial chemotherapy to select the best treatment

Differentiate medications that inhibitor cell-wall synthesis, bacterial protein synthesis, and nucleic acid synthesis

Answer questions about unclassified antibiotics

Describe the differences between standard antibacterial agents and antitubercular drugs

PRINCIPLES OF ANTIMICROBIAL CHEMOTHERAPY

λBactericidal

λBacteriostatic

λCombinations:

–Additive

–Synergistic (penicillins plus aminoglycosides)

–Antagonistic (penicillin plus tetracyclines)

λMechanisms:

Table V-1-1. Mechanism of Action of Antimicrobial Agents

Mechanism of Action

 

Antimicrobial Agents

Inhibition of bacterial cell-wall

 

Penicillins, cephalosporins,

synthesis

 

imipenem/meropenem, aztreonam,

 

 

vancomycin

Inhibition of bacterial protein

 

Aminoglycosides, chloramphenicol,

synthesis

 

macrolides, tetracyclines, streptogramins,

 

 

linezolid

Inhibition of nucleic synthesis

 

Fluoroquinolones, rifampin

Inhibition of folic acid synthesis

 

Sulfonamides, trimethoprim,

 

 

pyrimethamine

179

Section V λ Antimicrobial Agents

λ Resistance:

Table V-1-2. Mechanisms of Resistance to Antimicrobial Agents

Antimicrobial Agents

 

Primary Mechanism(s) of Resistance

Penicillins and cephalosporins

Production of beta-lactamases, which cleave

 

the beta-lactam ring structure; change in

 

penicillin-binding proteins; change in porins

Aminoglycosides (gentamicin,

Formation of enzymes that inactivate drugs

streptomycin, amikacin, etc.)

via conjugation reactions that transfer acetyl,

 

phosphoryl, or adenylyl groups

Macrolides (erythromycin,

Formation of methyltransferases that alter

azithromycin, clarithromycin,

drug binding sites on the 50S ribosomal

etc.) and clindamycin

subunit

 

Active transport out of cells

Tetracyclines

Increased activity of transport systems that

 

“pump” drugs out of the cell

Sulfonamides

Change in sensitivity to inhibition of target

 

enzyme; increased formation of PABA; use of

 

exogenous folic acid

Fluoroquinolones

Change in sensitivity to inhibition of target

 

enzymes; increased activity of transport

 

systems that promote drug efflux

Chloramphenicol

Formation of inactivating acetyltransferases

INHIBITORS OF CELL-WALL SYNTHESIS

λ All cell-wall synthesis inhibitors are bactericidal.

 

 

 

 

 

Penicillins

 

 

 

 

 

 

Cephalosporins

 

 

 

 

 

H

 

 

 

 

 

 

H

 

 

 

 

 

 

 

 

R

 

 

 

 

 

 

 

 

 

 

 

R1

 

 

 

 

 

 

 

 

 

 

 

S

 

N

 

 

 

 

 

N

 

 

 

 

 

 

 

C

 

 

 

 

 

 

 

 

S

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

O

 

 

N

 

 

 

 

 

CH3

 

 

O

 

O

 

 

 

 

N

 

CH2-R2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COOH

 

 

 

 

 

 

 

 

 

 

 

 

 

COOH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure V-1-1. Beta-Lactam Antibiotics

180

Penicillins

λMechanisms of action:

–Bacterial cell wall is cross-linked polymer of polysaccharides and pentapeptides

–Penicillins interact with cytoplasmic membrane-binding proteins (PBPs) to inhibit transpeptidation reactions involved in cross-link- ing, the final steps in cell-wall synthesis

λMechanisms of resistance:

–Penicillinases (beta-lactamases) break lactam ring structure (e.g., staphylococci)

–Structural change in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA], penicillin-resistant pneumococci)

–Change in porin structure (e.g., Pseudomonas)

λSubgroups and antimicrobial activity:

–Narrow spectrum, beta-lactamase sensitive: penicillin G and penicillin V

ºSpectrum: streptococci, pneumococci, meningococci, Treponema pallidum

–Very narrow spectrum, beta-lactamase resistant: nafcillin, methicillin, oxacillin

ºSpectrum: known or suspected staphylococci (not MRSA)

–Broad spectrum, aminopenicillins, beta-lactamase sensitive: ampicillin and amoxicillin

ºSpectrum: gram-positive cocci (not staph), E. coli, H. influenzae, Listeria monocytogenes (ampicillin), Borrelia burgdorferi (amoxicillin), H. pylori (amoxicillin)

–Extended spectrum, antipseudomonal, beta-lactamase sensitive: ticarcillin, piperacillin

ºSpectrum: increased activity against gram-negative rods, including

Pseudomonas aeruginosa

λGeneral considerations:

–Activity enhanced if used in combination with beta-lactamase inhibitors (clavulanic acid, sulbactam)

–Synergy with aminoglycosides against pseudomonal and enterococcal species

λPharmacokinetics:

–Most are eliminated via active tubular secretion with secretion blocked by probenecid; dose reduction needed only in major renal dysfunction

–Nafcillin and oxacillin eliminated largely in bile; ampicillin undergoes enterohepatic cycling, but excreted by the kidney

–Benzathine penicillin G—repository form (half-life of 2 weeks)

λSide effects:

− Hypersensitivity

ºIncidence 5 to 7% with wide range of reactions (types I–IV). Urticarial skin rash common, but severe reactions, including anaphylaxis, are possible.

ºAssume complete cross-allergenicity between individual penicillins

Chapter 1 λ Antibacterial Agents

Bridge to Biochemistry

Suicide Inhibitors

Metabolism of a substrate by an enzyme to form a compound that irreversibly inhibits that enzyme. Penicillinase inhibitors, such as clavulanic acid and sulbactam, are suicide inhibitors.

Bridge to Immunology

Drug Hypersensitivity Reactions

I.IgE mediated—rapid onset; anaphylaxis, angioedema, laryngospasm

II.IgM and IgG antibodies fixed to cells—vasculitis, neutropenia, positive Coombs test

III.Immune complex formation— vasculitis, serum sickness, interstitial nephritis

IV. T-cell mediated—urticarial and maculopapular rashes, StevensJohnson syndrome

181

Section V λ Antimicrobial Agents

–Other:

º GI distress (NVD), especially ampicillin

Clinical Correlate

Ceftaroline is an unclassified (fifth-generation) cephalosporin that can bind to the most often seen mutation of the PBP in MRSA.

Classic Clues

Organisms not covered by cephalosporins are “LAME”:

Listeria monocytogenes

Atypicals (e.g., Chlamydia,

Mycoplasma)

MRSA

Enterococci

º Jarisch-Herxheimer reaction in treatment of syphilis

Cephalosporins

λMechanisms of action and resistance: identical to penicillins

λSubgroups and antimicrobial activity:

–First generation: cefazolin, cephalexin

ºSpectrum: gram-positive cocci (not MRSA), E. coli, Klebsiella pneumoniae, and some Proteus species

ºCommon use in surgical prophylaxis

ºPharmacokinetics: none enter CNS

–Second generation: cefotetan, cefaclor, cefuroxime

ºSpectrum: ↑ gram-negative coverage, including some anaerobes

ºPharmacokinetics: no drugs enter the CNS, except cefuroxime

–Third generation: ceftriaxone (IM) and cefotaxime (parenteral), cefdinir and cefixime (oral)

ºSpectrum: gram-positive and gram-negative cocci (Neisseria gonorrhea), plus many gram-negative rods

ºPharmacokinetics: most enter CNS; important in empiric management of meningitis and sepsis

–Fourth generation: cefepime (IV)

ºEven wider spectrum

ºResistant to most beta-lactamases

ºEnters CNS

λPharmacokinetics:

ºRenal clearance similar to penicillins, with active tubular secretion blocked by probenecid

ºDose modification in renal dysfunction

ºCeftriaxone is largely eliminated in the bile

λSide effects:

ºHypersensitivity:

Incidence: 2%

Wide range, but rashes and drug fever most common Positive Coombs test, but rarely hemolysis

Assume complete cross-allergenicity between individual cephalosporins and partial cross-allergenicity with penicillins (about 5%)

Most authorities recommend avoiding cephalosporins in patients allergic to penicillins (for gram-positive organisms, consider macrolides; for gram-negative rods, consider aztreonam)

182

Chapter 1 λ Antibacterial Agents

Imipenem and Meropenem

λMechanism of action:

−Same as penicillins and cephalosporins

−Resistant to beta-lactamases

λSpectrum:

– Gram-positive cocci, gram-negative rods (e.g., Enterobacter, Pseudomonas spp.), and anaerobes

−Important in-hospital agents for empiric use in severe life-threaten- ing infections

λPharmacokinetics:

−Imipenem is given with cilastatin, a renal dehydropeptidase inhibitor, which inhibits imipenem’s metabolism to a nephrotoxic metabolite

−Both drugs undergo renal elimination— ↓ dose in renal dysfunction

λSide effects:

−GI distress

−Drug fever (partial cross-allergenicity with penicillins)

−CNS effects, including seizures with imipenem in overdose or renal dysfunction

Aztreonam

λMechanism of action:

−Same as for penicillins and cephalosporins

−Resistant to beta-lactamases

λUses:

−IV drug mainly active versus gram-negative rods

−No cross-allergenicity with penicillins or cephalosporins

Vancomycin

λMechanism of action:

−Binding at the D-ala-D-ala muramyl pentapeptide to sterically hinder the transglycosylation reactions (and indirectly preventing transpeptidation) involved in elongation of peptidoglycan chains

−Does not interfere with PBPs

λSpectrum:

– MRSA

– Enterococci

– Clostridium difficile (backup drug)

λResistance:

−Vancomycin-resistant staphylococcal (VRSA) and enterococcal (VRE) strains emerging

−Enterococcal resistance involves change in the muramyl pentapeptide “target,” such that the terminal D-ala is replaced by D-lactate

183

Источник: https://studfile.net/preview/16445239/

Смотрите также:

Изложение содержания дела, по которому приняты судебные постановления
_1-тема-СтрМетал
_1966(~1
_files_materials_5053_prog.ntr
_Антонян Ю.М., Сексуальные преступления. Чикатило и другие
_РГР № 1 (2)