книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

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

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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:

λ Site of action:

*4

#2

Chapter 1 λ Antibacterial Agents

Bridge to Microbiology

Once-Daily Dosing of Aminoglycosides

Antibacterial effects depend mainly on peak drug level (rather than time) and continue with blood levels < MIC—a postantibiotic effect (PAE).

Toxicity depends both on blood level and the time that such levels are > than a specific threshold (i.e., total dose).

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Clinical Correlate

Don’t Use in Pregnancy

Aminoglycosides, fluoroquinolones, sulfonamides, tetracyclines

Classic Clues

Phototoxicity

λTetracyclines

λSulfonamides

λQuinolones

−Neuromuscular blockade with ↓ release of ACh—may enhance effects of skeletal muscle relaxants

Tetracyclines

λActivity and clinical uses:

−Bacteriostatic drugs, actively taken up by susceptible bacteria

−“Broad-spectrum” antibiotics, with good activity versus chlamydial and mycoplasmal species, H. pylori (GI ulcers), Rickettsia, Borrelia burgdorferi, Brucella, Vibrio, and Treponema (backup drug)

λSpecific drugs:

−Doxycycline: more activity overall than tetracycline HCl and has particular usefulness in prostatitis because it reaches high levels in prostatic fluid

−Minocycline: in saliva and tears at high concentrations and used in the meningococcal carrier state

−Tigecycline: used in complicated skin, soft tissue, and intestinal infections due to resistant gram + (MRSA, VREF), gram –, and anaerobes

λPharmacokinetics:

−Kidney for most (↓ dose in renal dysfunction)

−Liver for doxycycline

−Chelators: tetracyclines bind divalent cations (Ca2+, Mg2+, Fe2+), which ↓ their absorption

λSide effects:

−Tooth enamel dysplasia and possible ↓ bone growth in children (avoid)

−Phototoxicity (demeclocycline, doxycycline)

−GI distress (NVD), superinfections leading to candidiasis or colitis

−Vestibular dysfunction (minocycline)

−Have caused liver dysfunction during pregnancy at very high doses (contraindicated)

Chloramphenicol

λActivity and clinical uses:

−Bacteriostatic with a wide spectrum of activity

−Currently a backup drug for infections due to Salmonella typhi, B. fragilis, Rickettsia, and possibly in bacterial meningitis

λPharmacokinetics:

−Orally effective, with good tissue distribution, including CSF

−Metabolized by hepatic glucuronidation, and dose reductions are needed in liver dysfunction and in neonates

−Inhibition of cytochrome P450

λSide effects:

−Dose-dependent bone marrow suppression common; aplastic anemia rare (1 in 35,000)

−“Gray baby” syndrome in neonates (↓ glucuronosyl transferase)

Macrolides

λDrugs: erythromycin, azithromycin, clarithromycin

λActivity and clinical uses:

−Macrolides are wide-spectrum antibiotics

ºGram-positive cocci (not MRSA)

ºAtypical organisms (Chlamydia, Mycoplasma, and Ureaplasma species)

ºLegionella pneumophila

ºCampylobacter jejuni

ºMycobacterium avium-intracellulare (MAC)

ºH. pylori

λPharmacokinetics:

−They inhibit cytochrome P450s

λSide effects:

−Macrolides stimulate motilin receptors and cause gastrointestinal distress (erythromycin, azithromycin > clarithromycin)

−Macrolides cause reversible deafness at high doses

−Increased QT interval

λTelithromycin: a ketolide active against macrolide-resistant S. pneumonia

Clindamycin

λNot a macrolide, but has the same mechanisms of action and resistance

λNarrow spectrum: gram-positive cocci (including community-acquired MRSA) and anaerobes, including B. fragilis (backup drug)

λConcentration in bone has clinical value in osteomyelitis due to grampositive cocci

λSide effect: pseudomembranous colitis (most likely cause)

Linezolid

λMechanism of action:

−Inhibits the formation of the initiation complex in bacterial translation systems by preventing formation of the N-formylmethionyl- tRNA-ribosome-mRNA ternary complex

λSpectrum:

−Treatment of VRSA, VRE, and drug-resistant pneumococci

λSide effects: bone marrow suppression (platelets), MAO-A and B inhibitor

Quinupristin–Dalfopristin

λMechanism of action:

−Quinupristin and dalfopristin streptogramins that act in concert via several mechanisms

−Binding to sites on 50S ribosomal subunit, they prevent the interaction of amino-acyl-tRNA with acceptor site and stimulate its dissociation from ternary complex

−May also decrease the release of completed polypeptide by blocking its extrusion

Chapter 1 λ Antibacterial Agents

Bridge to Microbiology

Community-Acquired Pneumonia

With no comorbidity, the most common organisms associated with community-acquired pneumonia are

M. pneumoniae, C. pneumoniae, and viruses. In smokers, the pneumococcus is a more frequent pathogen. Macrolide antibiotics have activity against most strains of these organisms (other than viruses) and are therefore commonly used in the treatment of a communityacquired pneumonia.

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Section V λ Antimicrobial Agents

Note

λStreptogramins for E. faecium, including VRE faecium, but not for E. faecalis

λLinezolid for both types of enterococci

λSpectrum:

−Used parenterally in severe infections caused by vancomycin-resistant staphylococci (VRSA) and enterococci (VRE), as well as other drugresistant, gram-positive cocci

λSide effects:

−Toxic potential remains to be established

Bridge to Biochemistry

Antimetabolites

Definition: a substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process

Sulfonamides and trimethoprim are antimetabolites, as are

many antiviral agents and drugs used in cancer chemotherapy.

INHIBITORS OF NUCLEIC ACID SYNTHESIS

Inhibitors of Folic Acid Synthesis

λ Drugs: sulfonamides, trimethoprim, and pyrimethamine

Figure V-1-3. Inhibitors of Folic Acid Synthesis