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Pharm S2015 > Antimicrobials > Flashcards

Antimicrobials Flashcards

1
Q

Combination therapy

A
  • Sequential blockade (eg, trimethoprim + sulfamethoxazole)
  • Blockade of drug-inactivating enzymes (eg, clavulanic acid + amoxicillin)
  • Enhanced drug uptake (eg, increased permeability to aminoglycosides after
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2
Q

Resistance

A
  • If maximal level of antibiotic tolerated by host does not halt growth
  • Primary resistance: Ex. Pseudomonas resistant to many antibiotics due to not having porins
  • Acquired drug resistance
    • Spontaneous mutations of DNA
    • DNA transfer of drug resistance
    • Altered expression of proteins in drug-resistant organisms
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3
Q

Antimicrobial Chemoprophylaxis

A
  • Should always be directed toward a specific pathogen
  • No resistance should develop
  • Use should be of limited duration
  • Conventional therapeutic doses should be employed
  • Should only be used in situations of documented drug efficacy
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4
Q

Cell wall synthesis inhibitors

A
  • Beta-lactam antibiotics
    • penicillins
    • cephalosporins
    • carbapenems
    • monobactams
  • Vancomycin
  • Daptomycin
  • Bacitracin
  • Fosfomycin
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5
Q

Penicillins

A
  • Cell wall synthesis inhibitors
    • Widely effective: except Staph aureus which have beta-lactamase
    • Little toxicity
    • Increasing levels of resistance
  • Structure: All include Beta-lactam ring

MOA:

  • Bactericidal
  • Inhibit last step in peptidogly can synthesis through binding to PBPs
  • Inactive against organisms without peptidoglycan cell wall eg, mycoplasma, protozoa, fungi, viruses
  • PBPs
    • Bacterial enzymes inactivated by penicillins
    • Include transpeptidases
    • Number varies with type of organism
    • Resistance can develop with PBP mutations
  • Autolysin production
    • Produced by bacteria and mediate cell lysis
    • Penicillins activate autolysins to initiate cell death
    • Bacteria eventually lyse due to activity of autolysins and inhibition of cell-wall assembly
  • Gram-positive bacteria have cell wall easily crossed by penicillin’s
  • Ability to reach PBPs determined by: size, charge, hydrophobicity
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6
Q

Penicillin G - Clinical application (DOC for)

A
  • Syphilis (benzathine penicillin G)
  • Strep infections (especially in prevention of rheumatic fever)
  • Susceptible pneumococci
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7
Q

Repository penicillins

A
  • Penicillin G Procaine, Penicillin G Benzathine
  • Developed to prolong duration of penicillin G
  • Penicillin G procaine
    • IM not IV (risk of procaine toxicity)
    • t1/2 = 12-24h
    • Seldom used (increased resistance)
  • Penicillin G **benazthine **
    • DOC for rheumatic fever prophylaxis & syph (but make sure no allergies)
    • IM
    • t1/2 = 3-4 weeks
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8
Q

Penicillin V

A
  • Natural penicillins
  • Similar antibacterial spectrum to penicillin G (less active against Gram –ve bacteria)
  • More acid stable than G (can give orally)
  • DOC: strep throat
    *
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9
Q

Methicillin, Nafcillin, Oxacillin, Dicloxacillin

A
  • Antistaphylococcal penicillins
  • Beta-lactamase resistant
  • Inactive against MRSA
  • Methicillin is never DOC (never used clinically)
  • Restricted to treatment of beta-lactamase-producing staphylococci
  • Recommended as first-line treatment for staphylococci endocarditis in patients without artificial heart valves
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10
Q

Ampicillin, Amoxicillin

A
  • Extended-spectrum penicillins
  • Similar to penicillin G (plus Gram-negative activity)
  • Susceptible to beta-lactamases
  • Activity enhanced with beta-lactamase inhibitor
  • Amoxicillin has higher oral bioavailability than other penicillins (including ampicillin) ie do not require empty stomach
  • Amoxicillin is a common antibiotic prescribed for **children and in pregnancy **
  • Used for treatment of a number of infections: acute otitis media, streptococcal pharyngitis, pneumonia, skin infections, UTIs etc.
  • **Widely used to treat upper respiratory infections (H.influenzae & S.pneumoniae) **
  • **Amoxicillin = standard regimen for endocarditis prophylaxis during dental or respiratory tract procedures **
  • **Ampicillin is used in combination with aminoglycoside to treat enterococci and Listerial infections **
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11
Q

Carbenicillin, Ticarcillin, Piperacillin

A
  • Antipseudomonal penicilins
  • Effective against many Gram-negative and Gram- positive bacilli
  • Often combined with beta-lactamase inhibitor
  • Piperacillin + Cipro Active against P.aeruginosa: Acute bronchitis in a Pt w acute bronchitis and COPD
  • Treatment of moderate-severe infections of susceptible organisms (eg, uncomplicated & complicated skin, gynecologic and intra-abdominal infections, febrile neutropenia)
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12
Q

Effective empiric treatment for infective endocarditis

A
  • penicillin + aminoglycoside
  • synergistic
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13
Q

Pencillins Resistance

A

One of 4 general mechanisms (primary or acquired):

  • Inactivation by beta-lactamase
  • Modification of target PBPs
  • Impaired penetration of drug to target PBPs
  • Increased efflux

MRSA (ORSA) = altered target PBPs (low affinity for

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14
Q

Penicillins: PK

A

Half-life: ~30-60 min (except repository penicillins)

Oral absorption:

  • Absorption impaired by food (except amoxicillin -> high oral bioavailability)
  • Nafcillin = erratic (not suitable for oral admin.)

Distribution

  • All achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids & urine
  • Nafcillin, ampicillin & piperacillin achieve high levels in bile,
  • Levels in prostate & eye = insufficient
  • CSF penetration = poor (except in meningitis)

Excretion

  • Most excreted primarily via kidney (beware in kidney failure)
  • Nafcillin = exception as primarily excreted in bile
  • Oxacillin & dicloxacillin = renal & biliary excretion
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15
Q

Penicillins: Adverse

A
  • Hypersensitivity
    • Penicilloic acid = major antigenic determinant
    • ~ 5 % patients claim to have some reaction (maculopapular rash -> anaphylaxis)
    • Cross-allergic reactions between beta-lactam antibiotics can occur
  • GI disturbances (eg, diarrhea)
  • Pseudomembranous colitis (ampicillin)
  • Maculopapular rash (ampicillin, amoxicillin)
  • Interstitial nephritis (particularly methicillin)
  • Neurotoxicity (epileptic patients at risk)
  • Hematologic toxicities (ticarcillin)
  • Neutropenia (nafcillin)
  • Hepatitis (oxacillin)
  • Secondary infections (eg, vaginal candidiasis)
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16
Q

Clavulanic acid, Sulbactam, Tazobactam

A
  • Beta-lactamase inhibitor
  • Contain beta-lactam ring but do not have sig. antibacterial activity
  • Bind to and inactivate most beta-lactamases
  • Available only in fixed combinations with specific penicillins
  • Indication: mild-mod diverticulitis (enteric Gram -ve bacteria + enterococci anearobes)
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17
Q

Cephalosporins

A
  • Beta-lactam antibiotics
  • Bactericidal
  • Same MOA as penicillin’s
  • Affected by similar resistance mechanisms
  • Classified into generations
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18
Q

Cephalosporins: antibacterial spectrum

A
  • In general, Gram positive activity diminishes while Gram- negative activity increases moving from the first-to third generations
  • 4th generation demonstrate similar activity to first- generation agents against Gram-positive cocci and are also active against most Gram-negative bacilli.
  • 5th generation have a similar spectrum to the 3rd generation. They are unique in that they have activity against MRSA.
  • All 1st-4th generation cephalosporins are considered inactive against MRSA,
  • All cephalosporins are considered inactive against enterococci, Listeria, Legionella, Chlamydia, mycoplasma, and acinetobacter species.
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19
Q

Cefazolin, Cephalexin

A
  • 1st gen Cephalosporins
  • Penicillin G substitutes
  • Resistant to staphylococcal penicillinase
  • Activity against Gram-positive cocci & P.mirabilis, E.coli, & K.pneumoniae

Indications

  • Rarely DOC for any infections
  • Cefazolin = DOC for surgical prophylaxis
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20
Q

Cefaclor, Cefoxitin, Cefotetan, Cefamandole

A
  • 2nd gen cephalosprins
  • Extended Gram-negative coverage
  • Greater activity against H.influenzae, Enterobacter aerogenes and some Neisseria species
  • Weaker activity against Gram-positive organisms

Indications

  • Primarily used to treat sinusitis, otitis & lower respiratory tract infections
  • Cefotetan & cefoxitin = prophylaxis & therapy of abdominal and pelvic cavity infections
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21
Q

Ceftriaxone, Cefoperazone, Cefotaxime, Ceftazidime, Cefixime

A
  • 3rd gen cephalosporin; most common cephalosporin
  • Enhanced activity against Gram-negative cocci
  • Highly active against enterobacteriacae, Neisseria, & H.influenzae
  • Less active against most Gram-positive organisms
  • Cefotaxime & ceftriaxone = usually active against pneumococci

Indications

  • DOC for gonorrhea (parenteral)
  • DOC for meningitis due to ampicillin-resistant H.influenzae
  • Prophylaxis of meningitis in exposed individuals
  • Treatment of Lyme disease (CNS or joint infection)
  • Activity against P.aeruginosa
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22
Q

Cefipime

A
  • 4th gen cephalosporins
  • Parenteral admin. Only
  • Wide antibacterial spectrum
  • Gram +ve activity of 1st generation + Gram -ve activity of 3rd generation
  • eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa

Indications

  • Treatment of infections with susceptible organisms
  • eg, UTI’s, complicated intra-abdominal infections, febrile neutropenia
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23
Q

Ceftaroline

A
  • 5th gen
  • Parenteral admin. only
  • Activity against MRSA !
  • Similar spectrum of activity to 3rd generation

Indications

  • Skin and soft tissue infection due to MRSA, particularly if gram-negative pathogens are coinfecting
  • **Community-acquired pneumonia (when first-line agents are unsuccessful) **
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24
Q

Cephalosporins - PK

A
  • Most administered parenterally (exceptions = cephalexin, cefaclor, cefixime)
  • Only 3rd generation reach adequate levels in CSF
  • Mainly eliminated via kidneys (exceptions = ceftriaxone & cefoperazone excreted in bile)
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25
Q

Cephalosporins - Adverse

A
  • Allergic reactions (cross-sensitivity with penicillins can occur)
  • However, minor penicillin allergic patients often treated successfully with a cephalosporin
  • Pain at infection site (IM), thrombophlebitis (IV)
  • Superinfections (eg, C.difficile)
  • Cefamandole, cefoperazone & cefotetan contain methyl-thiotetrazole group, all can cause:
    • hypoprothrombinemia (Vit. K1 admin can prevent) &
    • disulfiram-like reactions (avoid alcohol)
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26
Q

Imipenem, Meropenem

A
  • Carbapenem
  • Synthetic Beta-lactam antibiotics
  • Resist hydrolysis by most beta-lactamases
  • Very broad spectrum of activity
  • Active against penicillinase-producing Gram-positive & negative organisms; aerobes & anaerobes; P.aeruginosa
  • Not active against carbapenemase producing organisms eg, carbapenem-resistant enterobacteriaceae, carbapenem-resistant klebsiella
  • Not active against MRSA

Indications: use typically restricted to avoid resistance

  • DOC for:
    • enterobacter infections
    • extended-spectrum beta-lactamase producing Gram -ve
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27
Q

Carbapenems - PK

A
  • IV
  • Imipenem forms potentially nephrotoxic metabolite when activated by renal dehydropeptidase I. Combining with enzyme inhibitor Cilastatin prevents metabolism thus prevents toxicity & increases availability.
  • Meropenem is not metabolized by same enzyme (no need for Cilastatin)
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28
Q

Carbapenems - Adverse

A
  • GI distress (but all antibiotics can cause diarrhea)
  • High levels of imipenem can provoke seizures
  • Allergic reactions (partial cross-reactivity with penicillin’s)
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29
Q

Aztreonam

A
  • Monobactams
  • Aerobic Gram-negative rods ONLY (including pseudomonas)
  • No activity against Gram-positive bacteria or anaerobes
  • Resistant to action of beta-lactamases

Indications

UTI’s, lower respiratory tract infections, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible Gram- negative bacteria

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30
Q

Monobactam - PK

A
  • Mainly IV or IM
  • Can be given by inhalation in CF patients
  • Penetrates CSF when inflamed
  • Excreted primarily via urine
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31
Q

Monobactam - Adverse

A
  • Relatively nontoxic
  • Little cross-hypersensitivity with other beta-lactam antibiotics
  • Occasional skin rashes / elevation of serum aminotransferases
  • GI upset, vertigo, headache
  • Phlebitis or thrombophlebitis reported with IV use
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32
Q

Vancomycin

A
  • Bacterial glycoprotein
  • Bactericidal
  • Active against Gram-positive bacteria only
  • Virtually all Gram-negative organisms are intrinsically resistant
  • Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP)

MOA

  • Binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
  • Inhibits bacterial cell wall synthesis & peptidoglycan polymerization

Resistance

  • Plasmid-mediated changes in drug permeability
  • Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)

Indications: reserved for drug resistant bacteria

  • Treatment of serious infections caused by Beta-lactam resistant Gram +ve organisms eg, MRSA
  • Treatment of Gram +ve infections in patients severely allergic to Beta-lactams
  • In combination with an aminoglycoside for empirical treatment of infective endocarditis; 1st line: vancomycin + gentamycin
  • In combination with an aminoglycoside for treatment of enterococcal endocarditis or PRSP
  • Given orally for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (C.difficile)
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33
Q

Vancomycin - PK

A
  • Poor oral absorption
  • Requires slow IV infusion (60-90 min)
  • Penetrates CSF when inflamed
  • 90-100% excreted via kidneys
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34
Q

Vancomycin - Adverse

A
  • Mostly minor eg, fever, chills, phlebitis at infusion site
  • ‘Red man’ or ‘red neck’ syndrome (infusion-related flushing over face and upper torso)
  • Ototoxicity (drug accumulation)
  • Nephrotoxicity (drug accumulation)
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35
Q

Daptomycin

A
  • Bactericidal
  • Effective against multiple drugresistance organisms
  • Inactive against Gram-negative bacteria
  • Not effective in treatment of pneumonia

MOA

  • Novel mechanism of action -> useful against multi-drug resistant bacteria
  • Binds to cell membrane via calcium-dependent insertion of lipid tail
  • Results in depolarization of cell membrane with K+ efflux -> cell death

Indications

  • Recommended for treatment of severe infections caused by MRSA or VRE
  • Treatment of complicated skin/structure infections caused by susceptible S.aureus
36
Q

Daptomycin - PK

A
  • IV only
  • Can accumulate in renal insufficiency
37
Q

Daptomycin - Adverse

A
  • Constipation, nausea, headache, insomnia
  • Elevated creatine phosphokinases (recommended to discontinue coadmin. of statins)
38
Q

Bacitracin

A
  • Unique mechanisms -> no cross resistance
  • Interferes in late stage cell wall synthesis
  • Effective against Gram-positive organisms
  • Marked nephrotoxicity -> mainly topical use
39
Q

Fosfomycin

A
  • Inhibits cytoplasmic enzyme enolpyruvate transferase in early stage of cell wall synthesis
  • Active against Gram-positive and negative organisms
  • Oral
  • Used for treatment of uncomplicated lower UTI’s
40
Q

Protein synthesis inhibitors

A
  • Tetracyclines
  • Glycylcyclines
  • Aminoglycosides
  • Macrolides
  • Chloramphenicol
  • Clindamycin
  • Streptogramins
  • Linezolid
  • Mupirocin
41
Q

Protein synthesis inhibitors

A
  • Bind to and interfere with ribosomes
  • Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome
  • Mostly bacteriostatic
42
Q

Tetracyclines

A
  • Doxycycline, Minocycline, Tetracycline
  • Broad-spectrum: aerobe, anaerobe, parasites, etc…
  • Bacteriostatic
  • Activity against many aerobic and anaerobic Gram- positive & Gram-negative organisms

MOA

  • Entry via passive diffusion & energy-dependent transport unique to bacterial inner cytoplasmic membrane
  • Susceptible cells concentrate drug intracellularly
  • Bind reversibly to 30S subunit of ribosome, preventing binding of aminoacyl tRNA

Resistance

  • Widespread resistance (usually plasmid mediated)
  • 3 main mechanisms:
  • Impaired influx or increased efflux by active protein pump
  • Production of proteins that interfere with binding to ribosome
  • Enzymatic inactivation

Indications

  • Most common use = severe acne & rosacea
  • Used in empiric therapy of community-acquired pneumonia (outpatients)
  • Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract, & intestines
  • Syphilis (patients allergic to penicillin)
  • DOC
    • Chlamydia
    • Mycoplasma pneumoniae
    • Lyme disease
    • Cholera
    • Anthrax prophylaxis
    • Rickettsia (Rocky Mountain Spotted Fever, typhus)
  • Used in combination for
    • H. pylori eradication
    • Malaria prophylaxis and treatment
    • Treatment of plague, tularemia, brucellosis
43
Q

Tetracyclines - PK

A
  • Variable oral absorption (decreased by divalent & trivalent cations)
  • Doxycycline (lipid soluble) = preferred for parenteral admin. and good choice for STD’s and prostatitis
  • Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)
  • Concentrate in liver, kidney, spleen & skin
  • Excreted primarily in urine except doxycycline (primarily via bile)
  • TERATOGENIC – all cross placenta & are excreted into breast milk (FDA category D)
44
Q

Tetracylcine - Adverse

A
  • Gastric effects / superinfections (nausea, vomiting, diarrhea)
  • Discoloration & hypoplasia of teeth, stunting of growth (generally avoided in pregnancy & not given in children under 8y)
  • Fatal hepatotoxicity (in pregnancy, with high doses, patients with hepatic insufficiency)
  • Exacerbation of existing renal dysfunction
  • Photosensitization
  • Dizziness, vertigo (esp. doxycycline & minocycline)
45
Q

Tigecycline

A
  • Glycycyclines
  • Structurally similar to tetracyclines
  • Antibacterial spectrum
  • Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms

Resistance

  • Little resistance
  • Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)

Indications

  • Treatment of complicated skin, soft tissue and intra- abdominal infections
  • Increased risk of mortality has been observed with tigecycline compared with other antibiotics when used to treat serious infections
  • FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections
46
Q

Glycylcyclines - PK/Adverse

A
  • IV only
  • Excellent tissue & intracellular penetration
  • Primarily biliary/fecal elimination

Adverse effects

  • Well tolerated
  • AE similar to tetracyclines

Contraindications: Pregnancy & children <8y

47
Q

Amikacin, Gentamicin, Tobramycin, Streptomycin, Neomycin

A
  • Aminoglycosides
  • Bactericidal
  • Associated with serious toxicities
  • Largely replaced by safer antibiotics; reserved for serious infections and only used for short period of time

MOA

  • Passively diffuse across membranes of Gram-negative organisms
  • Actively transported (O2-dependent) across cytoplasmic membrane
  • Bind to 30S ribosomal subunit prior to ribosome formation leading to:
  1. misreading of mRNA, &
  2. inhibition of translocation

Resistance: 3 mechanisms

  • Plasmid-associated synthesis of enzymes that modify and inactivate drug
  • Decreased accumulation of drug
  • Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation
48
Q

Conc.- dependent vs. time-dependent killing

A
  • Concentration-dependent (aminoglycosides)
  • Time-dependent (penicillins, cephalosporins)
49
Q

Aminoglycosides - Antibacterial Spectrum

A
  • Most active against aerobic Gram-negative bacteria
  • Anaerobes lack O2-dependent transport

Indications

  • Used mostly in combination
  • Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc
  • Once organism is identified aminoglycosides are normally discontinued in favor of less toxic drugs
  • DOC for
    • Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin
    • Streptomycin is the drug of choice for Plague (Y.Pestis)
50
Q

Oral neomycin

A
  • Used as adjunct in treatment for hepatic encephalopathy
  • Alternative treatment options for hepatic encephalopathy:
    • Lactulose
    • Oral vancomycin
    • Oral metronidazole
    • Rifaximin
51
Q

Lactulose

A

Nonabsorbable disaccharide

MOA

  • Degraded by intestinal bacteria
52
Q

Aminoglycosides - PK

A
  • Parenteral admin. only (except neomycin - topical)
  • Once-daily admin.
  • Well distributed (excluding CSF, bronchial secretions)
  • High levels in renal cortex & inner ear
  • 99% excreted in urine (reduce dose in renal insufficiency)
53
Q

Aminoglycosides - Adverse

A

Both time- and concentration-dependent

  • Ototoxicity
  • Nephrotoxicity
  • Neuromuscular blockade (myasthenia gravis = contraindicated)
  • Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)
54
Q

Erythromycin, Clarithromycin, Azithromycin, Telithromycin

A
  • Macrolides
  • Mainly used to treat Gram-positive infections
  • Bacteriostatic (bactericidal at high conc.)

MOA

  • Reversibly bind to 50S subunit inhibiting translocation; bacteriostatic
  • Binding site is identical or close to that for clindamycin & chloramphenicol

Resistance: 3 mechanisms

  • Reduced membrane permeability or active efflux
  • Production of esterase that hydrolyze drugs (by enterobacteriaceae)
  • Modification of ribosomal binding site (by chromosomal mutation or by a methylase)
  • Complete cross-resistance between erythromycin, azithromycin, & clarithromycin
  • Partial cross-resistance with clindamycin & streptogramins

Antibacterial spectrum

  • Most active against Gram-positive bacteria (some activity against Gram-negatives)
  • Spectrum is slightly wider than that of penicillins
  • Azithromycin, clarithromycin & telithromycin have broader spectrum than erythromycin

Indications

  • Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with beta-lactam for inpatients)
  • DOC for Mycoplasma pneumoniae
  • Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci)
  • Erythromycin = DOC for whooping cough (B.pertussis)
  • **Common substitute for patients with penicillin allergy **
55
Q

Macrolides - PK

A
  • Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin
  • Azithromycin & telithromycin = greater tissue penetration compared to other macrolides
  • Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin)
  • Ex. HIV Pt on multiple meds and fighting pneumonia -> Azithromycin indicated
56
Q

Macrolides - Adverse & contraindications

A

Adverse

  • GI irritation
  • Hepatic abnormalities (erythromycin & azithromycin)
  • QT prolongation
  • Severe reactions are rare (anaphylaxis, colitis)

Contraindications

  • Statins (due to macrolides inhibiting CYP P450)
  • Telithromycin – fatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances
57
Q

Chloramphenicol

A
  • Potent inhibitor of protein synthesis
  • Broad-spectrum (aerobic & anaerobic Gram-positive & - negative organisms)
  • Bacteriostatic (usually)
  • Toxicity limits use to life-threatening infections with no alternatives

MOA

  • Enters cells via active transport process
  • Binds reversibly to 50S ribosomal subunit (site adjacent to site of action of macrolides & clindamycin)
  • Can inhibit protein synthesis in mitochondrial ribosomes -> bone marrow toxicity
  • Very broad spectrum
  • Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
  • N.meningitidis, H.influenzae, Salmonella & bacteroides = highly susceptible
  • Never given systemically for minor infections (due to adverse effects)

Resistance

  • Presence of factor that codes for chloramphenicol acetyltransferase (inactivates drug)
  • Changes in membrane permeability

Clinical applications

  • Serious infections resistant to less toxic drugs
  • When chloramphenicols penetrability to site of infection is clinically superior to other drugs
  • Active against many VRE
  • Topical treatment of eye infections (mainly outside US)

PK

  • Oral, IV or topical
  • Wide distribution (readily enters CSF)
  • Inhibits hepatic oxidases (3A4 & 2C9)

Adverse

  • GI distress
  • Bone marrow depression
    • dose-related reversible depression
    • severe irreversible aplastic anemia
  • Gray baby syndrome (cyanosis), due to drug accumulation
58
Q

Clindamycin

A
  • MOA = same as macrolides (binds to 50S subunit)
  • Mainly bacteriostatic
  • Primarily used against Gram-positive anaerobic bacteria (including bacteroides)
  • not many drugs effective against anaerobes (only clindamycin and metronidzaole)

**Resistance **

  • mutation of ribosomal receptor site
  • modification of the receptor
  • enzymatic inactivation of drug
  • Most Gram-negative aerobes & enterococci are intrinsically resistant
  • Cross-resistant with macrolides

Clinical applications

  • Anaerobic infections (eg, bacteroides infections, abscesses, abdominal infections)
  • Skin and soft tissue infections (streptococci and staphylococci, and some MRSA)
  • In combination with primaquine as an alternative in PCP
  • In combination with pyrimethamine as an alternative treatment for toxoplasmosis of brain
  • Prophylaxis of endocarditis in valvular patients allergic to penicillin

PK

  • Oral or IV
  • Good penetration (including abscesses and bones)
59
Q

Clindamycin - Adverse

A
  • Potentially fatal pseudomembranous colitis (superinfection of C.difficile)
  • GI irritation (~ 20% people experience diarrhea)
  • Skin rashes (~10 %)
  • Neutropenia & impaired liver function
60
Q

Quinupristin, Dalfopristin

A
  • Streptogramins
  • Given as a combination (act synergistically to have bactericidal action)
  • Long postantibiotic effect

MOA

  • Bind to separate sites on 50S bacterial ribosome
  • Resistance is uncommon
  • Gram-positive cocci
  • Multi-drug resistant bacteria (streptococci, PRSP, MRSA, E.faecium)

Clinical applications: Restricted to treatment of infections caused by drug- resistant Staphylococci or VRE

PK

  • IV only
  • Penetrates macrophages & polymorphonucleocytes
  • Inhibitors of CYP 3A4
61
Q

Streptogramins - Adverse

A
  • Infusion related (venous irritation, arthralgia & myalgia)
  • GI effects
  • CNS effects (headache, pain)
62
Q

Linezolid

A
  • Bacteriostatic (cidal against streptococci & Clostridium perfringens)
  • recommended in the treatment of vancomycin-resistant strains of MRSA

MOA

  • Inhibits formation of 70S initiation complex
  • Binds to unique site on 23S ribosomal RNA of 50S subunit
  • Most Gram-positive organisms (staphylococci, streptococci, enterococci, Corynebacterium, Listeria monocytogenes)
  • Moderate activity against mycobacterium tuberculosis

Resistance

  • Decreased binding to target site
  • No cross-resistance with other drug classes

**Clinical applications: **Treatment of multi-drug resistant infections

PK

  • Oral (100% bioavailable) & IV
  • Widely distributed (including CSF)
  • Weak reversible inhibitor of MAO
63
Q

Linezolid - Adverse

A

Well tolerated for short admin. (GI, nausea, diarrhea, headaches, rash)

Long-term admin. can cause:

  • Reversible myelosuppression
  • Optic & peripheral neuropathy, & lactic acidosis

Contraindications: Reversible, nonselective inhibitor of MAO -> potential interaction w NE and 5HT drugs

64
Q

Fidaxomicin

A
  • Narrow spectrum macrocyclic antibiotic
  • Activity against Gram-positive aerobes and anaerobes especially Clostridia (C. difficile)
  • No activity against Gram-negative bacteria

**MOA: ** Inhibits bacterial protein synthesis by binding to RNA polymerase

Clinical applications

  • Treatment of C.difficile colitis (in adults)
  • Metro, vanco, and Fida all equally effective
  • Fidaxomicin is DOC for C. difficile in UK

PK: When administered orally, systemic absorption is negligible but fecal concentrations are high

65
Q

Mupirocin

A
  • Antibiotic belonging to monoxycarbolic acid class
  • Activity against most Gram-positive cocci, including MRSA and most streptococci (but not enterococci)
  • Only topical/intranasal agent with activity against MRSA

**MOA: **Binds to bacterial isoleucyl transfer-RNA synthetase resulting in the inhibition of protein synthesis

Clinical applications

  • Intranasal: Eradication of nasal colonization with MRSA in adult patients and healthcare workers
  • Topically: Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes
66
Q

Mupirocin - Adverse

A
  • Resistance develops if used for long periods of time
  • Mainly local and dermatologic effects (eg, burning, edema, tenderness, dry skin, pruritus)
67
Q

Drugs that affect nuclei acid synthesis

A
  • Fluoroquinolones
  • Sulfonamides
  • Trimethoprim
68
Q

Flouroquinolones examples

A
  • First generation: Nalidixic Acid (quinolone)
  • Second generation: Ciprofloxacin
  • Third generation: Levofloxacin
  • Fourth generation: Gemifloxacin, Moxifloxacin

Lower generations have excellent Gram-negative activity

Higher generations have improved activity against Gram- positives

69
Q

Fluoroquinolones MOA, resistance, PK

A

MOA

  • Broad spectrum, bactericidal drugs
  • Enter bacterium via porins
  • Inhibit bacterial DNA replication via interference with topoisomerase II (DNA gyrase) & IV

Resistance

  • Emerged rapidly in 2nd generation (esp. C.jejuni, gonococci, Gram-positive cocci, P.aeruginosa & serratia).
  • Due to chromosomal mutations that:
    • encode subunits of DNA gyrase (eg, gonococci resistance) and topo IV
    • regulate expression of efflux pumps (eg, S.aureus, S.pneumonia, M.tuberculosis)
  • Cross-resistance between drugs occurs

PK

  • Good oral bioavailability
  • Well distributed into all tissues and fluids (including bones)
  • Iron, zinc, calcium (divalent cations) interfere with absorption
  • Dosage adjustments required in renal dysfunction (except moxifloxacin)
70
Q

Nalidixic acid Clinical applications

A

Uncomplicated UTI’s

71
Q

Ciprofloxacin clinical applications

A
  • Travelers diarrhea (E.coli)
  • P.aeruginosa (CF patients)
  • Prophylaxis against meningitis (alternative to ceftriaxone & rifampin)
72
Q

Levofloxacin

A
  • Prostatitis (E.coli)
  • STD’s (not syphilis)
  • Skin infections
  • Acute sinusitis, bronchitis, TB Community acquired pneumonia
73
Q

Moxifloxacin, Gemifloxacin

A

Community acquired pneumonia

74
Q

Respiratory fluoroquinolones

A

Levofloxacin, moxifloxacin & gemifloxacin (excellent activity against S.pneumoniae, H.influenzae & M.catarrhalis)

Used in treatment of pneumonia when:

  • First-line agents have failed
  • In the presence of comorbidities
  • Patient is an inpatient
75
Q

Fluoroquinolones - Adverse

A
  • GI distress
  • CNS, rash , photosensitivity
  • Connective tissue problems (avoid in pregnancy, nursing mother, under 18’s) – Black Box Warning!
  • QT prolongation/Torsade (moxifloxaci n, gemifloxacin, levofloxacin) -> use Cotrimoxazole instead
  • High risk of causing superinfections (C.difficile, C albicans, streptococci

Interactions

  • Theophylline, NSAIDs & corticosteroids = enhance toxicity of fluoroquinolones
  • 3rd & 4th generation = raise serum levels of warfarin, caffeine & cyclosporine

Contraindications

  • Pregnancy & nursing mothers
  • Children < 18y (unless benefits outweigh risks)
76
Q

Sulfonamides

A
  • Sulfamethoxazole, Sulfadiazine, Sulfasalazine
  • Structural analogs of p-aminobenzoic acid (PABA)
  • Bacteriostatic against Gram-positive & Gram-negative organisms

MOA

  • Inhibit bacterial folic acid synthesis
  • Synthetic analogs of PABA (p-amino-benzoic acid)
  • Competitive inhibitors (& substrate) of dihydropteroate synthase

Resistance

  • Altered dihydropteroate synthase
  • Decreased cellular permeability
  • Enhanced PABA production
  • Decreased intracellular drug accumulation

Clinical applications

  • Topical agents (ocular, burn infections)
  • Oral agents (simple UTI’s)
  • Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD

PK

  • Oral or topical
  • Can accumulate in renal failure
  • Acetylated in liver. Can precipitate at neutral or acidic pH -> kidney damage
77
Q

Sulfonamides - Adverse

A
  • GI distress, fever, rashes (Stevens-Johnson syndrome), photosensitivity are common
  • Crystalluria (nephrotoxicity)
  • Hypersensitivity reactions
  • Hematopoietic disturbances (esp. patients with G6PD deficiency)
  • Kernicterus (in newborns and infants <2 months); sulfonamides displace bilirubin -> kernicterus

**Drug interactions: **Warfarin, phenytoin and methotrexate can lead to increased plasma levels

**Contraindications: **Newborns & infants < 2 months (kernicterus) – drugs compete with bilirubin for binding sites on albumin

78
Q

Trimethoprim

A
  • Structurally similar to folic acid
  • Bacteriostatic against Gram-positive & Gram-negative organisms

MOA

  • Potent inhibitor of bacterial dihydrofolate reductase
  • Inhibits purine, pyrimidine & amino acid synthesis

Clinical applications

  • UTI’s
  • Bacterial prostatitis
  • Bacterial vaginitis

PK

  • Mostly (80-90%) excreted unchanged through kidney
  • Reaches high concentrations in prostatic & vaginal fluids
79
Q

Trimethroprim - Adverse

A
  • Antifolate effects (contraindicated in pregnancy)
  • Skin rash, pruritus
80
Q

Cotrimoxazole

A
  • Combination of trimethoprim & sulfamethoxazole
  • Bactericidal

**MOA: **

  • Synergistic: inhibition of sequential steps in tetrahydrofolic acid synthesis

Clinical applications

  • Uncomplicated UTI’s (drug of choice)
  • PCP (drug of choice)
  • Nocardiosis (drug of choice)
  • Toxoplasmosis (alternative drug)
  • Respiratory, ear, sinus infections (H.influenzae, M.catarrhalis)

PK

  • Oral admin. generally (can be given IV)
  • Well distributed (including CSF)
81
Q

Cotrimoxazole - Adverse

A
  • Dermatologic (common)
  • GI
  • Hematologic (hemolytic anemia)
  • AIDS patients = higher incidence
  • Contraindicated in pregnancy (esp. 1st trimester)
82
Q

Metronidazole

A
  • Antimicrobial, amebicide & antiprotozoal
  • Activity against anaerobic bacteria (including bacteroides & Clostridium)
  • Bactericidal

Clinical applications

  • Typically indicated for diseases below diaphragm except brain abscess
  • C.difficile infections (drug of choice)
  • Anaerobic or mixed intra-abdominal infections
  • Vaginitis (trichomonas & bacterial vaginosis, G.vaginalis)
  • Brain abscesses
  • H.pylori eradication (in combination)

PK

  • Oral, IV, rectal or topical
  • Wide distribution (including CSF)
  • Elimination = hepatic metabolism
83
Q

Metronidazole - Adverse

A
  • GI irritation, stomatitis, peripheral neuropathy (prolonged use)
  • Headache, dark coloration of urine
  • Leukopenia, dizziness, ataxia (rarer)
  • Opportunistic fungal infections
  • Disulfiram-like effect (avoid alcohol)
  • Use generally not advised in 1st trimester
84
Q

Nitrofurantoin

A
  • Bacteriostatic & bactericidal
  • Active against many Gram-positive and Gram-negative bacteria

MOA

  • Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA
  • Slow emergence of resistance and no cross-resistance

**PK: **Rapid elimination (only achieves adequate concentrations in urine)

85
Q

Nitrofurantoin: Adverse & contraindications

A

Adverse Effects

  • Anorexia, nausea & vomiting.
  • Neuropathies, hemolytic anemia (G6PD deficient patients)

Contraindications

  • Significant renal insufficiency
  • Pregnancy at term (38-42 weeks) but safe prior to 38 w
  • Infants <1 month (risk of hemolytic anemia)

Pharm S2015 (47 decks)

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