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Flashcards in Pharm Deck (102):
1

Triple Sulfa

Properties:
- rapidly absorbed
- rapidly excreted
- short acting

Single dosage contains equal amounts of 3 different sulfa drugs

Reduces incidence of crystalluria

2

Sulfisoxazole

Properties:
- highest urine solubility
- short acting

Most commonly used single sulfa

3

Sulfamethoxazole

Properties:
- urine solubility less than sulfisoxazole
- intermediate acting

Usually administered as fix-ed ratio combination with trimethoprim

4

Sulfacetamide

Properties:
- topical use for trachoma, 30% solutions have a pH of 7.4, which makes them non-irritating

5

Silver sulfadiazine

Properties:
- topical use only
- elemental silver has antibacterial activity

Prophylaxis of burn patients, little or no pain

6

Sulfasalazine

Properties:
- Split by intestinal flora to yield 5-amino-salicylate and sulfapyridine
- substitution on N1 nitrogen

Used in the treatment of ulcerative colitis and other inflammatory bowel disease, salicylate has therapeutic value

7

Sulfadoxine and Pyrimethamine

Properties:
- rapidly absorbed
- ultra long half life (~9 days)

Used for Chloroquine-resistant falciparum malaria

High incidence of dermatitis reactions

8

Sulfadiazine and Pyrimethamine

Properties:
- rapidly absorbed
- intermediate half life (18 hrs)

Used in treatment of toxoplasmosis

9

Adverse effects of Sulfonamides

1. drug allergy (rashes, eosinophilia, fever, Stevens-Johnson syndrome)
2. renal toxicity (crystalluria)
3. kernicterus (displacement of bilirubin from albumin)
4. displace drugs from albumin binding sites and/or decrease clearance (oral anticoagulants, uricosuric agents, methotrexate)
5. hemolytic anemia in individuals with G6PDH deficiency

10

Therapeutic Uses of Sulfonamides

- UTI's (E. coli)
- Nocardiosis
- Chlamydial infections, including trachoma

11

Mechanism of action of sulfonamides

Competitive inhibitor of pteroate synthetase

reaction: pteridine + p-aminobenzoic acid (PABA) --> pteroic acid + glutamic acid

absolute selective toxicity

bacteriostatic

12

Mechanism of action of trimethoprim/pyrimethamine

Competitive inhibitor of dihydrofolate reductase (DHFR)

reaction: dihydrofolate (DHF) --> tetrahydrofolate (THF)

absolute selective toxicity

bacteriostatic

Brand names: Bactrim, Septra
Generic form: cotrimoxazole

13

Advantages of SMZ-TMP

- increased potency
- increased spectrum
- decreased incidence of resistance

14

Therapeutic uses of SMZ-TMP

- UTI's
- respiratory and ear infections (H. influenzae and Strep pneumo infections)
- Shigella and Salmonella
- Pneumocystic jiroveci pneumonia
- Toxoplasmosis and Plasmodial infections

15

Adverse Effects of DHFR inhibitors (trimethoprim, pyrimethamine)

- crystalluria
- megaloblastic anemia (pregnancy, nutrition deficit, etc)

16

Mechanism of action of fluoroquinolones

- inhibit bacterial DNA gyrase (topoisomerase II)
- inhibit topoisomerase IV in gram positive organisms

- bactericidal
- relatively selectively toxic

17

Ciprofloxacin

Brand name: Cipro
Half life: 3-4 hrs
May interfere with metabolism of theophylline and warfarin

18

Levofloxacin

Unlike other fluoroquinolones, widely distributes into tissues, bone, AND CNS
Half life: 5 hrs
ADR: QT prolongation
May interfere with metabolism of theophylline and warfarin

19

Trovafloxacin

Not used anymore because of hepatic toxicity

20

Structural features of fluoroquinolones

- Fluoride on C6 - confers resistance
- Halogen on C8 leads to phototoxicity

21

Resistance mechanisms against fluoroquinolones

- point mutation of the A subunit of DNA gyrase, decreasing affinity of drug for gyrase

- efflux pump (Staph aureus, Pseudomonas aeruginosa, Mycobacteria)

22

Pharmacokinetics of fluoroquinolones

- orally active
- widely distributed into tissues, including bone; but not CNS except for Levofloxacin
- elimination: primarily renal, of which 20% are metabolites. exception: Moxifloxacin (feces)

23

Moxifloxacin

Unlike other fluoroquinolones, non-renal elimination. Eliminating is through feces.
Half life: 10 hrs
ADR: QT prolongation
Can target anaerobic organisms

24

Adverse effects of fluoroquinolones

GI (nausea, abdominal discomfort, vomiting, diarrhea)
CNS (headache, dizziness, agitation, insomnia, rarely seizures)
Allergy (rash, pruritis)
Photosensitivity
Anthropathy (damage to cartilage of weight bearing bones in adults)
Tendinitis (with concomitant steroid use)
Crystalluria (particularly at alkaline pH)
QT prolongation (risk for arrhythmias)

25

Drug Interactions of fluoroquinolones

- actacids and mineral supplements reduce oral absorption
- chelates with di and trivalent ions like magnesium, aluminum, zinc, iron. Sucralfate, a sugar derivative, contains alumni ions.
- Ciprofloxacin and Levofloxacin may interfere with metabolism of theophylline and warfarin

26

Therapeutic uses of fluoroquinolones

Urinary tract: E. coli, K. pneumoniae, Proteus, Pseudomonas aeruginosa
Prostatitis
STD's: N. gonorrhea
GI: Shigella, Salmonella, coliform infections
Resp: H. influenzae, CF, TB, anthrax
Bone/joints
Anaerobic organisms - Moxifloxacin

27

Methenamine

- urinary tract disinfectant
- spontaneously decomposes into ammonium and formaldehyde when placed in acidic water solution (must maintain urinary pH at 5.5 or less)
- safe because rate of dissociation is slow
- formaldehyde denatures proteins on the outside of an organism

28

Adverse reactions of Methenamine

- GI upset
- bladder irritation
- contraindicated in hepatic insufficiency because of ammonia production
- organic acids contraindicated in renal insufficiency because of crystalluria
- drug interaction with sulfas - formaldehyde reacts with sulfa, producing insoluble product

29

Nitrofurantoin

- Bacteriostatic against E. coli
- Rapidly excreted (half-life = 20-60 min)
- Resistance rarely develops
- Oral
- Okay to use in pregnancy

30

Nitrofurantoin adverse reactions

- NVD
- allergy (fever, chills, allergic pneumonitis in the elderly)
- neurological (vertigo, headache, nystagmus; high dose - polyneuropathy of motor and sensory nerves)
- hemolytic anemia in G6PDH deficient individuals
- colors urine brown

31

Phenazopyridine

Urinary tract analgesic, not antimicrobial
Given in early treatment of UTI
Alleviates dysuria, frequency, urgency, and burning
Colors urine orange-red

32

Mechanism of action of fosfomycin

Inhibits phosphoenolpyruvate transferase, important in muramic acid monomer synthesis for the peptidoglycan cell wall

reaction: NAG + phosphoenolpyruvate --> NAM

33

Fosfomycin

- rapidly absorbed from GI tract and excreted unchanged, achieving high concentrations in the urine
- approved for single dose therapy for uncomplicated UTI
- diarrhea = most common side effect
- no effect on fetus if given to pregnant woman
- expensive

34

Cephalosporin Structure

- Structure: 6 membered ring instead of 5

35

Carbapenem Structure (Imipenem, Meropenem, Doripenem, Ertapenem)

- Structure: Sulfur is no longer part of ring structure, it is outside of it

36

Monobactam Structure (Aztreonam)

- Structure: only one beta-lactam ring --> limited use

37

Mechanism of beta-lactam

- irreversibly inhibits the crosslinking of peptidoglycans (mimics D-ala-D-ala) in bacterial cell walls
- competitive inhibitor

- absolute selective toxicity
- bactericidal (osmotic pressure)

- requires growing culture
- activates autolysins in some organisms
bacteria are most vulnerable when undergoing cell division; they use autolysins to open cell wall and reseal during division. beta-lactam exploits this, contributing to bactericidal activity.

38

Mechanisms of resistance to beta-lactams

- beta-lactamase (chromosomal or plasmid) which breaks the beta-lactam ring, rendering drug inactive
- reduced binding to Penicillin binding proteins (MRSA)
- down-regulation of porins, leading to decreased access to gram negative organisms
- increased efflux pumps found in some gram negative organisms

39

Types of Penicillins

1. Penicillin G (parenteral) and Penicillin V (oral) - broad spectrum on gram positive organisms such as: meningococci, penicillin-susceptible pneumococci, streptococci, non-beta-lactamase producing staph, syphillis, clostridia, actinomyces

2. Acid-stable or Antistaphylococcal penicillins such as methicillin (not used anymore), oxacillin (IV), nafcillin (IV), cloxicillin, dicloxacillin (oral), and isoxazolyl penicillins aka flucloxacillin - act on gram positive penicillinase producing Staph aureas.

3. Extended-spectrum penicillins such as Amoxicillin (oral) and Ampicillin (IV) - act on both gram positive and negative bacteria such as Proteus marbles, H influenza, E. coli, Listeria monocytogenes, Salmonella, Shigella, Enterococcus faecalis

4. Antipseudomonal or ureido penicillins such as Piperacillin - act on gram negative bacteria such as Pseudomonas aeruginosa, Klebsiella app, Serrate marcescens

40

Penicillin G

Penicillin G/V:
broad spectrum on gram positive organisms such as: meningococci
penicillin-susceptible pneumococci
streptococci
non-beta-lactamase producing staph
syphillis
clostridia (Clostridium perfringens)
N. gonorrheae
actinomyces
bacillus anthracis
cornyebacterium diptheriae

41

Ampicillin

Orally active
Gram pos: Listeria monocytogenes
Gram neg: E. coli, H. influenzae, Proteus mirabilis, Salmonella typhi

42

Antipseudomonal penicillins such as Carbenicillin, Ticarcillin, Piperacillin

Gram neg: Enterbacter sp, E. coli, Proteus, H. influenza, Pseudomonas aeruginosa

43

Pharmacokinetics of beta-lactams

- Distributes well
- Time-dependent killing: requires around the clock dosing, making sure plasma levels are >MIC for at least 70% of every 24 hours
- Excreted unchanged by glomerular filtration and active secretion into tubular fluid
- Short half-lives (0.5 to 1 hr)
- Penetrates into CNS only in bacterial meningitis (inflamed meninges are more permeable to penicillin, permitting rapid penetration of the drug into the CSF. However, meninges heal rather quickly and if penicillin is given late, less penicillin will enter the CNS, some organisms will remain, and leave the patient vulnerable to reinfection

Orally active: Penicillin V, Amoxicillin, Isoxozolyl

IV only: Piperacillin, Penicillin G, Methicillin, Ampicillin

44

Adverse Effects of Penicillins

- Generally safe
- Most serious adverse effect are hypersensitivities (allergies). Penicillin cross reacts with other beta lactamases so if patient as anaphylactic reaction to penicillin, do not give another beta-lactam
- Ampicillin use can produce a maculopapular rash that is NOT allergic
- Methicillin use can induce nephritis
- Neurotoxicity may provoke seizures in high concentrations (interfere with GABA receptor)
- Diarrhea may result due to disruption of normal balance of intestinal flora
- Ticarcillin use may result in decreased platelet aggregation
- Augmentin (amoxicillin and clavulanic acid) may result in a false positive for urinary glucose
- Cation toxicity (sodium is formulated with the actual penicillin molecule during drug development) - ampicillin, ticarcillin, piperacillin

45

Adjunct medications to beta-lactams

- Probenecid (inhibits renal tubular secretion of penicillins)
- Beta lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam. NOT antibacterial, only inhibits beta lactase

46

Cephalosporins

3rd generation are generally more resistant to beta lactamases than penicillins are

47

Adverse effects of Cephalosporins

Similar to penicillin: generally safe except occasional hypersensitivity reaction

Unique:
- Cefamandole and Cefoperazone can create a Disulfiram-like effect when taken with alcohol (vomiting, cardiac changes, nausea, etc)
- They can also create risk of hypoprothrombinemia (deficiency of prothrombin, which results in impaired blood clotting, leading to increased risk for bleeding)

48

First generation cephalosporin

Spectrum aimed mostly at gram positive bacteria like pen G

Cafazolin used to treat bone infections and prophylactically at a one time dose before surgery to prevent skin infection

49

Second generation cephalosporin

Similar to first generation (gram positive bacteria), but broader spectrum to include H. influenza, E. coli, Neisseria spp

Cefoxitia - for mixed infections containing both gram neg and pos bacteria

50

Third generation cephalosporin

Given parenterally

Very effective against gram neg (Neisseria spp, H. influenza), somewhat effective against gram pos BUT NOT LISTERIA (Listeria = ampicillin)

Also effective as empiric therapy of sepsis of unknown origin in both immunocompetent and immunocompromised hosts

Ceftriaxone - gets into CNS very well, relatively long half life (~7 hrs), parenterally

Ceftazidime - antipseudomonal

51

Fourth generation cephalosporin

Wide spectrum against both gram pos and neg, used first for treatment of septicemia or treatment of infection for immunosuppressed until diagnosis can be made

Cefepime - antipseudomonal

52

Carbapenems

Imipenem, Meropenem

Wide spectrum: gram pos/neg, aerobic/anaerobic, cocci/bacilli

Given parenterally only

Penetrates fluids well, including CSF in the absence of meningitis

Adverse effects: NVD, skin rashes, infusion site reactions; Imipenem is convulsant at high doses

53

Therapeutic uses of Carbapenems

- treatment of hospital-acquired resistant infections
- mono therapy for septicemia, respiratory tract infections, GU tract infections
- given to patients who cannot tolerate cephalosporins
- Meropenem is used to treat bacterial meningitis

54

Monobactam

Aztreonam

Spectrum is like aminoglycosides: gram negative aerobic bacteria

Given IM or IV

Filtered and secreted by the kidney, enters the CNS without inflammation

Injection site reactions ex) pain

Used as an alternative to aminoglycosides, penicillins, and cephalosporins

55

Vancomycin

- large tricyclic glycopeptide
- effective against gram pos bacteria only: MRSA, MRSE, strep pneumo, strep viridians, enterococcus, clostridium, listeria monocytogenes

56

Mechanism of action of Vancomycin

physically binds to the D-ala-D-ala on NAM and NAG --> inhibits cell wall synthesis

bactericidal

57

Vancomycin resistance

Bacteria can acquire vancomycin resistance by acquiring 9 genes on a transposable element present on a plasmid. Bacteria with this plasmid can change D-ala-D-ala to D-ala-D-lactate. Therefore, vancomycin can't bind.

58

Pharmacokinetics of Vancomycin

- must be administered parenterally (large molecular weight, highly charged)
- distributes well into pleural, pericardial, synovial, and ascitic fluids
- does not enter CNS unless there is inflammation - may require intrathecal administration
- filtered unchanged in the urine (not secreted)

59

Adverse effects of Vancomycin

- must administer slowly because it causes release of histamine, causing hypotension and erythema of face and upper trunk (usually give anti-histamine as pre-treatment to minimize this problem) --> Red Man Syndrome
- phlebitis
- ototoxic
- nephrotoxic

60

Therapeutic uses of Vancomycin

- MRSA causing sepsis or endocarditis
- vancomycin + gentamicin for enterococcal endocarditis in patient with serious penicillin allergy
- vancomycin + cefotaxime, ceftriaxone, or rifampin for highly penicillin-resistant pneumococcal meningitis
- resistant strains of Enterococcus faecalis and faecium have emerged
- no longer drug of choice for C. difficile pseudomembranous colitis - oral vancomycin used to be given but fear of developing resistance --> use metronidazole now

61

Macrolides

Erythromycin, Clarithromycin, Azithromycin

62

Mechanism of action of Macrolides

2 effects:
- bind reversibly to the P site on the 50S ribosomal subunit, causes the dissociation of the peptide t-RNA from the ribosome
- inhibits the translocation step: movement of peptide t-RNA from the acceptor to the donor site

63

Macrolide resistance

- decreased affinity of binding site because of methylation of adenine nucleotide in ribosomal RNA
- decreased penetration or increased efflux
- enzymatic inactivation of macrolide by an esterase

64

Spectrum of Macrolides

Erythromycin:
- gram positives (strep, staph, corynebacteria)
- intracellular organisms (mycoplasma, legionella, chlamydia spp, mycobacteria)
- syphillis for patients allergic to pen G

Clarithromycin: similar to erythromycin and active against H. influenza

Azithromycin: less active against strep and staph
- preferred treatment for Chlamydia trachoma's - single dose of 1 gram

65

Pharmacokinetics of Macrolides

- well absorbed orally
- given as esters or in enteric coated tablet to protect against stomach acid
- well distributed with high intracellular concentrations (azithromycin is the highest)
- does not penetrate CNS

66

Metabolism and Excretion of Macrolides

Erythromycin: extensively metabolized by CYP 450 dependent enzymes

Clarithromycin: has an active metabolite, 14-hydroxyclarithromycin

Excreted in urine and bile - biliary excretion is more important because Macrolide molecules are rather large

67

Adverse Effects of Macrolides

Erythromycin:
- epigastric distress (stimulates gastric motilin receptor)
- cholestatic jaundice
- ototoxicity at high doses
- drug interactions - inhibits the metabolism of many drugs like warfarin, cyclosporine, theophylline, digoxin

Clarithromycin: similar to erythromycin

Azithromycin - does not inhibit P450 dependent drug metabolism, mostly secreted in the bile

68

Clindamycin

Not too different from macrolides, just different in structure
Lincosamidine antibiotic
Binds to 50S ribosomal subunit and interferes with translocation
Bacteriostatic

69

Clindamycin resistance

- decreased penetrability
- decreased affinity to binding site of 50S subunit because of methylation of adenine nucleotide in ribosomal RNA
- enzymatic inactivation by an O-nucleotidyl transferase (seen in Staph aureus)

70

Clindamycin spectrum

- Strep
- Anaerobes like Bacteroides, oral anaerobes
- Toxoplasmosis in combination with pyrimethamine
- Topically for rosacea and acne

71

Pharmacokinetics of Clindamycin

- 90% bioavailability
- distributed well into the bone and body fluids, except CNS
- accumulates in macrophages and leukocytes
- crosses the placenta
- over 90% hepatic metabolism via oxidative demethylation to an active metabolite
- biliary excretion

72

Therapeutic uses of Clindamycin

- refractory bone infections
- treatment of anaerobic infections of female GU, pelvic infections, abdominal penetrating wounds
- as a substitute for amoxicillin or penicillin V for acute orofacial infections in situations where the organisms are penicillinase producing
- alternative to penicillin-sensitive patients requiring prophylaxis to prevent endocarditis

73

Adverse effects of Clindamycin

- NVD
- hypersensitivity - rashes/fever
- risk of C. diff
- Neuromuscular junction blockage at high IV doses (inhibits transmission and contraction)

74

Streptogramins and Oxazolidinones

Protein synthesis inhibitors reserved for serious life-threatening infections

--
Group A Streptogramins = macrolactones ex) dalfopristin

Group B Streptogramins = hexadepsipeptides ex) quinupristin

--
Oxazolidinone: Linezolid

75

Quinupristin/Dalfopristin

Always given together. Brand name= Synercid.

76

Mechanism of action of Quinupristin/Dalfopristin

Bind to 50S ribosomal subunit
Together, bactericidal. Separately, bacteriostatic.

Dalfopristin (Group A Streptogramins) inactivates donor and acceptor sites of peptidyltransferase, and induces a conformational change to increase the binding of Quinupristin (Group B Streptogramins) synergy!

Quinupristin prevents the translocation step

77

Quinupristin/Dalfopristin Resistance

- methylation of 23S RNA binding site, prevents binding of quinupristin

- bacterial enzymatic inactivation; particularly dalfopristin

- increased efflux

78

Pharmacokinetics of Quinupristin/Dalfopristin

- must be given IV
- penetrates macrophages and PMNs
- undergoes extensive non-enzymatic conversion to non-active products (does not require P450)
- excretion: 80% bile, 20% urine
- short half lives:
Quinupristin 0.8 hr
Dalfopristin 0.7 hr

79

Adverse effects of Quinupristin/Dalfopristin

- Injection related: pain, inflammation, edema, reactions (incompatible with saline)
- NVD, headache, myalgia, arthralgia
- marked drug reactions because of CYP3A4 (ex) cyclosporine levels should be monitored)

80

Therapeutic use of Streptogramins

Treatment of vancomycin resistant Enterococcus faecium (NOT faecalis)

81

Mechanism of action of Linezolid

Binds to site on 50S subunit similar to chloramphenicol, prevents formation of 70S initiation complex

Resistant strains of S. aureus bind less antibiotic but there is no cross-resistance with other antibiotics

Bacteriostatic

82

Linezolid spectrum of action

Gram positive and anaerobic organisms (similar to vancomycin)
- approved for nosocomial pneumonia, community-acquired pneumonia, skin infections, vancomycin resistant enterococcal infections, MRSA

Has interactions with SSRI's - if taken together can cause serotonin syndrome

83

Tetracyclines

Structure: 4 fused six-membered unsaturated rings

84

Mechanism of action of Tetracyclines

- inhibits protein synthesis by binding to the 30S subunit: blocks access of the amino acyl-t-RNA to mRNA-ribosome complex at the acceptor site
- active uptake mechanisms by susceptible organisms imparts some selective toxicity
- greater affinity of non-host ribosomes since intracellular rickettsiae and chlamydiae are treatable

85

Spectrum of action of Tetracycline

- Broad: both bacteria and Rickettsia are susceptible
- intracellular diseases like Lymes Disease, Mycoplasma pneumonia, Chlamydia, cholera, Ricketssia rickettsia
- bacteriostatic
- similar spectrum to erythromycin - Mycoplasma pneumonia, Chlamydia app, Legionella spp, Ureaplasma, Rickettsiae
- treatment of acne vulgaris and rosacea

86

Tetracycline resistance

- resistance is widespread, transposable, and commonly permanent because multi-drug resistance gene cassettes exist
- most important: active efflux
- enzymatic inactivation
- decreased affinity of target

87

Pharmacokinetics of Tetracycline

- orally active - range from 30% bioavailability for chlortetracycline to 95% for doxycycline
- dairy products and ions chelate tetracyclines and produce a non-absorbable complex
- binds to tissues undergoing calcification like teeth and bones
- penetrates tissues well: high concentrations in the liver and the kidney
- crosses the placenta
- Minocycline has high concentration in tears and saliva , often given to carriers of meningococcus

88

Elimination of Tetracycline

- metabolized to varying extents, especially glucuronide formation
- all undergo enterohepatic circulation and renal excretion except doxycycline glucuronide, which is excreted in bile but does not get reabsorbed; goes out via feces

89

Adverse effects of Tetracycline

- GI distress
- deposition in bone and primary dentition during calcification --> contraindicated in children less than 8 y/o
- hepatotoxic in pregnant women
- phototoxicity
- vestibular disturbance with Minocycline
- Azotemia (abnormally high levels of nitrogen containing compounds like urea, creatinine, etc in the blood; related to insufficient filtering of blood by the kidneys) and Fanconi-like syndrome (disease of proximal renal tubules of the kidney in which glucose, aa, uric acid, phosphate, and bicarbonate are passed into the urine) with outdated preparations

90

Drug interactions with Tetracyclines

- antacids
- increased digoxin toxicity in 10% of patients
- increased Warfarin activity due in part to decreased intestinal flora which produce vitamin K

91

Mechanism of action of Chloramphenicol

- Works in a similar area as macrolides and clindamycin
- interferes with translocation and peptidation, which inhibits formation of the growing peptide chain
- REVERSIBLE binding to site
- NO2 group on benzene ring = very reactive, plays into chloramphenicol's adverse effects

92

Chloramphenicol resistance

- enzymatic conversion to an inactive product via acetylation
- decreased affinity --> cross resistance - changing the binding site so that chloramphenicol can't bind as well also makes the macrolides and clindamycin have decreased affinity for the 50S binding site

93

Spectrum of Chloramphenicol

similar to tetracyclines
- H influenzae
- acute typhoid fever
- Rickettsial infections (Rocky Mountain Spotted fever)
- anaerobic infections

94

Pharmacokinetics of Chloramphenicol

- orally active; can be given parenterally as well
- well distributed; can enter CNS in the absence of inflammation
- crosses the placenta
- extensive metabolism by the host - ultimate product is glucuronide
- excreted in urine

95

Adverse effects of chloramphenicol

- Hematological:
~hemolytic anemia in G6PDH deficiency
~reversible anemia, leukopenia, thrombocytopenia - dose related; occurs during therapy
~irreversible idiosyncratic aplastic anemia; probably allergic in origin ; no immediate solution --> why doctors in the US don't give this drug that much. Since it is allergic in origin, reaction depends on how many times you've been treated with chloramphenicol. The more exposure, the bigger the risk of developing aplastic anemia

- gray baby syndrome: decay of chloramphenicol in neonates is much slower than for older children --> exposure to high concentration for high amounts of time --> mitochondria can no longer utilize oxygen --> baby becomes blue gray, lethargic and does not thrive

- drug interactions because of CYP 450 inhibition: caution in patients on warfarin, phenytoin (anti-seizure med)

96

Therapeutic uses of Chloramphenicols

- anaerobic infections due to Bacteroides fragilis
- Typhoid fever and H. influenzae meningitis when first line therapy fails or cannot be employed
- pneumococcal or meningococcal meningitis in penicillin-allergic patients
- Rickettsial diseases as a substitute for tetracycline

97

Mechanism of Aminoglycosides

- binds to 30S subunit and prevents initiation of protein synthesis
- blocks further translation and causes premature termination
- causes misreading of mRNA codon
- entry across bacterial cell membrane occurs via an active transport system that requires oxygen

98

Aminoglycoside Resistance

- does not affect anaerobes by default (requires oxygen dependent transport system to get into bacterial cell membrane)
- decreased affinity at the 30S subunit binding site
- plasmid associated inactivating enzymes that can acetylate, adenylate, or phosphorylate the aminoglycoside
--> resistance to one class of aminoglycosides does not necessarily confer resistance to all of them:
ex) There is only one acetylation enzyme that does not work very well at inactivating Kanamycin
ex) None of the acetylation, phosphorylation, or adenylation enzymes work well at inactivating Amikacin

99

Spectrum of Aminoglycoside

- Streptomycin - M. tuberculosis
- Gentamicin, Tobramycin, Amikacin - gram neg aerobic bacteria like Pseudomonas
- aminoglycosides are frequently combined with beta-lactams to treat serious, life threatening infections (synergistic - beta lactic increases the permeability of those organisms to aminoglycosides --> get higher amounts of aminoglycosides into the bacteria)

100

Pharmacokinetics of Aminoglycoside

- must be given parenterally
- dose-dependent killing: once a day dose is better than multiple doses throughout the day
- distribution is in the extracellular fluid; does not enter CSF
- crosses the placenta
- concentrated in the renal cortex and endolymph
- dependent on glomerular filtration for elimination; excreted unchanged; no secretion
- therapeutic monitoring

101

Adverse effects of Aminoglycosides

- ototoxicity - can cause problems in either cochlear or vestibular portions of CN 8
- fetal auditory toxicity (contraindicated in pregnancy)
- renal toxicity - not only are aminoglycosides dependent on renal fxn but they can impair it as well - need to monitor
- neuromuscular paralysis - can cause death from paralysis of diaphragm

102

Patient factors affecting dosing of aminoglycosides

- age: renal fxn decreases with age
- obesity: since the drug is water soluble and stays in the extracellular fluid, if you base dosage on weight, you might give incorrect dose since obese person has a lot of fat and a lower proportion of ECF
- renal function
- pregnancy: potential fetotoxic effects
- hepatic function: aminoglycosides are not metabolized so liver function does not have to be considered when dosing someone