[3S] Sulfonamides, Trimethoprim & Quinolones Flashcards
(119 cards)
1
Q
Antifolate Drugs
A
● Sulfonamides
● Trimethoprim
● Trimethoprim-Sulfamethoxazole mixtures
2
Q
MOA
- Inhibit dihydropteroate synthase and folate production.
- Bacteriostatic when given alone.
- Usually given in combination with trimethoprim or
pyrimethamine.
A
Antifolate drugs
3
Q
One of the earliest and most successful antibiotics ever developed
A
Sulfa drugs
4
Q
SULFONAMIDES
Introduced in 1935 by _______ ______ and marketed as ___________.
A
Gerhard Domagk, Prontosil
5
Q
ANTIFOLATE DRUGS PKINETICS
● Similar to p-aminobenzoic acid (PABA)
● Weakly acid compounds
A
Sulfonamides
6
Q
ANTIFOLATE DRUGS PKINETICS
Modest tissue absorption
A
Sulfonamides
7
Q
ANTIFOLATE DRUGS PKINETICS
Sulfonamides metabolism & excretion
A
M = Liver
E = Urine
8
Q
ANTIFOLATE DRUGS PKINETICS
Triple Sulfa
1) Short-acting
2) Intermediate-acting
3) Long-acting
A
1) Sulfisozaxole
2) Sulfamethosaxole
3) Sulfadoxine
9
Q
ANTIFOLATE DRUGS
Sulfonamides ROA
A
Oral absorbable, Oral non-absorbable, Topical
10
Q
MOA
● Competitive inhibitor of Dihydropteroate synthase and folate production
● Usually given in combination with Trimetophrim or Pyrimethamine
A
Antimetabolites
11
Q
ANTIFOLATE DRUGS MOA
• Bacteriostatic (when given alone)
• Competitive inhibitor of dihydropteroate synthase
• Antimetabolate of PABA
• Act as substrates
• Selective toxicity
A
Sulfonamides
12
Q
ANTIFOLATE DRUGS RESISTANCE MECHANISM
- Plasmid-mediated
- Decreased accumulation of the drug
- Increase production of PABA by bacteria
- Decrease in the sensitivity of dihydropteroate synthase
A
Sulfonamides
13
Q
RESISTANCE MECHANISM
• Some bacteria depends on exogenous sources of folate
• Mutations in the following:
o Overproduction of PABA
o Production of a folic acid synthesizing enzyme that has low affinity for sulfonamides
o Impaired permeability to the sulfonamides
• Antibiotic efflux
A
Antimetabolites
14
Q
Provides synergistic activity because of
sequential inhibition of folate synthesis
Resistance occurs but development is slow.
A
Sulfonamides and Trimethoprim
15
Q
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
• Gram (+)
• Gram (-)
o Klebsiella pneumoniae o Salmonella
o Shigella
o Enterobacter sp.
o Nocardia sp.
o Chalmydia trachomatis
A
Sulfonamides
16
Q
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
• Poor against: anaerobes
• Not active against:
o Ricketssiae
o P. aeruginosa
A
Sulfonamides
17
Q
SULFONAMIDES CLINICAL APPLICATIONS
Simple UTI
A
Oral Triple sulfa & Sulfisoxazole
18
Q
SULFONAMIDES: NON-ABSORBABLE CLINICAL APPLICATIONS
Ocular infection
A
Topical Sulfacetamide
19
Q
SULFONAMIDES: NON-ABSORBABLE CLINICAL APPLICATIONS
Burn infections
A
Topical Mafenide & Silver sulfadiazine
20
Q
SULFONAMIDES: NON-ABSORBABLE CLINICAL APPLICATIONS
● Ulcerative colitis (oral)
● Rheumatoid arthritis (oral)
● Enteritis
● Other Inflammatory Bowel Diseases (IBDs)
A
Sulfasalazine
21
Q
SULFONAMIDES: NON-ABSORBABLE CLINICAL APPLICATIONS
Effective in the treatment of bacterial conjunctivitis; considered to be second-line
A
Sodium Sulfacetamide
22
Q
ANTIFOLATE DRUGS TOXICITIES
Common toxicity of sulfonamides
A
Hypersensitivity
23
Q
ANTIFOLATE DRUGS TOXICITIES
• Hypersensitivity
o Skin rash & fever (common)
o Exfoliative dermatitis (rare)
o Polyarteritis nodosa (rare)
o Stevens-Johnson syndrome (rare)
o Cross-allergenicity
A
Sulfonamides
24
Q
ANTIFOLATE DRUGS TOXICITIES
Gastrointestinal
o Nausea, vomiting, & diarrhea
o Mild hepatic dysfunction
o Hepatitis (rare)
A
Sulfonamides
25
ANTIFOLATE DRUGS TOXICITIES
Nephrotoxicity
o Crystalluria and hematuria
Sulfonamides
26
ANTIFOLATE DRUGS TOXICITIES
Kernicterus (3rd trimester of pregnancy)
Sulfonamides
27
ANTIFOLATE DRUGS TOXICITIES
Hematotoxicity (Hematopoietic Disturbances)
○ Rare
○ Granulocytopenia
○ Thrombocytopenia
○ Aplastic anemia
○ Leukemoid reactions
○ May provoke acute hemolysis in G6PD patients
Sulfonamides
28
ANTIFOLATE DRUGS PKINETICS
● Structurally similar to folic acid
● Weak base
Trimethoprim
29
ANTIFOLATE DRUGS PKINETICS
● Trapped in acidic environments
● High conc: prostatic and vaginal fluids
Trimethoprim
30
ANTIFOLATE DRUGS PKINETICS
Trimethoprim excretion
Urine
31
ANTIFOLATE DRUGS
Trimethoprim ROA
PO, IV
32
ANTIFOLATE DRUGS MOA
• Bactericidal (with sulfamethoxazole)
• Selective inhibitor of bacterial dihydrofolate reductase
Trimethoprim
33
ANTIFOLATE DRUGS RESISTANCE MECHANISM
1. Production of dihydrofolate reductase that has reduced affinity for the drug
2. Reduced cell permeability
3. Overproduction of dihydrofolate reductase
4. Production of an altered reductase with reduced drug binding
Trimethoprim
34
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
Acute UTIs
Oral Trimethoprim
35
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
o P. jirovecii
o UTIs
o Prostatitis
o Shigella
o Salmonella
o Nontuberculous mycobacteria
Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)
36
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
Effective against most Staphylococcus aureus strains (MRSA) and respiratory tract pathogens such as Haemophilus sp., Moraxella catarrhalis, and K pneumoniae (but not Mycoplasma pneumoniae)
Trimethoprim
37
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
Commonly used for the treatment of uncomplicated skin and soft tissue infections
Trimethoprim
38
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
- Moderately severe to severe pneumocystis pneumonia
- G(-) bacteremia
- MDR: Enterobacter & Serratia, Shigellosis, or Typhoid
- Preferred alternate therapy for serious Listeria infections
IV Trimethoprim-Sulfamethoxazole
39
ANTIFOLATE DRUGS CLINICAL APPLICATIONS - TRIMETHOPRIM
Used in the treatment of toxoplasmosis
Oral Pyrimethamine with Sulfonamide
40
TRIMETHOPRIM CLINICAL APPLICATIONS
○ Aka folinic acid
○ 10 mg orally each day should be administered
to minimize bone marrow suppression seen with pyrimethamine
Leucovorin
41
ANTIFOLATE DRUGS TOXICITIES
Megaloblastic anemia, Leukopenia, & Granulocytopenia
Trimethoprim
42
ANTIFOLATE DRUGS TOXICITIES
• HIV patients
o Fever
o Rashes
o Leukopenia
o Diarrhea
• Mild elevation of blood creatinine
Trimethoprim
43
ANTIFOLATE DRUGS ROA
TMP-SMX ROA
PO, IV
44
ANTIFOLATE DRUGS MOA
● Bactericidal
● Sequential blockade of folate synthesis
TMP-SMX
45
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
• Urinary tract
• Respiratory
• Ear
TMP-SMX
46
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
Sinus infections caused by
o H. influenzae
o M. catarrhalis
TMP-SMX
47
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
DOC
o Pneumocystis pneumonia o Toxoplasma
o Nocardiosis
TMP-SMX
48
ANTIFOLATE DRUGS CLINICAL APPLICATIONS
Treatment of infections
o MR staphylococci
o L. monocytogenes
TMP-SMX
49
ANTIFOLATE DRUGS TOXICITIES
● Nausea
● Vomiting
● Drug fever
● Vasculitis
● Renal damage
● CNS disturbances
TMP-SMX
50
ANTIFOLATE DRUGS TOXICITIES
HIV: Fever Rashes Leukopenia Diarrhea
Trimethoprim & TMP-SMX
51
SULFONAMIDES: NON-ABSORBABLE CLINICAL APPLICATIONS
Can cause metabolic acidosis
Mafenide Acetate & Silver Sulfadiazine
52
SULFONAMIDES: ORAL ABSORBABLE AGENTS CLINICAL APPLICATIONS
● P. jirovecii pneumonia
● Toxoplasmosis
● Nocardiosis
Sulfamethoxazole
53
SULFONAMIDES: ORAL ABSORBABLE AGENTS CLINICAL APPLICATIONS
First line for Acute Toxoplasmosis
Sulfadiazine + Pyrimethamine
54
SULFONAMIDES: ORAL ABSORBABLE AGENTS CLINICAL APPLICATIONS
● Marketed in some countries
● Second-line antimalarial agent
Sulfadoxine + Pyrimethamine
55
DNA GYRASE INHIBITORS PKINETICS
Originally developed because of their gram-negative aerobic coverage (with gram+ coverage as well)
Fluoroquinolones
56
DNA GYRASE INHIBITORS PKINETICS
Impaired absorption when combined with antacids, divalent, and trivalent cations
Fluoroquinolones
57
DNA GYRASE INHIBITORS PKINETICS
Fluoroquinolones excretion
Both = Dela & Gemi
Renal (tubular/glomerular)
Liver = Moxi
58
DNA GYRASE INHIBITORS PKINETICS
Long half-lives permit once-a-day dosing
○ Levofloxacin
○ Gemifloxacin
○ Moxifloxacin
59
DNA GYRASE INHIBITORS MOA
• Interfere with bacterial DNA synthesis
o Topoisomerase II (relaxation)
o Topoisomerase IV (separation)
• Bactericidal
• Exhibit post-antibiotic effects
Fluoroquinolones
60
DNA GYRASE INHIBITORS MOA
Prevents the relaxation of positively charged supercoiled DNA that is required for normal transcription and replication
Topoisomerase II (DNA gyrase)
61
DNA GYRASE INHIBITORS MOA
Interferes with separation of replicated
chromosomal DNA into the respective
daughter cells during cell division
Topoisomerase IV
62
DNA GYRASE INHIBITORS MOA
Primary target for gram negative
DNA Gyrase
63
DNA GYRASE INHIBITORS MOA
Primary target for gram positive
Topoisomerase IV
64
Fluoroquinolone Resistance Mechanism
1. Mutation / Change permeability
2. Efflux pumps
3. Changes in porin
4. Changes in sensitivity (point mutations)
65
DNA GYRASE INHIBITORS RESISTANCE MECHANISM
Resistant organism appears in about every 107-109
o Staphylococci
o P. aeruginosa
o S. marcesens
66
DNA GYRASE INHIBITORS RESISTANCE MECHANISM
Emerged rapidly for 2nd generation:
o C. jejuni and gonococci
o Gram (+) cocci (MRSA)
o Pseudomonas and Serratia
Fluoroquinolones
67
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Urogenital and gastrointestinal tract infection
• Atypical and intracellular pathogens
Fluoroquinolones
68
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gr (+) bacteria
• Gram (-) organisms
o Gonococci
o E. coli
o K. pneumoniae
o C. jejuni
o Enterobacter
o P. aeruginosa o Salmonella
o Shigella
Fluoroquinolones
69
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Bacterial diarrhea
• Meningococcal carriers
• Prophylaxis of bacterial infections w/ neutropenia
Fluoroquinolones
70
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
Effectiveness is variable due to resistance
o Respiratory tract
o Skin and soft tissue infection
Fluoroquinolones
71
DNA GYRASE INHIBITORS TOXICITIES
Fluoroquinolones most common toxicity
Gastrointestinal distress
72
DNA GYRASE INHIBITORS TOXICITIES
• Occasionally: headache, dizziness, insomnia, skin rash or abnormal LFTs
• Tendinitis and tendon rupture
• Superinfection caused by C. albicans and streptococci
Fluoroquinolones
73
DNA GYRASE INHIBITORS TOXICITIES
Photosensitivity
Lomefloxacin, Pefloxacin, Sparfloxacin
74
DNA GYRASE INHIBITORS TOXICITIES
• Temporary to Permanent Peripheral Neuropathy
• Increase levels of theophylline and other methylxanthines
Fluoroquinolones
75
DNA GYRASE INHIBITORS TOXICITIES
• May damage growing cartilage and cause arthropathy
• Avoid in pregnancy
Fluoroquinolones
76
DNA GYRASE INHIBITORS PKINETICS
Derived from nalidixic acid (earliest)
1st Gen - Norfloxacin
77
DNA GYRASE INHIBITORS PKINETICS
• Common pathogens that cause UTI
• Does not achieve adequate plasma levels for use in systemic infections
• Oral bioavailability: 80%
1st Gen - Norfloxacin
78
DNA GYRASE INHIBITORS PKINETICS
Norfloxacin excretion
Renal
79
DNA GYRASE INHIBITORS PKINETICS
Fluoroquinolones ROA
PO
80
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
Least active of the fluoroquinolones against both gram negative and gram positive organisms
1st Gen - Norfloxacin
81
DNA GYRASE INHIBITORS PKINETICS
• Synthetic fluorinated derivatives
• Oral bioavailability: 70%
2nd Gen - Ciprofloxacin
82
DNA GYRASE INHIBITORS PKINETICS
Ciproflaxin excretion
Renal
83
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gram (-): greater activity
o P. aeruginosa
• Gram (+) cocci
• Gonococcus
• Mycobacteria
• MSSA
• Atypical organisms (M. pneumoniae)
• N. gonorrhea (single oral doses)
o Alternative to 3rd generation cephalosporin
• Anthrax
2nd Gen - Ciprofloxacin
84
DNA GYRASE INHIBITORS PKINETICS
Oral bioavailability: 95%
2nd Gen - Ofloxacin
85
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gram (-): greater activity
• Gram (+) cocci
• Gonococcus
• Mycobacteria
• MSSA
• Atypical organisms (M. pneumoniae)
• Will eradicate accompanying organisms like Chlamydia (7 day course)
o Urethritis
2nd Gen - Ofloxacin
86
DNA GYRASE INHIBITORS PKINETICS
• Synthetic fluorinated derivatives
• Oral bioavailability: 95%
3rd Gen - Levofloxacin
87
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Slightly less active against gram (-)
• Greater activity against gram (+) cocci
• Streptococci
• S. pneumoniae
• Staphylococci
• MRSA
• MSSA
• Some strains of enterococci
3rd Gen - Levofloxacin & Gatifloxacin
88
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Community-acquired pneumonia
• Atypical pneumonia (M. pneumoniae)
• Anthrax prophylaxis
3rd Gen - Levofloxacin
89
DNA GYRASE INHIBITORS TOXICITIES
QT Prolongation
3rd Gen - Levofloxacin & Gatifloxacin
4th Gen - Moxifloxacin & Gemifloxacin
90
DNA GYRASE INHIBITORS PKINETICS
Levofloxacin excretion
Renal
91
DNA GYRASE INHIBITORS PKINETICS
Gatifloxacin excretion
Renal
92
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
Gram (+)
o S pneumoniae
o Some staphylococci
3rd Gen - Gatifloxacin
93
DNA GYRASE INHIBITORS TOXICITIES
• QT prolongation
• Hypoglycemia when given with oral
hypoglycemic agents
3rd Gen - Gatifloxacin
94
DNA GYRASE INHIBITORS PKINETICS
Sparfloxacin excretion & elimination
• Excretion: renal
• Eliminated partly by hepatic metabolism and biliary excretion
95
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Enhanced activity against anaerobes
• Gram (+) organisms
• Penicillin-resistant pneumococci
3rd Gen - Sparfloxacin
96
DNA GYRASE INHIBITORS TOXICITIES
• Risk for cardiac arrhythmia
• Photosensitivity
Sparfloxacin
97
DNA GYRASE INHIBITORS PKINETICS
• Broadest spectrum
• Oral bioavailability: >85%
4th Gen - Moxifloxacin
98
DNA GYRASE INHIBITORS PKINETICS
Moxifloxacin elimination
Eliminated partly by hepatic metabolism and biliary excretion
99
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
Enhanced activity against anaerobes
4th Gen
100
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gram (+)
o S pneumoniae
o Some staphylococci
• Gram (-) organisms
4th Gen - Moxifloxacin & Trovafloxacin
101
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Anaerobic bacteria
• Lacks appreciable activity against:
o P. aeruginosa
4th Gen - Moxifloxacin
102
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Used in meningococcal carrier state
• Tuberculosis
• Neutropenia prophylaxis
4th Gen - Moxiflaxocin
103
DNA GYRASE INHIBITORS PKINETICS
Broadest spectrum
4th Gen
104
DNA GYRASE INHIBITORS PKINETICS
Trovafloxacin elimination
Eliminated partly by hepatic metabolism and biliary excretion
105
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Prophylactic management: neutropenic patients
4th Gen - Trovafloxacin
106
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gram (+)
• Gram (-) organisms
• Anaerobic bacteria
• Used in meningococcal carrier state
• Tuberculosis
4th Gen - Trovafloxacin & Moxifloxacin
107
DNA GYRASE INHIBITORS TOXICITIES
Hepatotoxic potential
4th Gen - Trovafloxacin
108
DNA GYRASE INHIBITORS PKINETICS
• Broadest spectrum
• Oral bioavailability: 70%
4th Gen - Gemifloxacin
109
DNA GYRASE INHIBITORS PKINETICS
Gemifloxacin excretiom
Renal & Nonrenal
110
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gram (+)
o S. pneumoniae
o Some staphylococci
• + Azithromycin o Lower RTIs
4th Gen - Gemifloxacin
111
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
Gram (+)
o S. pneumoniae
o Some staphylococci
o Pneumococci
o Beta-hemolytic streptococci
o MSSA
o MRSA
4th Gen - Delafloxacin
112
DNA GYRASE INHIBITORS CLINICAL APPLICATIONS
• Gram (-): similar to ciprofloxacin
o P. aeruginosa
• In vitro activity against anaerobes but not proven
4th Gen - Delafloxacin
113
DNA GYRASE INHIBITORS ANTIBACTERIAL ACTIVITY
T/F: Most exist in zwitterionic forms in vivo except delafloxacin. Anionic at neutral pH & no charge at acidic pH.
T
114
DNA GYRASE INHIBITORS
Modest activity against anaerobic bacteria
4th Gen - Moxiflaxocin
115
DNA GYRASE INHIBITORS
Most active agent of this group against gram-negative organisms particularly P aeruginosa
2nd Gen - Ciprofloxacin
116
DNA GYRASE INHIBITORS
● L-isomer of ofloxacin
● Has greater activity than ciprofloxacin against
gram-positive organisms especially Streptococcus pneumoniae
3rd Gen - Levofloxacin
117
DNA GYRASE INHIBITORS
Minimum inhibitory concentrations fourfold to eightfold higher than those of ciprofloxacin
1st Gen - Norfloxacin
118
DNA GYRASE INHIBITORS
Has threefold to fivefold more potent in vitro activity against most gram-positive organisms including pneumococci, beta-hemolytic streptococci, MSSA, and MRSA
4th Gen - Delafloxacin
119
Occasionally used as part of a treatment regimen for tuberculosis and nontuberculous mycobacterial infection (same goes for ciprofloxacin and moxifloxacin)
Levofloxacin
