[3S] Chemotherapeutic Agents Flashcards
(102 cards)
1
Q
An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria
A
Bactericidal
2
Q
An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the infection; does not kill bacteria
A
Bacteriostatic
3
Q
Drugs with structures containing a beta-lactam ring: includes the penicillins, cephalosporins and carbapenems. This ring must be intact for antimicrobial action
A
Beta-lactam
antibiotics
4
Q
Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins
A
Beta-lactamases
5
Q
Potent inhibitors of some bacterial beta-lactamases used
in combinations to protect hydrolyzable penicillins from
inactivation
A
Beta-lactam inhibitors
6
Q
Lowest concentration of antimicrobial drug capable of
inhibiting growth of an organism in a defined growth medium
A
Minimal inhibitory concentration
(MIC)
7
Q
Bacterial cytoplasmic membrane proteins that act as the
initial receptors for penicillins and other beta-lactam
antibiotics
A
Penicillin binding proteins (PBPs)
8
Q
Chains of polysaccharides and polypeptides that are cross-linked to form the bacterial cell wall
A
Peptidoglycan
9
Q
More toxic to the invader than to the host; a property of useful antimicrobial drugs
A
Selective toxicity
10
Q
Bacterial enzymes involved in the cross-linking of linear
peptidoglycan chains, the final step in cell wall synthesis
A
Transpeptidases
11
Q
First to suggest that a Penicillium mold (now known as (Penicillium chrysogenum) must secrete an antibacterial substance
A
Alexander Fleming
12
Q
Chemotherapeutic Agents
- Production of antibiotic-inactivating enzymes
- Changes in the structure of target receptors
- Increased efflux via drug transporters
- Decreases in the permeability of microbes’ cellular
membrane to antibiotics
A
Microbial Resistance
13
Q
Chemotherapeutic Agents
- Use of adjunctive agents that can protect against antibiotic
inactivation - Use of antibiotic combinations
- Introduction of new (and often expensive) chemical
derivatives of established antibiotics - Efforts to avoid indiscriminate use or misuse of antibiotics
A
Strategies
14
Q
Bacteria
A
Antibacterial
15
Q
Viruses
A
Antiviral
16
Q
Fungi
A
Antifungal
17
Q
Parasites
A
Antiparasitic
18
Q
Major antibiotics that inhibit cell wall synthesis
A
Penicillins & Cephalosporins
19
Q
T/F: More than 50 drugs that act as cell wall inhibitors are currently available
A
T
20
Q
T/F: Not as important as beta-lactam drugs
○ Vancomycin
○ Fosfomycin
○ Bacitracin
A
T
21
Q
Classification
Derivatives of 6-aminopenicillanic acid
Contains a beta-lactam ring structure
Essential for antibacterial activity
A
Penicillin
22
Q
MOA
- Bactericidal
- Prevents bacterial cell wall synthesis by binding to and inhibiting cell wall transpeptidases
- Inhibition of transpeptidase enzyme that act to cross-link linear peptidoglycan chains
- Activation of autolytic enzymes that cause lesions in the bacterial cell wall
A
Penicillin
23
Q
Penicillin Classification
Additional chemical substituents that
confer differences in
A
- Antimicrobial activity
- Susceptibility to acid and enzymatic hydrolysis
- Biodisposition
24
Q
PKINETICS
Vary in resistance to gastric acid
Vary in their oral bioavailability
Polar compounds
Not metabolized extensively
A
Penicillin
25
Penicillin is excreted unchanged in urine via
Glomerular filtration & tubular excretion
26
Penicillin is inhibited by
Probenecid
27
Penicillin PKINETICS
Partly excreted in bile
Ampicillin and Nafcillin
28
Penicillins
* Given intramuscularly
* Long half-lives
* Drug is released slowly
* Cross blood-brain barrier when meninges
are inflamed
Procaine and Benzathine Penicillin G
29
Enzymatic hydrolysis of the beta-lactam ring results in
the lost of antibacterial activity
30
Resistance
○ Penicillinases
○ Formed by most staphylococci and gram (-)
organisms
○ Major mechanism for bacterial resistance
Beta-lactamases
31
Resistance
Inhibitors of this enzymes are used in combination with penicillin to prevent their inactivation
○ Clavulanic acid
○ Sulbactam
○ Tazobactam
32
Resistance
Structural changes in target PBPs:
Methicillin resistance in ________
Penicillin G resistance in _________
staphylococci
pneumococci
33
Penicillin Resistance
T/F: Changes in the porin structure in the outer membrane contribute to resistance by impeding access of penicillin to PBPs. Resistance in some gram (-) rods like P. aeruginosa
T
34
Narrow-spectrum penicillinase-susceptible agents
○ Prototype
○ Parenteral
○ Limited spectrum of activity
○ susceptibility to beta-lactamases
PENICILLIN G
35
Narrow-spectrum penicillinase-susceptible agents
infections caused by
■ Streptococci
■ Meningococci
■ gram (+) bacilli
■ Spirochetes
PENICILLIN G
36
Narrow-spectrum penicillinase-susceptible agents
Penicillin-resistant S. pneumoniae (PRSP) strains
PENICILLIN G
37
Narrow-spectrum penicillinase-susceptible agents
Some strains resistant via production of beta-lactamases
■ S. aureus
■ N. gonorrhoeae
PENICILLIN G
38
Narrow-spectrum penicillinase-susceptible agents
○ drug of choice for syphilis
○ activity against enterococci enhanced by
aminoglycoside
PENICILLIN G
39
Narrow-spectrum penicillinase-susceptible agents
○ Oral
○ Oropharyngeal infections
PENICILLIN V
40
Very-narrow-spectrum penicillinase-resistant agents
Treatment of known or suspected staphylococcal
infections
METHICILLIN (prototype), NAFCILLIN, OXACILLIN
41
Very-narrow-spectrum penicillinase-resistant agents
● Methicillin-resistant S. aureus (MRSA)
● S. epidermidis (MRSE) are resistant to other
members of this subgroup and often to multiple
antimicrobial drugs
METHICILLIN (prototype), NAFCILLIN, OXACILLIN
42
Wider spectrum penicillinase-susceptible agents
● Wider spectrum than pen G
● Susceptible to penicillinases
● Uses similar to pen G
○ Enterococci
○ L. monocytogenes
○ E. coli
○ P. mirabilis
○ H. influenzae
○ M. catarrhalis
AMPICILLIN and AMOXICILLIN
43
Wider spectrum penicillinase-susceptible agents
● Enhanced activity in combination with inhibitors of
penicillinases
● Synergistic (1+1=3) with aminoglycosides in
enterococcal and listerial infections
AMPICILLIN and AMOXICILLIN
44
Wider spectrum penicillinase-susceptible agents
● Activity against gram (-) rods
○ Pseudomonas
○ Enterobacter
○ Some cases of klebsiella species
● Synergistic action with aminoglycoside
PIPERACILLIN and TICARCILLIN
45
Wider spectrum penicillinase-susceptible agents
● Susceptible to penicillinases
● Enhanced activity in combination with inhibitors of
penicillinases
PIPERACILLIN and TICARCILLIN
46
Penicillin main toxicity
allergy
47
can cause neutropenia
Nafcillin
48
causes maculopapular rashes
Ampicillin
49
causes interstitial nephritis more than other
penicillins
Methicillin
50
T/F: Penicillin Toxicity
● Antigenic determinants include degradation products like penicilloic acid
● Complete cross-allergenicity exists
T
51
Penicillin Toxicity
● Oral penicillins especially ampicillin
○ Nausea and diarrhea
○ Pseudomembranous colitis
■ Maybe caused by direct irritation or by
overgrowth of gram (+) organisms or yeasts
GI Disturbances
52
● Derivatives of 7-aminocephalosporanic acid
● Contain the beta-lactam ring structure
CEPHALOSPORINS
53
First generation Cephalosporins
● Cephalexin
● Cefazolin
● Cefadroxil
● Cephalotin,
● Cephradine
● Cephapirin
Cephalexin is the prototype
54
2nd generation Cephalosporins
● Cefuroxime
● Cefoxitin
● Cefotetan
● cefamandole
Cefuroxime is the prototype
55
3rd generation Cephalosporins
● Ceftriaxone
● Cefotaxime
● Cefoperazone
● Ceftazidime
● Cefixime
56
4th generation Cephalosporins
Cefepime
57
Pkinetics
● Oral
● Some given parenterally
Cephalosporins
58
Cephalosporins with side chains undergo
hepatic metabolism
59
Cephalosporins Major elimination is via
renal tubular excretion
60
Cephalosporins
Excreted mainly in the bile
Cefoperazone and ceftriaxone (3rd generation)
61
Do not enter the CSF when the meninges are
inflamed
1st- and 2nd-generation
62
Cephalosporins Resistance
Less susceptible to penicillinases produced by
_________
staphylococci
63
Resistance
● Structural differences from penicillin
● Decrease membrane permeability to the drug
● Changes in PBPs
● MRSA are also resistant to this drug
Cephalosporins
64
Cephalosporins Resistance
Resistance develops through the production of other
_______
beta-lactamases
65
Clinical Uses
● Gram (+) cocci
○ Staphylococci
○ Streptococci
● E. coli
● K. pneumoniae
First generation: Cefazolin (IV), cephalexin (oral)
66
Clinical Uses
● Surgical prophylaxis in selected conditions
● Minimal activity
○ Gram (-) cocci
○ Enterococci
○ MRSA
○ Most gram (-) rods
First generation
67
Clinical Uses
● Less activity against gram (+)
● Extended coverage for gram (-)
● Marked differences in activity occur among the drug
2nd generation
68
Clinical Uses
B. fragilis
2nd generation: Cefotetan, cefoxitin
69
Clinical Uses
H. influenzae or M. catarrhalis
Cefamandole, cefuroxime, cefaclor
70
Clinical Uses
Increased activity against gram (-) organisms
resistant to other beta-lactam drugs
3rd generation: Ceftazidime, cefoperazone, cefotaxime
71
Clinical Uses
Ability to penetrate the blood-brain barrier
3rd generation: Ceftazidime, cefoperazone, cefotaxime
Except cefoperazone, cefixime
72
Clinical Uses
● Providencia
● S. marcescens
● Beta-lactamase producing strains
○ H. influenzae
○ Neisseria
● Less active against enterobacter strains that produce
extended-spectrum beta-lactamases
3rd generation
73
Clinical Uses
Pseudomonas
3rd generation: Cefoperazone, ceftazidime
74
Clinical Uses
○ B. fragilis
○ a & b for serious infection
3rd generation: Ceftizoxime
75
Clinical Uses
Drug of choice for gonorrhea
3rd generation: Ceftriaxone (IV) and cefixime
76
Clinical Uses
○ Single injection for acute otitis media
○ As effective as 10 days of amoxicillin
3rd generation: Ceftriaxone
77
Clinical Uses
○ More resistant to beta-lactamases produced by gram (-) organisms
■ Enterobacter
■ Haemophilus
■ Neisseria
■ Some penicillinase-resistant pneumococci
4th generation
78
Clinical Uses
Combines the gram (+) activity of 1st gen and wider
gram (-) spectrum of 3rd gen
4th generation
79
Cephalosporins Toxicity
Allergy & oth adverse effects
80
Other Beta Lactams Drugs
● Monobactam
● Resistant to beta-lactamases produced by certain gram (-) rods
○ Klebsiella
○ Pseudomonas
○ Serratia
Aztreonam
81
Other Beta Lactams Drugs
● No activity against gram (+) and anaerobes
● An inhibitor of cell wall synthesis binding to PBP3
● Synergistic with aminoglycosides
● Given IV
● Eliminated via renal tubular secretion
● Half-life is prolonged in renal failure
● No cross-allergenicity with penicillin
Aztreonam
82
Other Beta Lactams Drugs
Adverse effects
○ GI upset with possible superinfection
○ Vertigo
○ Headache
○ Rare hepatotoxicity
○ Skin rash
Aztreonam
83
Other Beta Lactams Drugs
● Carbapenems
● Chemically different from penicillins
● Retain the beta-lactam ring
● Low susceptibility to beta-lactamases
IMIPENEM, MEROPENEM, AND ERTAPENEM
84
Other Beta Lactams Drugs
● Wide activity against
○ Gram(+) cocci
○ Gram (-) rods
○ Anaerobes
● For pseudomonal infections
○ Combine with aminoglycosides
IMIPENEM, MEROPENEM, AND ERTAPENEM
85
Other Beta Lactams Drugs
● Given IV
● Useful for infections caused by organisms resistant to other antibiotics
● Drug of choice for Enterobacter
IMIPENEM, MEROPENEM, AND ERTAPENEM
86
Other Beta Lactams Drugs
● Rapidly deactivated by renal
dehydropeptidases I
● Imipenem-cilastatin inhibits
renal dehydropeptidases I,
increases half life, and
inhibits formation of
nephrotoxic metabolites
● Renal excretion
IMIPENEM
87
Other Beta Lactams Drugs
● Similar to imipenem
● Not metabolized by
dehydropeptidases
● Renal excretion
MEROPENEM
88
Other Beta Lactams Drugs
● Longest half-life among
the carbapenems (4 hours)
● Renal excretion
ERTAPENEM
89
Other Beta Lactams Drugs
○ Used in fixed combination with certain hydrolyzable
penicillins
○ Plasmid-encoded beta-lactamases
■ Gonococci
■ Streptococci
■ E. coli
■ H. influenzae
BETA-LACTAMASE INHIBITORS: CLAVULANIC ACID, SULBACTAM, and TAZOBACTAM
90
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Bactericidal glycoprotein
● Binds to the D-Ala-D-Ala terminal of the nascent
peptidoglycan pentapeptide side chain
● Inhibits transglycosylation
VANCOMYCIN
91
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Prevents elongation of peptidoglycan chain ¡ Interferes with cross-linking
● Narrow spectrum of activity
VANCOMYCIN
92
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Drug-resistant gram (+) organisms
○ MRSA
○ Penicillin-resistant pneumococci
○ C. difficile
VANCOMYCIN
93
OTHER INHIBITORS OF CELL WALL SYNTHESIS
Due to decreased affinity of the drug to the binding
site
○ Replacement of D-Ala by D-lactate
Vancomycin-resistant enterococci (VRE) and
vancomycin-resistant S. aureus (VRSA)
94
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Not absorbed orally
● Maybe given for bacterial enterocolitis
● When given IV, penetrates most tissues
VANCOMYCIN
95
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Eliminated unchanged in urine
● Dosage modification in patients with renal impairment
VANCOMYCIN
96
OTHER INHIBITORS OF CELL WALL SYNTHESIS: VANCOMYCIN
Rapid IV infusion may cause diffuse blushing a syndrome known as
Red man syndrome
97
Vancomycin toxic effects
○ Chills
○ Fever
○ Phlebitis
○ Ototoxicity
○ Nephrotoxicity
98
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Antimetabolite inhibitor of cytosolic enolpyruvate
transferase
● Prevents the formation of N- acetylmuramic acid which is essential in peptidoglycan chain formation
FOSFOMYCIN
99
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Resistance occurs via decreased intracellular
accumulation of the drug
● Excreted in the kidney with urinary levels exceeding the MICs for many urinary tract pathogens
FOSFOMYCIN
100
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● In a single dose
○ Drug is less effective than the 7-day course of
treatment with fluoroquinolones
● Multiple dosing can result to resistance rapidly
● Diarrhea is common
● Synergistic with beta-lactam and quinolones in specific infections
FOSFOMYCIN
101
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Peptide antibiotic
● Interferes with a late stage in cell wall synthesis in gram
(+) organisms
● Marked toxicity
● Limited to topical use only
BACITRACIN
102
OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Antimetabolite
● Blocks the incorporation of D-Ala into the pentapeptide
side chain of the peptidoglycan
● Used only in TB caused by organisms resistant to first-line
antituberculous drugs
● Potentially neurotoxic
○ Tremors
○ Seizure
○ Psychosis
CYCLOSERINE
