Antibiotics 3

Front 1

Who invented sulfonamide?

Back 1

Gerhard Johannes Paul Domagk; Nobel Peace Prize in 1939

Front 2

Know the structural similarity between sulfonamides and PABA

Back 2

Both are amines; PABA has –COOH, sulfonamides have a sulfanilamide nucleus: SOONH-R
Sulfonamides are PABA analogs

Front 3

mechanism of action of sulfonamides

Back 3

 MOA: Compete with PABA; Inhibit dihydropteroate synthase (DHPS) from converting PABA and dihydropteroate diphosphate to dihydropteroic acid (which then goes to DHF)
 Broad spectrum: Active against G(+), G(-), chlamydia trachomatis and some protozoa
 Bacteriostatic
 Syntergistic (bactericidal) when combined with trimethoprim or pyrimethamine
 Metabolized in liver; eliminated by kidney
 Mammalian cells lack DHPS (hence rely on exogenous sources of folates) and are not susceptible to sulfonamide activity

Front 4

major clinical use of sulfonamides (including sulfasalazine)

Back 4

• Mammalian cells lack DHPS (hence rely on exogenous sources of folates) and are not susceptible to sulfonamide activity
• Sulfasalazine is used in ulcerative colitis and other inflammatory bowel disease
• Topical use: trachoma, conjunctivitis
 The fixed combination of trimethoprim- sulfamethoxazole (TMP-SMZ) is the drug of choice for Pneumocystis jirovecci pneumonia and Toxoplasmosis

Front 5

major side effects of sulfonamides and the precautions to take

Back 5

• Urinary tract disturbances
• Crystalluria, hematuria or obstruction (e.g., large dose of sulfadiazine with poor uptake of fluid)
*less seen in sulfisoxazole (more soluble)
*Crystalluria can be treated by administration of sodium bicarbonate (to alkalinize the urine) and fluids
 Hematopoietic disturbances Hemolytic reactions may be provoked in p’ts with glucose-6-phosphate dehydrogenase deficiency
 Stevens-Johnson syndrome (uncommon but serious)-skin and mucous membrane eruption

Front 6

MOR of sulfonamides

Back 6

 Mechanism of Resistance:
• Mutations that cause overproduction of PABA
• Mutations that cause production of a plasmid-encoded DHPS that has a low affinity for sulfonamides
• Mutations that impair permeability to the drugs

Front 7

mechanism of action of trimethoprim

Back 7

 Trimethoprim
• A pyrimidine derivative
• Selectively inhibits bacterial DHFR (dihydrofolate reductase) from convertin DHF to THF
• Bacteriostatic
• Treat urinary tract infection
 Sulfonamide + trimethoprim (TMP-SMZ)
• Synergistic
• Bactericidal
• Treat pneumocystis jirovecii pneumonia (PCP)

Front 8

Adverse Reactions and MOR of Trimethoprim and trimethoprim-sulfamethoxazole

Back 8

Adverse Reaction:
• Trimethoprim
• Megaloblastic anemia, granulocytopenia
• TMP-SMZ
• Similar to sulfonamides (GI upset, renal damage, CNS disturbances)
Mechanism of Resistance
• Reduced cell permeability
• Overproduction of DHFR
• Altered DHFR with reduced drug binding (plasmid-encoded; transposable)

Front 9

mechanism of action of fluoroquinolones

Back 9

 Synthetic fluorinated analog of nalidixic acid
 MOA: Blocks DNA synthesis by inhibiting
topoisomerase II (DNA gyrase) and
topoisomerase IV
 Active against various G(+) and G(-) bacteria
***The bacterial enzyme DNA gyrase is a topoisomerase that introduces negative supercoils into DNA, which relax positive supercoil and allow replication to proceed

Front 10

Fluoroquinolone Pharmacokinetics

Back 10

• Oral absorption impaired by divalent cations (e.g., antiacids)
• Widely distributed in body fluids and tissues
• Most are excreted by kidney (dosage must be adjusted in renal failure)
• Moxifloxacin and gemifloxacin are eliminated through nonrenal mechanism
• Levofloxacin, gemifloxacin, moxifloxacin, ciprofloxacin- once daily dosing possible

Front 11

Who invented sulfonamide?

Back 11

Gerhard Johannes Paul Domagk; Nobel Peace Prize in 1939

Front 12

Know the structural similarity between sulfonamides and PABA

Back 12

Both are amines; PABA has –COOH, sulfonamides have a sulfanilamide nucleus: SOONH-R
Sulfonamides are PABA analogs

Front 13

mechanism of action of sulfonamides

Back 13

 MOA: Compete with PABA; Inhibit dihydropteroate synthase (DHPS) from converting PABA and dihydropteroate diphosphate to dihydropteroic acid (which then goes to DHF)
 Broad spectrum: Active against G(+), G(-), chlamydia trachomatis and some protozoa
 Bacteriostatic
 Syntergistic (bactericidal) when combined with trimethoprim or pyrimethamine
 Metabolized in liver; eliminated by kidney
 Mammalian cells lack DHPS (hence rely on exogenous sources of folates) and are not susceptible to sulfonamide activity

Front 14

major clinical use of sulfonamides (including sulfasalazine)

Back 14

• Mammalian cells lack DHPS (hence rely on exogenous sources of folates) and are not susceptible to sulfonamide activity
• Sulfasalazine is used in ulcerative colitis and other inflammatory bowel disease
• Topical use: trachoma, conjunctivitis
 The fixed combination of trimethoprim- sulfamethoxazole (TMP-SMZ) is the drug of choice for Pneumocystis jirovecci pneumonia and Toxoplasmosis

Front 15

major side effects of sulfonamides and the precautions to take

Back 15

• Urinary tract disturbances
• Crystalluria, hematuria or obstruction (e.g., large dose of sulfadiazine with poor uptake of fluid)
*less seen in sulfisoxazole (more soluble)
*Crystalluria can be treated by administration of sodium bicarbonate (to alkalinize the urine) and fluids
 Hematopoietic disturbances Hemolytic reactions may be provoked in p’ts with glucose-6-phosphate dehydrogenase deficiency
 Stevens-Johnson syndrome (uncommon but serious)-skin and mucous membrane eruption

Front 16

MOR of sulfonamides

Back 16

 Mechanism of Resistance:
• Mutations that cause overproduction of PABA
• Mutations that cause production of a plasmid-encoded DHPS that has a low affinity for sulfonamides
• Mutations that impair permeability to the drugs

Front 17

mechanism of action of trimethoprim

Back 17

 Trimethoprim
• A pyrimidine derivative
• Selectively inhibits bacterial DHFR (dihydrofolate reductase) from convertin DHF to THF
• Bacteriostatic
• Treat urinary tract infection
 Sulfonamide + trimethoprim (TMP-SMZ)
• Synergistic
• Bactericidal
• Treat pneumocystis jirovecii pneumonia (PCP)

Front 18

Adverse Reactions and MOR of Trimethoprim and trimethoprim-sulfamethoxazole

Back 18

Adverse Reaction:
• Trimethoprim
• Megaloblastic anemia, granulocytopenia
• TMP-SMZ
• Similar to sulfonamides (GI upset, renal damage, CNS disturbances)
Mechanism of Resistance
• Reduced cell permeability
• Overproduction of DHFR
• Altered DHFR with reduced drug binding (plasmid-encoded; transposable)

Front 19

mechanism of action of fluoroquinolones

Back 19

 Synthetic fluorinated analog of nalidixic acid
 MOA: Blocks DNA synthesis by inhibiting
topoisomerase II (DNA gyrase) and
topoisomerase IV
 Active against various G(+) and G(-) bacteria
***The bacterial enzyme DNA gyrase is a topoisomerase that introduces negative supercoils into DNA, which relax positive supercoil and allow replication to proceed

Front 20

Fluoroquinolone Pharmacokinetics

Back 20

• Oral absorption impaired by divalent cations (e.g., antiacids)
• Widely distributed in body fluids and tissues
• Most are excreted by kidney (dosage must be adjusted in renal failure)
• Moxifloxacin and gemifloxacin are eliminated through nonrenal mechanism
• Levofloxacin, gemifloxacin, moxifloxacin, ciprofloxacin- once daily dosing possible

Front 21

Clincal Uses of Fluoroqinolones

Back 21

Clinical uses
• Urinary tract infection and bacterial diarrhea
• Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax
• Respiratory fluoroquinolones (levofloxacin, gemifloxacin, moxifloxacin) have enhanced activity against G(+) and are used for RTI

Front 22

Adverse Reactions to fluoroquinolones

Back 22

• GI upset (nausea, vomiting, diarrhea)
• CNS (headache, dizziness, insomnia)
• Skin rash, photosensitivity
• QT prolongation (potential arrhythmia)
• Arthropathy (not routinely recommended for <18-yr old)
• Tendinitis, tendon rupture

Front 23

What determines choice of antimicrobial agents

Back 23

 Host factors
• Concomitant disease states
• Previous adverse drug reactions
• Impaired elimination or detoxification of the drug
• Age
• Pregnancy status
 Pharmacologic factors
• The kinetics of absorption, distribution and elimination
• Drug delivery to the site of infection
• Potential drug toxicity
• Drug interactions

Front 24

Guide to determine therapy of established infections

Back 24

1. Susceptibility testing (in vitro)
A. MIC (minimal inhibitory conc.)
 Routinely measured for most infections
B. MBC (minimal bactericidal conc.)
 Useful info for bactericidal therapy (e.g., meningitis, endocarditis, sepsis in the granulocytopenic host)
2. Specialized assay methods
 A. b-lactamase assay
 e.g., nitrocef disc
 Useful for Haemophilus sp., staphylococci, N. gonorrhoeae
 B. Synergy studies
 Measure synergistic, additive, indifferent, or antagonistic drug interactions

Front 25

Antimicrobial Pharmacodynamics

Back 25

 Pharmacodynamic factors
• Pathogen susceptibility testing
• Drug bactericidal versus bacteriostatic activity
• Drug synergism
• Antagonism
• Post-antibiotic affects

Front 26

Bacterial vs Bacteriostatic Activity

Back 26

 Bactericidal- cell wall synthesis inhibitors
 Bacteriostatic- protein synthesis inhibitors
 Bacteriostatic and bactericidal antibiotics are equivalent for the treatment of most infectious diseases in immunocompetent hosts
 Bactericidal agents are preferred when host defenses are impaired
 Bactericidal agents are required for treatment of endocarditis and other endovascular infections, meningitis and infections in neutropenic cancer p’ts

Front 27

Bactericidal Agents

Back 27

 Concentration-dependent killing
 The rate and extent of killing increase with increasing drug conc.
 e.g., aminoglycosides, quinolones
***KNOW THAT THESE DRUGS HAVE CONC DEPENDENT KILLING (TEST ?)
 Contribute to the efficacy of once-daily dosing of aminoglycosides
 Time-dependent killing
 Bactericidal activity continues as long as serum conc.> MBC
e.g., b-lactams, vancomycin
 Drug conc. should be > MIC for the entire interval between doses for agents that lack a post-antibiotic effect

Front 28

Post-antibiotic Effect

Back 28

 Persistent suppression of bacterial growth after limited exposure to an antimicrobial agent
 PAE reflects the time required for bacteria to return to logarithmic growth
 PAE contributes to the efficacy of once-daily dosing regimens (e.g., aminoglycosides and quinolones)
 PAE = T - C
 T: the time required for the viable count in the test culture to increase 10x above the count observed immediately before drug removal
 C: the time required for the count in an untreated culture test culture to
 increase 10x above the count observed immediately after completion
 of the same procedure used on the test culture

Front 29

Mechanisms of PAE

Back 29

 Slow recovery after reversible nonlethal damage to cell structure
 Persistence of the drug at a binding site or within the periplasmic space
 The need to synthesize new enzymes before growth can resume
 in vivo PAE is longer than in vitro PAE due to post-antibiotic leukocyte enhancement (PALE)

Front 30

List two main properties of aminoglycosides and quinolones

Back 30

 Possess concentration-dependent PAE
 Once daily high doses result in enhanced bactericidal activity and extended PAE

Front 31

Route of administration for antimicrobials

Back 31

1. Oral (parenteral/ less costly/ less complicaitons): tetracyclines, TMP-SMZ, quinolones, chloramphenicol, metronidazole, clindamycin, rifampin, linezolid fluconazole
2. IV (preferred): for agents that are poorly absorbed when orally administered; critically ill patients; pts w/ bacterial meningitis or endocarditis; w/ nausea, vomiting, gastrectomy or conditions that may impair oral absorption

Front 32

Monitoring serum concentration

Back 32

Routine serum concentration monitoring is necessary only when:
 a direct relationship exists between drug conc. and efficacy or toxicity
 substantial interpatient variability exists on serum conc. on standard doses
 a small difference exists between therapeutic and toxic serum conc.
 the clinical efficacy or toxicity of the drug is delayed or difficult to measure
 an accurate assay is available
ex. Aminoglycosides, vancomycin

Front 33

Management of Antimicrobial Drug Toxicity

Back 33

 Adverse reactions to antimicrobial agents occurs with increased frequency in neonates, geriatric p’ts, renal failure p’ts, and AIDS p’ts
• Obtain a clear history of drug allergy and other adverse reactions
• Use alternative agents
• Dosage reduction
• Desensitization (for pts w/ neurosyphilus who have a history of anaphylaxis to penicillin
Polypharmacy can cause drug toxicity
• The use of multiple medications by a patient can predispose to drug interactions
• e.g., AIDS p’ts exhibit high incidence of toxicity to clindamycin, aminopenicillins, and sulfonamides

Front 34

Reasons for Antimicrobial Drug Combinations

Back 34

 Rationale for combination antimicrobial therapy
 To provide broad-spectrum empiric therapy in seriously ill p’ts
 To treat polymicrobial infections
 To ¯ the emergence of resistant strains
 To ¯ dose-related toxicity by using reduced doses of one/more components of the drug regimen
 To obtain enhanced inhibition or killing

Front 35

Synergism vs. Antagonism

Back 35

Synergism: drug (A+B) is more effective than A or B alone
Antagonism: one drug has ability to inactivate the other drug

Front 36

Describe the Mechanisms of Synergistic Action

Back 36

 Tetracycline is not to be used with penicillin???????
 Blockade of sequential steps in a metabolic sequence
 - e.g., TMP-SMZ
 Inhibition of enzymatic inactivation
 - e.g., Augmentin® (amoxicillin-clavulanate)
 Enhancement of antimicrobial agent uptake
 - e.g., penicillin + aminoglycoside
 Synergistic combination of antimicrobials is needed for the treatment of enterococcal endocarditis
 e.g., penicillins + gentamicin
 * Synergistic combination of TMP-SMZ is successful for the treatment of bacterial infections and pneumocystis jiroveci pneumonia (PCP)

Front 37

Mechanisms of Antagonistic Action

Back 37

 Inhibition of cidal activity by static agents
 e.g., tetracycline and chloramphenicol can antagonize the bactericidal activity of cell wall synthesis inhibitors
 * Penicillin + chlortetracycline ­ mortality in p’ts with pneumococcal meingitis
 Induction of enzymatic inactivation
 - e.g., b-lactam antibiotics such as imipenem, cefoxitin and
 ampicillin are potent inducers of b-lactamases
 production. Antagonism may occur when these agents
 are combined with an intrinsically active but
 hydrolyzable b-lactam such as piperacillin

Front 38

Criteria for antimicrobial prohylaxis

Back 38

Antimicrobial prophylaxis is recommended based on the
NRC Wound Classification Criteria (4 classes: clean, clean-
contaminated, contaminated, dirty)
 Surgical wound infections: a major category of nosocomial infections
Risk factors for prospective wound infections (identified by SENIC)
- operations on the abdomen
- operations lasting more than 2 hrs
- contaminated or dirty would classification
- > 3 medical diagnoses
Surgical prophylaxis is needed for
• contaminated and clean-contaminated operations
• selected operations in which postoperative infection may be catastrophic (e.g., open heart surgery)
• clean procedures that involve placement of prosthetic materials
• an procedures in an immunocompromised host

Front 39

General Principles of Surgical Prophylaxis

Back 39

• The antibiotic should be active against common surgical wound pathogens (avoid unnecessarily broad spectrum coverage)
• The antibiotic should have proved efficacy in clinical trials
• The antibiotic must achieve conc. > MIC of suspected pathogens (at the time of incision)
• The shortest possible course of the most effective and least toxic antibiotic should be used
• The newer broad-spectrum antibiotics should be reserved for therapy of resistant infections
• The least expensive agent should be used when all other factors are equal
• Proper selection and administration of antimicrobial prophylaxis is critical
• Common errors in antibiotic prophylaxis include
• Selection of the wrong antibiotic
• Administering too early or too late
• Failure to repeat doses during prolonged procedures
• Excessive duration of prophylaxis
• Inappropriate use of broad-spectrum antibiotics

Front 40

Nonsurgical Prophylaxis

Back 40

• Administering antimicrobials to prevent colonization or asymptomatic infections
• Administering of drugs following colonization or inoculation of pathogens but before the development of disease
• Nonsurgical prophylaxis is indicated in:
• - individuals who are at high risk for temporary exposure to selected virulent pathogens
• - patients who are at increased risk for developing infection because of underlying disease (e.g., immunocompromised hosts)