Antimicrobial Drugs

Chapter 27 Antimicrobial Drugs

I. General Considerations

A. Keys to successful antimicrobial therapy

1. Selective toxicity

• Destroy pathogenic microorganisms with minimal adverse effects to host

Antimicrobial therapy is an exercise in selective toxicity.

2. Adequate blood levels

• Sufficient levels to destroy microorganisms in order to prevent development of microbial resistance

Inadequate blood levels of antimicrobials leads to drug resistance.

B. Mechanism of action

1. Sites of action antimicrobial drugs (Fig. 27-1)

2. Molecular targets of antimicrobial drugs (see Fig. 27-1)

a. Cell wall synthesis

b. Cell membrane

c. Folic acid metabolism

d. DNA replication

e. RNA synthesis

f. Protein synthesis

27-1 Sites of action of antimicrobial drugs and enzymes that inactivate these drugs. DHFA, dihydrofolic acid; PABA, p-aminobenzoic acid; THFA, tetrahydrofolic acid.

Know molecular target of individual drugs.

C. Mechanisms of microbial resistance

1. Resistance often correlates with:

a. Frequency of antimicrobial use

Overuse of antimicrobials markedly contributes to antimicrobial resistance.

b. Total quantity of drug dispensed

c. Location of the patient when receiving the medication

d. Immune status of the patient

2. Processes that contribute to resistance (see Table 27-1 for examples)

a. Drug resistance due to altered targets

b. Drug resistance due to decreased accumulation

(1) Decreased uptake

(2) Increased efflux

c. Drug resistance due to enzymatic inactivation

3. Multidrug resistance is often transmitted by plasmids.

4. To minimize the emergence of resistance:

a. Only use chemotherapeutic agents when they are clearly indicated

b. Use a narrow-spectrum drug known to be effective against the pathogen.

c. Use an effective dose of the chemotherapeutic agent.

d. Ensure that the duration of chemotherapy is adequate.

e. Use older chemotherapeutic drugs whenever possible.

f. Use multiple drugs in combination chemotherapy when the pathogen is noted to develop resistance to an individual drug rapidly.

TABLE 27-1 Mechanism of Microbial Resistance

Know modes of resistance for individual drugs.

D. Functions

1. Antibacterial selection (Table 27-2)

a. Bactericidal agents (Table 27-3)

• Kill microorganisms

(1) Concentration-dependent killing

(a) Aminoglycosides

(b) Fluoroquinolones

(2) Time-dependent killing

(a) β-Lactam antibiotics

b. Bacteriostatic agents (see Table 27-3)

TABLE 27-2 Microbial Organisms with Sites of Infection and Drugs of Choice for Treatment

TABLE 27-3 Bactericidal and bacteriostatic antibacterial agents

Bactericidal Agents	Bacteriostatic Agents
β-lactam antibiotics Bacitracin Fosfomycin Vancomycin Isoniazid Aminoglycosides Quinupristin/dalfopristin Metronidazole Polymyxins Fluoroquinolones Tigecycline Rifampin Pyrazinamide	Tetracyclines Chloramphenicol Macrolides Clindamycin Ethambutol Linezolid Sulfonamides Trimethoprim Nitrofurantoin

Know which drugs are bacteriostatic versus bactericidal.

• Suppress bacterial growth and multiplication

2. Prophylactic use of anti-infective agents (Table 27-4)

E. Adverse effects of antimicrobial drugs (Table 27-5)

1. Organ-directed toxicity

b. Hematopoietic toxicity

TABLE 27-4 Prophylactic Use of Anti-infective Drugs

Drug	Use
Cefazolin	Surgical procedures
Cefoxitin, cefotetan	Surgical procedures in which anaerobic infections are common
Ampicillin or penicillin	Group B streptococcal infections
Trimethoprim-sulfamethoxazole	Pneumocystis jiroveci pneumonia UTIs
Rifampin	Haemophilus influenzae type B Meningococcal infection
Chloroquine, mefloquine	Malaria
Isoniazid, rifampin	Tuberculosis
Azithromycin	Mycobacterium avium complex in patients with AIDS
Ciprofloxacin	Bacillus anthracis (anthrax)
Ampicillin or azithromycin	Dental procedures in patients with valve abnormalities

AIDS, acquired immunodeficiency syndrome; UTI, urinary tract infection.

TABLE 27-5 Adverse reactions to antimicrobials

Drugs that cause hepatotoxicity: tetracyclines, isoniazid, erythromycin, clindamycin, sulfonamides, amphotericin B

c. Hepatotoxicity

d. Renal toxicity

Drugs that cause renal toxicity: cephalosporins, vancomycin, aminoglycosides, sulfonamides, amphotericin B

2. Idiosyncrasies (unexpected individual reactions)

a. Hemolytic anemias (e.g., in glucose-6-phosphate dehydrogenase [G6PD]-deficient people)

b. Photosensitivity reactions (e.g., tetracycline)

3. Hypersensitivity reactions

• These reactions are most notable with penicillins and sulfonamides but can occur with most antimicrobial drugs.

4. Superinfections

Candidiasis is most common superinfection caused by antimicrobial therapy.

• Treatment with oral nystatin (local effects), miconazole (local vaginal effects), fluconazole (oral medication for vaginal candidiasis)

b. Pseudomembranous colitis caused by Clostridium difficile

• Treatment with oral metronidazole or vancomycin

Treat pseudomembranous colitis with metronidazole.

c. Staphylococcal enterocolitis

• Treatment with oral vancomycin

a. Aminoglycosides plus penicillins

b. Sulfamethoxazole plus trimethoprim

c. Amphotericin B plus flucytosine

d. Fosfomycin plus β-lactams

e. Fosfomycin plus aminoglycosides

f. Fosfomycin plus fluoroquinolones

Be able to distinguish drug combinations that lead to synergism, potentiation, or antagonism.

6. Potentiation

a. Imipenem plus cilastatin

b. Ampicillin plus sulbactam

c. Amoxicillin plus clavulanic acid

d. Piperacillin plus tazobactam

e. Ticarcillin plus clavulanic acid

a. Penicillin G plus chloramphenicol

b. Penicillin G plus tetracycline

II. Cell Wall Synthesis Inhibitors (Box 27-1)

A. General information

1. Intracellular or extracellular steps in the synthesis of the cell wall (Fig. 27-1 and Fig. 27-2)

2. β-Lactam antibiotics are most often used

3. Structural relationships of β-lactam antibiotics (Fig. 27-3)

BOX 27-1 β-Lactam Drugs and other Cell Wall Synthesis Inhibitors

Penicillins

Amoxicillin (O)

Carbenicillin indanyl (O)

Dicloxacillin (O)

Penicillin V (O)

Other β-Lactam Drugs

Imipenem-cilastatin

Other Cell Wall Synthesis Inhibitors

Bacitracin (topical)

O, often given orally

27-2 Sites of action of cell wall synthesis inhibitors. The peptidoglycan substrate for Step 2 is inhibited by fosfomycin and cycloserine; the transport of the peptidoglycan across the cell membrane is inhibited by bacitracin (Step 1); the linkage of peptidoglycan monomers via transglycosylation is inhibited by vancomycin (Step 6); the cross-linking of strands by transpeptidation is inhibited by β-lactams (Site 6).

(From Brenner G and Stevens C: Pharmacology, 3rd ed. Philadelphia, Saunders, 2010, Figure 38-2.)

27-3 Structures of β-lactam drugs.

(From Wecker L, et al.: Brody’s Human Pharmacology, 5th ed. Philadelphia, Mosby, 2010, Figure 46-1.)

β-Lactam antimicrobials include: penicillins, cephalosporins, carbapenems, monobactams.

B. Penicillins

1. Key characteristics of penicillin G (see Fig. 27-3)

a. β-lactam ring

b. Penicillinase sensitivity

d. Tubular secretion (organic anion)

e. Inhibition of cell wall synthesis

f. Hypersensitivity

Learn how other β-lactams differ from penicillin G.

2. Pharmacokinetics

(1) May be destroyed by gastric acid

(2) Acid-resistant preparations for oral administration

(a) Amoxicillin

(b) Carbenicillin indanyl

(c) Dicloxacillin

(e) Penicillin V

Acid resistant (orally effective) penicillins include: penicillin V, amoxicillin, carbenicillin indanyl, oxacillin, and dicloxacillin.

b. Distribution

(1) Good to most tissues and fluids, including:

(a) Pleural fluid

(b) Pericardial fluid

(c) Synovial fluid

(2) Poor penetration

(c) Central nervous system (CNS) (except in meningitis)

Penicillins are poor for treating infections in the eye, prostate, or CNS (except in meningitis).

(1) Unchanged in urine by tubular secretion

• Exception; nafcillin is biliary excretion

Exceptions: Nafcillin and, to a lesser extent, oxacillin and dicloxacillin depend on biliary secretion.

(2) Inhibited by probenecid

3. Pharmacodynamics

a. Mechanism of action (see Fig. 27-2)

(1) Bind to specific penicillin-binding proteins (PBPs)

(a) Inhibit transpeptidase enzymes

• Inhibits cross-linking of peptidoglycan chains

(b) Activates autolytic enzymes

• Causes holes in bacterial cell wall

(2) Bactericidal

Inhibitors of cell wall synthesis cause osmotic rupture of the bacterial cell.

b. Causes of resistance

(1) Inactivation by β-lactamases (most common)

(2) Alteration in target PBPs (methicillin-resistant species)

• Methicillin-resistant Staphylococcus aureus (MRSA)

Alterations in PBPs: responsible for methicillin resistance in staphylococci (MRSA) and penicillin resistance in pneumococci.

Methicillin resistant strains are resistant to all β-lactam antibiotics.

(3) Permeability barrier, preventing drug penetration

• Contributes to the resistance of many gram-negative bacteria

a. Penicillin G

(1) Pharyngitis (Group A streptococcus)

(2) Syphilis (Treponema pallidum)

(3) Pneumonia (pneumococcus, streptococcus)

(4) Meningitis (meningococcus, pneumococcus)

Primary use of penicillin G: infections with gram-positive (+) bacteria.

b. Benzathine penicillin G

(1) Intramuscular injection gives low blood levels for up to 3 weeks.

(2) Useful in situations in which organisms are very sensitive

(a) T. pallidum in syphilis

Benzathine penicillin G is the drug of choice for syphilis.

(b) β-Hemolytic streptococcal pharyngitis prophylaxis

• Monthly injection prevents reinfection

c. Ampicillin and amoxicillin (extended spectrum penicillins)

(1) Route of administration

(a) Ampicillin is usually given by injection.

• Often given with sulbactam

(b) Amoxicillin is given orally.

• Often given with clavulanic acid

(a) Urinary tract infections (UTIs) (Escherichia coli)

(b) Infectious diarrhea (Salmonella)

(c) Otitis media or sinusitis (Haemophilus)

(d) Meningitis (Listeria)

Intravenous ampicillin is an excellent choice for treatment of following conditions: actinomycosis; cholangitis (acute); diverticulitis; endocarditis; group B strep prophylaxis (intrapartum); Listeria infections; sepsis/meningitis; urinary tract infections (enterococcus suspected).

(e) Endocarditis (prevention)

(f) Bacteremia (Enterococcus) combined with an aminoglycoside

Penicillins but not cephalosporins are active against Enterococcal infections in combination with aminoglycosides.

d. Ticarcillin (antipseudomonal penicillin) potent against nosocomial (Pseudomonas) infections

(1) Usually combined with an aminoglycoside

(2) Often given with clavulanic acid

e. Piperacillin (antipseudomonal penicillin)

(1) More active against Pseudomonas than ticarcillin

(2) Often given with tazobactam

Antipseudomonal penicillins and cephalosporins are combined with aminoglycosides to prevent resistance.

f. Penicillinase-resistant β-lactam antibiotics

(a) Nafcillin (parenteral)

• Biliary excretion

(b) Oxacillin (oral; parenteral)

• Both biliary and renal excretion

(c) Dicloxacillin (oral)

• Both biliary and renal excretion

Antistaphylococcal penicillins (e.g., nafcillin): ineffective against infections with MRSA

(2) Used against penicillinase-producing microorganisms

(a) Endocarditis (streptococci, staphylococci)

(b) Osteomyelitis (staphylococci)

5. Adverse effects

a. Allergic reactions (most serious)

Ampicillin rash: nonallergic rash; high incidence in patients with Epstein-Barr virus infection (mononucleosis).

b. Seizures with high levels in brain

C. Cephalosporins

• Cephalothin, the prototype first-generation cephalosporin, is no longer available in the United States.

1. Key characteristics of cephalosporins

a. β-Lactam ring (see Fig. 27-3)

b. Increased resistance to penicillinases

c. Inhibition of cell wall synthesis

d. Acid resistance (some agents)

• Some agents are orally effective (see Box 27-1)

e. Nephrotoxicity

f. Tubular secretion

• Exception, ceftriaxone is eliminated by biliary excretion

Exceptions: Cefoperazone and ceftriaxone are mostly eliminated by biliary secretion.

2. Mechanism of action

a. Similar to penicillins

b. Bactericidal

c. Penicillinase-resistant

d. Many are cephalosporinase sensitive

a. First-generation

(a) Cefazolin (parenteral)

(b) Cephalexin (oral)

(c) Cefadroxil (oral)

First-generation cephalosporins have good activity against gram-positive bacteria and modest activity against gram-negative bacteria.

(2) Cefazolin has good activity against gram-positive bacteria and modest activity against gram-negative bacteria.

(a) Cellulitis (Staphylococcus, Streptococcus)

(b) Surgical prophylaxis

• Exception, cefoxitin for abdominal surgery prophylaxis

b. Second-generation

(a) Cefaclor (oral)

(d) Cefoprozil (oral)

(e) Cefuroxime (parenteral, oral)

(f) Loracarbef (oral)

Second-generation cephalosporins have increased activity against gram-negative bacteria (E. coli, Klebsiella, Proteus, Haemophilus influenzae, Moraxella catarrhalis).

(2) Increased activity against gram-negative bacteria (E. coli, Klebsiella, Proteus, Haemophilus influenzae, Moraxella catarrhalis)

(a) Pelvic inflammatory disease

(b) Diverticulitis

(c) Abdominal surgical prophylaxis

(e) Bronchitis (H. influenzae)

First or second generation cephalosporins are drugs of choice against E. coli, Klebsiella and Proteus.

c. Third-generation

(a) Cefdinir (oral)

(b) Cefditoren (oral)

(c) Cefixime (oral)

(d) Cefotaxime (parenteral)

(e) Cefpodoxime (oral)

(f) Ceftazidime (parenteral)

(g) Ceftibuten (oral)

(h) Ceftizoxime (parenteral)

(i) Ceftriaxone (parenteral)

(2) Decreased activity against gram-positive bacteria but increased activity against gram-negative bacteria (Enterobacter, Serratia)

Third-generation cephalosporins have decreased activity against gram-positive bacteria but increased activity against gram-negative bacteria (Enterobacter, Serratia).

(3) Activity against Pseudomonas aeruginosa in a subset

(a) Ceftazidime

(b) Cefoperazone

(4) Specific uses

(a) Meningitis (Neisseria gonorrhoeae)

• Third-generation good penetration of blood-brain barrier

Many third-generation cephalosporins that penetrate into the CNS are useful in treatment of meningitis.

(b) Community-acquired pneumonia

(c) Lyme disease

(d) Osteomyelitis (ceftazidime)

• Ceftriaxone (parenteral) or cefixime (oral) are drugs of choice

Cephalosporins are not active against Listeria, Enterococci, MRSA and Atypicals.

d. Fourth-generation (cefepime)

(1) Extensive gram-positive and gram-negative activity

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Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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