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SECTION VIII Anti-infective Drugs

27 ANTIMICROBIAL DRUGS
General Considerations
Keys to successful antimicrobial therapy
1. Selective toxicity
Antimicrobial therapy is an exercise in selective toxicity.
Destroy pathogenic microorganisms with minimal adverse effects to host
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.

Mechanism of action
1. Sites of action antimicrobial drugs (Fig. 27-1)
2. Molecular targets of antimicrobial drugs (see Fig. 27-1)
Know molecular target of individual drugs.
a.
b.
c.
d.
e.
f.

Cell wall synthesis


Cell membrane
Folic acid metabolism
DNA replication
RNA synthesis
Protein synthesis

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.
Know modes of resistance for individual drugs.

Functions
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1. Antibacterial selection (Table 27-2)


a. Bactericidal agents (Table 27-3)
Kill microorganisms

Kill microorganisms
(1) Concentration-dependent killing
(a) Aminoglycosides
(b) Fluoroquinolones
(2) Time-dependent killing
(a) -Lactam antibiotics
(b) Vancomycin
b. Bacteriostatic agents (see Table 27-3)
Know which drugs are bacteriostatic versus bactericidal.
Suppress bacterial growth and multiplication
2. Prophylactic use of anti-infective agents (Table 27-4)

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

Table 27-1. Mechanism of Microbial Resistance


DRUG RESISTANCE DUE TO
ALTERED TARGETS

DRUG RESISTANCE DUE TO DECREASED


ACCUMULATION

DRUG RESISTANCE DUE TO


ENZYMATIC INACTIVATION

-Lactams
Vancomycin
Aminoglycosides
Chloramphenicol
Clindamycin
Macrolides
Tetracyclines
Rifampin
Sulfonamides
Trimethoprim
Fluoroquinolones

Decreased
permeability
-Lactams
Tetracyclines
Fluoroquinolones

Increased efflux
Macrolides
Tetracyclines
Fluoroquinolones

-Lactams
Aminoglycosides
Macrolides
Tetracyclines
Chloramphenicol

Table 27-2. Microbial Organisms with Sites of Infection and Drugs of Choice for Treatment
MICROORGANISM
Gram-positive
Staphylococcus
aureus

Streptococcus
pyogenes (group A)
Streptococcus (group
B)

INFECTION

Methicillin susceptible
Nafcillin
Oxacillin
Methicillin resistant
Vancomycin

Linezolid
Quinupristin/dalfopristin
TMP/SMX
Teicoplanin

Pharyngitis
Cellulitis

Penicillin G
Penicillin V

Other -lactams
Macrolides

Meningitis
Cellulitis
Sepsis

Penicillin G (+/aminoglycoside)
Clindamycin

Other -lactams
Macrolides

Bacteremia

Enterococcus

Endocarditis

Enterococcus

Urinary tract

Streptococcus
(viridans group)

Endocarditis

Streptococcus
pneumoniae

Pneumonia

Streptococcus

Streptococcus
pneumoniae
Listeria
monocytogenes

ALTERNATIVES*

Abscess
Cellulitis
Bacteremia
Pneumonia
Endocarditis

Enterococcus

pneumoniae

DRUGS OF CHOICE

Penicillin G (+/aminoglycoside)
Ampicillin
Penicillin G (+/aminoglycoside)
Ampicillin
Ampicillin

Penicillin G (+/aminoglycoside)
Ceftriaxone
Penicillin G
Vancomycin (+/- rifampin)

Vancomycin/gentamicin

Vancomycin
Dalfopristin/quinupristin
Linezolid
Fluoroquinolone
Nitrofurantoin
Cephalosporin
Vancomycin

Levofloxacin

Amoxicillin (+/- clavulanic acid)


Otitis
Sinusitis

Meningitis

Bacteremia
Meningitis
Endocarditis

Azithromycin
TMP/SMX
Oral cephalosporin

Ceftriaxone
Cefotaxime
Ampicillin

Penicillin G

TMP/SMX

Endocarditis
Gram-negative
Escherichia coli

Urinary tract

Escherichia coli

Bacteremia

TMP/SMX
Ciprofloxacin
Third-generation cephalosporin

Klebsiella pneumoniae Urinary tract

Ciprofloxacin

Klebsiella pneumoniae

Third generation Cephalosporin

Proteus mirabilis
Haemophilus
influenzae

Moraxella catarrhalis

Pneumonia
Bacteremia

Urinary tract
Otitis
Sinusitis
Bronchitis
Otitis
Sinusitis

Neisseria
gonorrhoeae

Genital

Pseudomonas
aeruginosa

Urinary tract

Ampicillin
Cefotaxime
Ceftriaxone

Amoxicillin/Clavulanic acid

Ceftriaxone
Cefixime
Ciprofloxacin

Nitrofurantoin
Fosfomycin
TMP/SMX
Ciprofloxacin
TMP/SMX
Oral cephalosporin
Fluoroquinolone
TMP/SMX
Imipenem
Aztreonam
TMP/SMX
Fluoroquinolone
TMP/SMX

TMP/SMX
Macrolide
Sulfonamide
Chloramphenicol
TMP/SMX
Imipenem
Aztreonam
Third generation
cephalosporin

Pseudomonas
aeruginosa

Vibrio cholerae

Helicobacter pylori

Pneumonia
Bacteremia

Cholera

Peptic ulcer (use


multiple drugs)

Antipseudomonal penicillin +
aminoglycoside
Ceftazidime
Doxycycline
Fluoroquinolone
Amoxicillin
Clarithromycin
Tinidazole (Rabeprazole,
proton pump inhibitor)

Aztreonam
Carbapenems
Cefepime
TMP/SMX

Tetracycline
Bismuth
Metronidazole

Anaerobes
Bacteroides spp.

Clostridium
perfringens
Clostridium difficile

Abdominal infections
Abscesses

Abscesses
Gangrene
Pseudomembranous colitis

Metronidazole

Clindamycin
Carbapenems
Cefoxitin
Ticarcillin/clavulanic
acid

Penicillin G + clindamycin

Doxycycline

Metronidazole

Vancomycin (oral)

Clostridium difficile

Pseudomembranous colitis

Metronidazole

Vancomycin (oral)

Other
Legionella spp.

Pulmonary

Mycoplasma
pneumoniae

Pulmonary

Chlamydia
pneumoniae

Pulmonary

Chlamydia
trachomatis

Genital

Rickettsia

Rocky Mountain spotted fever

Doxycycline

Chloramphenicol

Ehrlichia spp.

Ehrlichiosis

Doxycycline

Chloramphenicol

Borrelia burgdorferi

Lyme disease

Azithromycin
Levofloxacin
Azithromycin
Clarithromycin
Erythromycin
Levofloxacin

Clarithromycin

Doxycycline

Doxycycline

Erythromycin
Fluoroquinolone

Doxycycline
Azithromycin

Mycobacterium
tuberculosis

Tuberculosis (Always
use multiple drugs)

Treponema
pallidum

Syphilis

Erythromycin

Ceftriaxone
Cefuroxime axetil
Doxycycline
Amoxicillin

Penicillin G (high dose)


Cefotaxime

Isoniazid
Rifampin
Ethambutol
Pyrazinamide

Streptomycin
Rifabutin

Benzathine penicillin G

Doxycycline

*Only a few common alternative drugs are listed. TMP/SMX, trimethoprim/sulfamethoxazole

Table 27-3. Bactericidal and bacteriostatic antibacterial agents


BACTERICIDAL AGENTS
-lactam antibiotics
Bacitracin
Fosfomycin
Vancomycin
Isoniazid
Aminoglycosides
Quinupristin/dalfopristin
Metronidazole
Polymyxins
Fluoroquinolones
Tigecycline
Rifampin
Pyrazinamide

BACTERIOSTATIC AGENTS
Tetracyclines
Chloramphenicol
Macrolides
Clindamycin
Ethambutol
Linezolid
Sulfonamides
Trimethoprim
Nitrofurantoin

Adverse effects of antimicrobial drugs (Table 27-5)


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1. Organ-directed toxicity
a. Ototoxicity
b. Hematopoietic toxicity
Drugs that cause hepatotoxicity: tetracyclines, isoniazid, erythromycin, clindamycin, sulfonamides,
amphotericin B
c. Hepatotoxicity

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
a. Candidiasis
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
5. Synergism
a. Aminoglycosides plus penicillins
b. Sulfamethoxazole plus trimethoprim
c. Amphotericin B plus flucytosine
d. Fosfomycin plus -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
7. Antagonism
a. Penicillin G plus chloramphenicol
b. Penicillin G plus tetracycline

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

Rifampin

Pneumocystis jiroveci pneumonia


UTIs
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


ORGAN-DIRECTED
TOXICITY

IDIOSYNCRATIC
RESPONSES

HYPERSENSITIVITY
REACTIONS

SUPERINFECTIONS

TOXICITY

RESPONSES

REACTIONS

SUPERINFECTIONS

Ototoxicity
Aminoglycosides
Vancomycin
Minocycline

Hemolytic anemia (in


G6PD deficiency)
Primaquine
Sulfonamides
Nitrofurantoin

-Lactams
Penicillins
Cephalosporins
Carbapenems

Candidiasis
Broad spectrum
antibiotics
Treatment
Nystatin
Fluconazole
Miconazole

Hematopoietic toxicity
Chloramphenicol
Sulfonamides

Photosensitivity
Tetracyclines
Sulfonamides
Fluoroquinolones

Sulfonamides
Stevens-Johnson
syndrome most
serious

Staphylococcal
enterocolitis
Treatment
Vancomycin

Hepatotoxicity
Tetracyclines
Macrolides
Isoniazid
Sulfonamides
Amphotericin B

Renal toxicity
Aminoglycosides
Vancomycin
Amphotericin B
Cephalosporins
Sulfonamides

G6PD, Glucose-6-phosphate dehydrogenase

Lower incidence with other


antimicrobials

Pseudomembranous
colitis (Clostridium
difficile)
Clindamycin
Treatment
Metronidazole
Vancomycin