Chapter 14

Antimicrobial Agents

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 Principles of
Antimicrobial Therapy
 Gram stain, simplest and most common
 Bacteria stain differently depending on the
structural components of their cell wall
• Gram positive (stain purple)
• Gram negative (stain pink)
 Acid-fast stain (AFB)
 Enzyme-linked immunosorbent assay
(ELISA)
 Latex agglutination

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Susceptibility Testing and Resistance
 Results usually obtained within 24 hours
 Kirby-Bauer disk diffusion

 Use antibiotic-impregnated disks on an agar plate

 E-test
 Strip creates an antimicrobial gradient
• Minimal inhibitory concentration (MIC)
• Minimal bactericidal concentration (MBC)

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 Minimal Inhibitory Concentration (MIC) is
defined as the least concentration of
antimicrobial that prevents visible growth.
 The lowest concentration of antimicrobial
agent that prevents growth of the organism
on the agar plate after a 24-hour incubation is
termed the minimal bactericidal concentration
(MBC).

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Disk Diffusion and
E-Test Methods

Figure 14-1 ​Disk diffusion test and E-test methods.

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 MIC and MBC

Figure 14-2 ​Minimal inhibitory concentration (MIC) and minimal

bactericidal concentration (MBC) by broth macrodilution.

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 Principles of
Antimicrobial Therapy
 Antimicrobial therapy is dependent on:
 Host factors
 Susceptibility/resistance to antimicrobial
 Pharmacodynamics

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 Principles of
Antimicrobial Therapy (Cont.)
 Host factors
 Impaired immune function
 Age
• Liver and kidney function
• Stomach pH
 Pregnancy
• Could drug harm the fetus?

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 Principles of
Antimicrobial Therapy (Cont.)
 Pharmacodynamics
 The science of understanding the optimal effect
of a drug as a function of its concentration and the
in vitro (MIC) against an organism
 Measured in vitro by time-kill studies
• Concentration-dependent effect
• Time-dependent effect (concentration independent)
• Postantibiotic effect (PAE)

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 Antimicrobial Combinations

 Using two or more classes of antimicrobials

 May need to cover broad spectrum of organisms
initially
 Regimen may be narrowed once organism is
identified
 Certain infections are polymicrobial
 Drugs can be synergistic or antagonistic

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 Monitoring Response to Therapy

 Monitoring response to therapy involves

laboratory parameters and clinical
assessment
 Fever?
 WBC?
 Cultures still positive?
 Symptoms resolved?
 Drug toxicity?
 Monitor for treatment failure

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 Antibiotics

 β-Lactams
The b-lactams are a large class of antibiotics
that includes
 Penicillins
 Cephalosporins
 Carbapenems
 Monobactams

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 Antibiotics (Cont.)

 Penicillins
 Mechanism of action
• Inhibit cell wall synthesis
• Bactericidal
• Activate endogenous autolytic system in bacteria
• Can act synergistically with aminoglycosides

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 Clinical Uses of Antibiotics
 Natural penicillins eg Penicillin G
 Streptococcus pyogenes, Clostridium perfringes,
 Penicillinase-resistant penicillins eg : Oxacillin
 MSSA, MSSE
 Aminopenicillins eg Ampicillin, Amoxicillin
 Listeria monocytogenes, H. influenzae, E. coli
 Carboxypenicillins eg: Carbenicillin
 P.aeruginosa
 Ureidopenicillins Piperacillin
 P.aeruginosa
 β-Lactam and β-lactamase inhibitor combinations
Eg Amoxicillin–clavulanic acid,
S. aureus, H. influenzae, Moraxella catarrhalis

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Adverse Reactions and Precautions
with Antibiotic Therapy
 Adverse reactions and precautions for
penicillins
 Hypersensitivity (most common)
 Hematological reactions
 Gastrointestinal disturbances
 CNS toxicity

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 Cephalosporins

 Mechanism of action
 Inhibit bacterial cell wall synthesis
 Bactericidal

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 Clinical Uses: Cephalosporins

 First-generation cephalosporins
 Wide variety of gram-positive organisms
 Second-generation cephalosporins
 Gram-positive and some gram-negative
organisms
 Third-generation cephalosporins
 Active against most gram-negative organisms
 Fourth-generation cephalosporins
 Extended gram-positive and gram-negative
coverage

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 Adverse Reactions/Precautions:
Cephalosporins
 Hypersensitivity (1–3%)
 Minor gastrointestinal complaints
 Hypoprothrombinemia

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 Carbapenems

 Mechanisms of action
 Similar to other β-lactams
 Inhibit cell wall synthesis
 Bactericidal

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 Carbapenems (Cont.)

 Clinical uses
 Pseudomonas aeruginosa (except ertapenem),
gram-negative bacilli, most anaerobes, gram-
positive organisms
 MSSA and Streptococcus species
 Adverse reactions and precautions
 Low incidence of adverse reactions
 Seizures in patients with decreased renal function

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 Monobactams (Aztreonam)

 Mechanism of action
 Similar to other β-lactams
 Bactericidal
 Clinical uses
 Gram-negative aerobic bacilli
 Adverse reactions and precautions
 Well tolerated
 Rare: Rash, anaphylaxis

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 Aminoglycosides

 Gentamicin
 Tobramycin
 Netilmicin
 Amikacin

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 Aminoglycosides (Cont.)
 Mechanism of action
 Inhibit RNA translation
 Destabilize cell wall
 Bactericidal
 Clinical uses
 Nosocomial gram-negative infections (VAP)
 Adverse reactions and precautions
 Nephrotoxicity
 Ototoxicity
 Rare: neuromuscular blockade with rapid high-dose use

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 Tetracyclines
 Mechanism of action
 Inhibit attachment of RNA to acceptor site
 Bacteriostatic
 Clinical uses
 Gram-positive and gram-negative microorganisms
 Protozoa
 Mycobacteria

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 Adverse Reactions/Precautions:
Tetracyclines
 Gastrointestinal: nausea, vomiting, diarrhea
 Inhibit bone growth and Ca, Mg, and Fe
absorption

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 Tigecycline

 Mechanism of action
 Inhibits protein synthesis (even against most
tetracycline-resistant organisms)
 Bacteriostatic
 Bactericidal against S. pneumoniae
 Clinical uses
 Complicated skin and intraabdominal infections
 Adverse reactions and precautions
 Gastrointestinal: nausea, vomiting, diarrhea,
abdominal pain

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 Macrolides
 Mechanism of action
 Induce dissociation of transfer RNA from ribosome during
elongation phase
 Bacteriostatic
 Clinical uses
 Atypical and community-acquired pneumonia
 Chlamydial infections in pregnant women
 Adverse reactions and precautions
 Gastrointestinal complaints
 May increase the concentration of other drugs
• Theophylline
• Warfarin
• Triazolam

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 Telithromycin

 Mechanism of action
 Inhibits bacterial protein synthesis
 Clinical uses
 Sinusitis and community-acquired pneumonia
 Adverse reactions and precautions
 Gastrointestinal: nausea and diarrhea
 Visual disturbances
 Prolonged Q-T interval

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 Quinolones (Fluoroquinolones)
 Mechanism of action
 Inhibit DNA synthesis
 Bactericidal
 Clinical uses
 Upper/lower respiratory infections
 Gastrointestinal infections
 Skin infections
 Adverse reactions and precautions
 One of the safest antimicrobial classes
 Gastrointestinal: nausea, vomiting, diarrhea
 Prolonged Q-T interval

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 Chloramphenicol

 Mechanism of action
 Inhibits protein synthesis
 Bacteriostatic
 Clinical uses
 Gastroenteritis/sepsis
 Salmonella
 Adverse reactions and precautions
 Bone marrow suppression
 Optic neuritis (blindness)

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 Colistin (Colistimethate)

 Mechanism of action
 Surface active: incorporates into cell membranes
causing disruption
 Clinical uses
 Systemic infections by gram-negative bacteria
 Nebulized against multidrug-resistant
P. aeruginosa and Acinetobacter
 Adverse reactions and precautions
 Reversible nephrotoxicity
 Dose-dependent neuromuscular blockade

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 Daptomycin

 Mechanism of action
 Possibly disrupts cytoplasmic membrane
 Clinical uses
 Complicated skin infections by gram-positive
bacteria
 Staphylococcus aureus bacteremia
 Adverse reactions and precautions
 Creatine phosphokinase (CPK) elevation
 Rhabdomyolysis

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 Trimethoprim-Sulfamethoxazole
(TMP-SMX)
 Mechanism of action
 Blocks enzymes needed for bacteria to produce folic acid
 Bacteriostatic
 Clinical uses
 Pneumocystis pneumonia (PCP) prophylaxis
 Acute bronchitis, otitis media, shigellosis
 Displays good activity against MRSA
 Adverse reactions and precautions
 Relatively well tolerated
 Nausea, vomiting, diarrhea, hypersensitivity
 Neutropenia, thrombocytopenia, hemolytic anemia, jaundice,
hepatic necrosis, drug-induced lupus (all due to
sulfamethoxazole)
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 Clindamycin

 Mechanism of action
 Inhibits protein synthesis
 Bacteriostatic
 Clinical uses
 Active against gram-positive and anaerobic
bacteria
 Has fairly significant activity against MRSA
 Adverse reactions and precautions
 Nausea, vomiting, diarrhea

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 Metronidazole

 Mechanism of action
 Unknown
 Bactericidal against most anaerobic pathogens
 Clinical uses
 Anaerobic infections
 Trichomonas, Clostridium difficile
 Adverse reactions and precautions
 Metallic taste, nausea, vomiting
 Long-term use can lead to peripheral neuropathy

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 Vancomycin
 Mechanism of action
 Prevents formation of rigid cell wall
 Bactericidal against gram-positive organisms
 Bacteriostatic against enterococci
 Clinical uses
 Methicillin-resistant S. aureus (MRSA)
 Oral formulation used to treat C. difficile
 Adverse reactions and precautions
 Red man syndrome
 Ototoxicity
 Nephrotoxicity

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 Telavancin
 Mechanism of action
 Prevents formation of rigid cell wall
 Lipophilic side chain contributes to potency over
vancomycin
 Clinical uses
 Methicillin-resistant S. aureus (MRSA)
 VRE, and VRSA
 Complicated skin infections
 Adverse reactions and precautions
 Dysgeusia
 Headache
 Nausea

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 Antimycobacterials

 Used against Mycobacterium tuberculosis

 Isoniazid (INH)
 Mechanism of action
• Inhibits cell wall synthesis
• Bactericidal
 Adverse reactions and precautions
• Hepatotoxicity
• Neurotoxicity
• Nausea, loss of appetite, abdominal pain

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 Antimycobacterials (Cont.)

 Rifampin and Rifabutin

 Mechanism of action
• Inhibit RNA polymerase
• Bactericidal against actively dividing bacteria
 Adverse reactions and precautions
• Hepatotoxicity
• Rarely: fever, chills, nausea, vomiting
• Rifampin may cause bodily fluids to turn an orange
color

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 Antimycobacterials (Cont.)

 Pyrazinamide
 Mechanism of action
• Unknown
• Bactericidal
 Adverse reactions and precautions
• Nausea and vomiting
• Hepatotoxicity

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 Antimycobacterials (Cont.)

 Ethambutol
 Mechanism of action
• Decreases synthesis of cell wall polysaccharides
• Bacteriostatic
 Adverse reactions and precautions
• Optic neuropathy

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 Antimycobacterials (Cont.)

 Streptomycin
 Mechanism of action
• Similar to other aminoglycosides
 Adverse reactions and precautions
• Nephrotoxicity
• Ototoxicity

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 Antifungals
 The number of fungal infections is increasing
dramatically
 Polyenes (amphotericin B and nystatin)
 Mechanism of action
• Increases permeability of the cell membrane
 Clinical uses
• Aspergillosis,
Adverse reactions and precautions
• Flushing, fever, chills (infusion related)
• Renal impairment

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 Antiviral Agents
 Acyclovir and Valacyclovir
 Mechanism of action
• Terminate viral replication
 Clinical uses
• Herpesvirus family
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
• Varicella-zoster virus (VZV)
 Adverse reactions and precautions
• Neuropathy
• Burning, irritation if used topically

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 Antiviral Agents (Cont.)

 Penciclovir and Famciclovir

 Mechanism of action
• Interfere with viral DNA synthesis and replication
 Clinical uses
• Genital herpes simplex virus (HSV) and VZV
 Adverse reactions and precautions
• Considered well tolerated
• Occasional nausea, vomiting, diarrhea, headache
• Rare: neutropenia

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 Antiviral Agents (Cont.)

 Foscarnet
 Mechanism of action
• Blocks viral polymerase phosphorylation (inhibits viral
replication)
 Clinical uses
• Herpesvirus, VZV, EBV, hepatitis B, influenza A and B
 Adverse reactions and precautions
• Nephrotoxicity (25%)
• Fever, nausea, vomiting, headache, diarrhea,
electrolyte imbalance

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 Antiviral Agents (Cont.)

 Amantadine and Rimantadine

 Mechanism of action
• Inhibit viral replication and assembly
• May inhibit uncoating of influenza virus
 Clinical uses
• Active against influenza A virus
 Adverse reactions
• Well tolerated
• CNS: tremor, insomnia, light-headedness, seizure,
cardiac arrhythmias, agitation

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 Antiviral Agents (Cont.)

 Oseltamivir and Zanamavir

 Neuraminidase inhibitors
 Mechanism of action
• Inhibits influenza A and B neuraminidase
• Prevents virus from leaving host cells
 Clinical uses
• Treatment of influenza A and B infection
 Adverse reactions and precautions
• Nausea and vomiting in first 2 days of therapy

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 Respiratory Care Assessment of
Antibiotic Therapy
 Before treatment
 Assess the effectiveness of drug therapy on the basis of
indications
 During treatment and short term
 Consider susceptibility testing
 Patient assessment
 Long term
 Monitor response to therapy
 Consider combination of agents
 General contraindications
 Should not be used unless a specific pathogen is known or
suspected

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