Antimicrobial Therapy Principles

• Antimicrobials are widely used therapeutic agents, developed from natural compounds or created synthetically.
• The development of new antimicrobials with novel mechanisms of action has declined recently, with most new agents being chemical modifications of older ones.
• Microbes are developing resistance to commonly used antimicrobial agents, posing a challenge to clinicians.
• Techniques to identify organisms and determine their susceptibility are vital for selecting effective antimicrobial therapy.
• Host factors, antimicrobial pharmacodynamics, antimicrobial combinations, and methods of monitoring therapy are important considerations before selecting an antimicrobial agent.
• This chapter focuses on basic principles of antimicrobial therapy, mechanism of action and adverse effects, and clinical use of antimicrobial classes for respiratory infections.

Key Terms

• Antagonism: When one antibiotic interferes with another resulting in less activity than when the drugs are used individually.
• Antibiotics: Substances derived from microorganisms that inhibit or kill other microorganisms.
• Antimicrobials: Natural and synthetic compounds that inhibit or kill microorganisms.
• Synergy: The combined effect of two antimicrobials is greater than their added effect.

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 Principles of Antimicrobial Therapy •Antimicrobial therapy is dependent on: •Host factors •Susceptibility/resistance to antimicrobial •Pharmacodynamics •Host factors •Impaired immune function •Age •Liver and kidney function •Stomach pH •Pregnancy •Could drug harm the fetus? 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) 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 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 Antibiotics β-Lactams Penicillins Cephalosporins Carbapenems Monobactams.
Penicillin: •Mechanism of action: •Inhibit cell wall synthesis •Bactericidal •Activate endogenous autolytic system in bacteria •Can act synergistically with aminoglycosides •Adverse reactions and precautions for penicillins: •Hypersensitivity (most common) •Hematological reactions •Gastrointestinal disturbances •CNS toxicity.

Cephalosporins •Mechanism of action •Inhibit bacterial cell wall synthesis •Bactericidal •Adverse Reactions ●Hypersensitivity (1–3%) ●Minor gastrointestinal complaints •Hypoprothrombinemia (those with MTT side chain) •Flushing •Nausea •Thirst •Palpitations •Chest pain •Vertigo •Death (in some cases)

Carbapenems •Mechanisms of action •Similar to other β-lactams •Inhibit cell wall synthesis •Bactericidal •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

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

Aminoglycosides •Gentamicin •Tobramycin •Netilmicin •Amikacin •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

Other-Clinically significant Antibacterials:

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

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

Examples of Bactericidal/Fungicidal and Bacteriostatic/Fungistatic Antimicrobials “Cidal” • Aminoglycosides • Carbapenems • Cephalosporins • Colistin • Daptomycin • Isoniazid • Metronidazole • Penicillins • Polyenes • Fluoroquinolones • Rifampin, rifabutin • Vancomycin* “Static” • Azoles • Chloramphenicol • Clindamycin • Linezolid* • Macrolides, azalides, ketolides • Nitrofurantoin • Quinupristin/dalfopristin* • Tetracyclines • Tigecycline • Trimethoprim-sulfamethoxazole

Tuberculosis Quick Review: 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

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

Antifungals Quick Review- clinically significant drugs mentioned: 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, blastomycosis, histoplasmosis, coccidioidomycosis, and cryptococcosis •Adverse reactions and precautions •Flushing, fever, chills (infusion related) •Renal impairment

Antifungals (Cont.) •Azoles •Mechanism of action •Reduce ergosterol production •Fungistatic effect •Clinical uses •Candidiasis (fluconazole) •Adverse reactions and precautions •Anorexia •Nausea •Vomiting

Antifungals (Cont.) •Echinocandins •Mechanism of action •Inhibit fungal cell wall synthesis •Fungicidal or fungistatic depending on isolate •Clinical uses •Candida and Aspergillus •Adverse reactions and precautions •Fever, rash, flushing, thrombophlebitis

Antifungals (Cont.) •Flucytosine •Mechanism of action •Inhibits fungal RNA formation •Fungistatic •Clinical use •Candida, Cryptococcus, Aspergillus •Adverse reactions and precautions •Bone marrow suppression

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

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 of suspected.