Module 3 - Antimicrobials
N609

Discuss factors that may influence the selection of an appropriate antimicrobial regimen.
Given a clinical scenario, recommend a safe, effective and patient-specific antimicrobial treatment option.
Identify common mechanisms of antimicrobial resistance and the antimicrobial stewardship strategies that may be utilized.

Identify the source and site of the infection.
Conduct medical history and physical examination to identify the signs and symptoms of the infection.
Identify underlying medical or social conditions.
Identify causative pathogen.
Collect specimens from most likely body sites.
Grow the causative organism in culture and perform antibiotic susceptibility testing.

The patient is responding to therapy, as evidenced by a return to normal or a trend toward normal values in the patient's temperature and white blood cell count.
The patient can take oral medications and absorb them adequately.
An oral equivalent to the parenteral regimen exists. In choosing the oral equivalent, the goal is to select an agent (or agents) that provides a similar spectrum of antimicrobial activity and possesses good oral bioavailability.

They are classified based on their spectra of activity.
Most are administered parenterally.
They are widely distributed in the body and penetrate cerebrospinal fluid (CSF).
Most are excreted by the kidneys.
Half-life is typically 30 to 90 minutes.
They exhibit time-dependent bactericidal activity and postantibiotic effect (PAE) against most gram-positive organisms.

Mechanism of action: inhibition of bacterial cell growth by interference with cell wall synthesis.
Spectrum of activity: binding to and inactivating the penicillin-binding proteins (PBPs).
Clinical uses: treating infections of upper and lower respiratory tract, urinary tract, and central nervous system (CNS) and sexually transmitted diseases.
Adverse events: low incidence; most common are hypersensitivity reactions.

Role: to prevent the breakdown of the beta-lactam by organisms that produce the enzyme-enhancing antibacterial activity.
Pharmacokinetics: diffuse into most body tissues except brain and CSF, and their half-life is approximately 1 hour; they are eliminated by glomerular filtration.
Mechanism of action: wall-active agents.
Clinical uses: treating polymicrobial infections.
Adverse effects: hypersensitivity and gastrointestinal (GI) side effects.

Divided into five "generations" based on their antimicrobial spectrum of activity.
Pharmacokinetics: well absorbed from the GI tract; penetrate into tissues and body fluids; are high concentrations in urinary tract; and most are excreted by the kidneys.
Action: interfere with bacterial cell wall synthesis by binding to and inactivating PBPs.
Uses: used in treating many infections; favorable toxicity profile.

Unique class of beta-lactams with a four-membered ring lacking a fifth or sixth member, like other beta-lactams.
Aztreonam (Azactam): only available agent of its class.
Pharmacokinetics: distribute well into most tissues; not extensively bound to proteins; half-life is 3 hours; excreted primarily unchanged by glomerular filtration.
Mechanism of action: interfere with bacterial cell wall synthesis; safe toxicity profile.
Clinical uses: treating urinary tract infections (UTIs) and respiratory tract infections.

Bicyclical beta-lactams with a common carbapenem nucleus; most broad-spectrum agents available.
Pharmacokinetics: widely distributed into most tissues, are minimally bound to plasma proteins; 1 hour half-life; and are primarily eliminated by urinary excretion.
Mechanism of action: bind to the PBPs on cell wall and interfere with bacterial cell wall synthesis.
Clinical uses and adverse events: treating polymicrobial infections; neurotoxicity GI side effects reported.

Display a concentration-dependent killing effect.
Excellent bioavailability for transition from intravenous (IV) to oral form.
Distribute well into most tissues and fluids except CNS.
Half-life ranges from 4 to 12 hours; elimination is renal.
Strong inhibitors of deoxyribonucleic acid (DNA) gyrase and topoisomerase IV.
Possess activity against aerobic gram-negative organisms.
Effective in treating many infections; safe side effect profile.

Erythromycin (E-Mycin), the prototypical macrolide, has been used in treating many infections over the years. However, its use has been diminished by GI side effects.
Pharmacokinetics: oral; are absorbed from the GI tract; have good tissue penetration, high intracellular concentration, and minimal protein binding; and are metabolized via liver.
Clinical uses: treating respiratory tract, skin, and soft-tissue infections; sexually transmitted diseases; HIV-related Mycobacterium avium-intracellulare complex infection; and other infections caused by atypical organisms.

Major drawback is potential for nephrotoxicity and ototoxicity.
Pharmacokinetics: poorly absorbed from GI tract, parenteral administration is necessary to treat systemic infections; they are weakly bound to serum proteins (10%) and freely distribute into the extracellular fluid.
Clinical uses: primarily used in treating gram-negative infections, including neutropenic fever and nosocomial infections.

A clinician is choosing an antibiotic for a patient diagnosed with syphilis. What would be the best choice for this type of infection?
A. Penicillin
B. Beta-lactamase inhibitor
C. Quinolone
D. Aminoglycoside

A. Penicillin
Rationale: The penicillin class is effective in many infections, including upper and lower respiratory tract, urinary tract, and CNS infections as well as sexually transmitted diseases. It is the treatment of choice for all stages of syphilis.

Possess activity against gram-positive, gram-negative, and atypical organisms, including rickettsiae, chlamydia, mycobacteria, and spirochetes.
They are separated into short-, intermediate-, and long-acting agents.
Doxycycline and minocycline are considered long-acting and the most active of the class.
Used in many settings and as alternatives when beta-lactams are not an option; frequently used to treat rickettsial, chlamydial, and gram-negative infections.

By-product of the dye prontosil rubrum.
Pharmacokinetics: readily absorbed from GI tract, distributed through all body tissues, enter CSF, pleural fluid, and synovial fluid; eliminated through glomerular filtration and hepatic metabolism.
Mechanism of action: inhibiting the incorporation of para-aminobenzoic acid, a basic building block of bacteria.
Clinical uses: treating ulcerative colitis, and in combination with other drugs for UTIs, pneumonia, toxoplasmosis, and resistant gram-negative infections.

Vancomycin: originally known as "Mississippi Mud" for impurities; important antibiotic has been used since 1980s; drug of choice for methicillin-resistant Staphylococcus aureus (MRSA) and other gram-positive infections.
Dalbavancin, oritavancin, and telavancin: newer additions to class; have a narrow spectrum of activity directed toward gram-positive organisms.
Serum drug monitoring is used for vancomycin in patients with unpredictable kidney function or severe infections or those receiving therapy for more than 3 to 5 days.

Totally synthetic antibiotic class was first investigated in the late 1980s as antidepressant agents, then was discovered to have excellent antibacterial activity.
Main reason for their development is the emergence and spread of resistance in gram-positive pathogens.
Linezolid (Zyvox): treatment of community and nosocomial pneumonia, skin and skin structure infections, and vancomycin-resistant Enterococcus faecium.
Tedizolid: treatment of skin and skin structure infections.

A practitioner is prescribing an aminoglycoside for a patient who contracted a nosocomial infection. What serious side effect would the practitioner monitor in this patient?
A. QTc prolongation
B. Pancreatitis
C. Peripheral neuropathy
D. Ototoxicity

D. Ototoxicity
Rationale: The major drawback of the aminoglycosides has been their potential for drug-related toxicities (nephrotoxicity and ototoxicity). Because of these, their use or the length of therapy has been restricted. Peripheral neuropathy and QTc prolongation are rare but serious side effect of the fluoroquinolones (FQs). A rare side effect of metronidazole is pancreatitis.

Daptomycin: natural product developed for the treatment of multidrug-resistant gram-positive pathogens.
Pharmacokinetics: nearly linear and time independent at doses up to 6 mg/kg administered once daily for 7 days. Its half-life is approximately 8 hours.
Clinical uses: treating complicated skin and skin structure infections, bacteremia, including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.

Quinupristin/dalfopristin (Synercid): the only streptogramin antibiotic available in the United States.
Pharmacokinetics: not absorbed from the GI tract; IV administration, serum half-life of approximately 1 hour; moderately protein bound; metabolism is through liver; excreted in feces.
Clinical uses: treating skin and skin structure infections and vancomycin-resistant E. faecium infections.
Adverse events: infusion-related reactions; increased conjugated bilirubin.

Lefamulin (Xenleta) belongs to a new class of agents known as the pleuromutilins.
Following IV and oral administration, lefamulin has a half-life of approximately 8 hours in patients with community-acquired bacterial pneumonia.
Lefamulin is generally well tolerated, with nausea and abdominal upset being the most common adverse effects reported after oral administration, and local infusion reactions are most commonly reported after IV administration.

A clinician is treating a patient diagnosed with MRSA. What is the drug of choice for this type of infection?
A. Sulfasalazine
B. Vancomycin
C. Tigecycline
D. Doxycycline

B. Vancomycin
Rationale: Vancomycin is frequently used to treat serious gram-positive infections in patients allergic to or unable to tolerate beta-lactam antibiotics, and it is the drug of choice for MRSA and other resistant gram-positive infections. Sulfasalazine (Azulfidine) is poorly absorbed and is used in the management of ulcerative colitis. Tigecycline is approved by the Food and Drug Administration for treating complicated skin and skin structure infections, intra-abdominal infections, and community-acquired pneumonia (CAP). Doxycyline is the drug of choice for the treatment of early Lyme disease and CAP.

Clindamycin: used extensively in treating gram-positive and anaerobic bacterial infections.
Clinical uses
Providing anaerobic coverage in mixed infections
Treating gram-positive infections, toxoplasmosis, and P. jiroveci pneumonia or in combination with other agents to treat pelvic inflammatory disease
Inhibiting toxin production as part of the treatment for staphylococcal or streptococcal toxic shock

Metronidazole (Flagyl): first recognized for its antiprotozoal activity in treating Trichomonas vaginalis infections. Subsequently, its utility as an antianaerobic agent was used in treating Bacteroides fragilis infections.
A treatment of choice for anaerobic infections, Clostridium difficile colitis, and is part of a number of regimens to eradicate Helicobacter pylori-associated duodenal ulcers.

Chloramphenicol has a wide spectrum of activity against gram-positive, gram-negative, and anaerobic organisms. However, its use has been limited by its toxicity profile, which includes "gray baby" syndrome, optic neuritis, and fatal aplastic anemia.
Rifampin is a macrocyclic antibiotic used in a variety of settings, and it is a first-line agent in treating tuberculosis. It is typically combined with other antibiotics such as vancomycin in treating MRSA infections.
Nitrofurantoin is an antimicrobial agent used only for treating and preventing UTIs.

Bacterial enzyme production
Decreased membrane permeability
Promotion of antibiotic efflux
Altered target sites/protection of target sites
Altered target enzymes
Overproduction of target enzymes

Extended spectrum beta-lactamases against Escherichia coli and Klebsiella, carbapenem-resistant Klebsiella
Fluoroquinolone-resistant gonococcus
MRSA
Vancomycin-intermediate S. aureus.

Formulary restrictions
Evidence-based prescribing
Dose optimization
Antibiotic streamlining
De-escalation

Overuse of antibiotics is well documented and has led to increased resistance to various strains of bacteria worldwide.
The Infectious Diseases Society of America has developed antibiotic stewardship guidelines, which recommend a multidisciplinary approach to improving antibiotic use, particularly in the hospital setting.
To minimize resistance, all prescribers must make an effort to ensure appropriate antibiotic use.

Arcangelo, V. (2022). Pharmacotherapeutics for Advanced Practice: A Practical Approach. 5th ed.
Wolters Kluwer. Philadelphia, PA