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1. Principles of Antimicrobial Therapy
a. Overview and Selection Criteria Antimicrobials are agents that injure or kill invading pathogens without harming host cells. Selecting an antimicrobial requires knowledge of: the pathogen's identity and susceptibility the site of infection patient factors the agent's safety and efficacy cost Empiric therapy , initiated before definitive identification and susceptibility testing, is often necessary for acutely ill patients, those with neutropenia, or meningitis. Choosing a drug without susceptibility data is influenced by the infection site, patient history, and local susceptibility patterns. Broad-spectrum agents are indicated initially when the pathogen is unknown or polymicrobial infections are suspected.
b. Determining Susceptibility and Resistance
Antibiotic susceptibility testing, performed after cultures, guides the selection of effective therapy.
Some pathogens, like Streptococcus pyogenes, have predictable susceptibility
while others, such as gram-negative bacilli and staphylococcus species, require specific testing. □ If culture nonconfirmatory, or not an option: detection of antigens, DNA or RNA; detection of an inflammatory response Newest techniques PCR and matrix assisted laser desorption/ionization time of flight [MALDI-TOF] mass spectrometry to obtain accurate, rapid identification of the organism Empiric Therapy: Timing: • Acutely ill patient with FUO • Neutropenic patient • Patient with meningitis • Others that require immediate therapy. Can’t wait for cultures Selecting a Drug for empiric therapy: Choosing a drug without susceptibility is influenced by site, patient history, local susceptibility patterns Broad spectrum indicated initially when pathogen unknown or polymicrobes are suspected Choice may also be guided by known association of particular organisms in a given clinical setting
c. Bacteriostatic vs. Bactericidal Action Bacteriostatic agents are thought to arrest the growth and replication of bacteria at achieved drug levels. But unable to meet arbitrary cut off value for bacterial definition Bactericidal agents effectively kill pathogens, typically defined as killing greater than or equal to 99% within 18-24 hours. A drug's effect can vary; it may be bacteriostatic for one microbe and bactericidal for another, and host immune status and drug concentration are also critical factors. d. Measuring Antimicrobial Activity (MIC/MBC) The Minimal Inhibitory Concentration (MIC) is the lowest antimicrobial concentration that prevents visible growth of a microbe after 24 hours of incubation. Quantitative measure of in-vitro susceptibility Most common in practice The Minimum Bactericidal Concentration (MBC) is the lowest concentration of an antimicrobial agent that results in a 99.9% decline in colony count after overnight incubation. e. Factors Influencing Drug Efficacy i. Site of Infection (e.g., Blood-Brain Barrier) Antibiotic levels must reach the site of infection for bacteria to be eradicated. Natural barriers, such as the blood-brain barrier , limit drug delivery to certain bodily structures. The blood-brain barrier, a single layer of endothelial cells with tight junctions, restricts the entry of most molecules into the brain. Inflammation can compromise the blood-brain barrier's integrity, increasing local permeability. ii. Lipid Solubility and Molecular Weight Lipid solubility is a major determinant of a drug's ability to penetrate the blood-brain barrier. Ex. Flagyl and chloramphenicol are lipid soluble -have significant penetration into CNS PCN has Low lipid solubility- limited penetration Drugs with low molecular weight generally have an enhanced ability to cross the blood-brain barrier compared to high molecular weight compounds. Drugs with high weight (ex vanco) penetrate poorly, even if there is inflammation iii. Protein Binding and Transporter Affinity A high degree of protein binding restricts a drug's entry into the CSF the free, unbound drug concentration is key for CSF penetration Antibiotics with an affinity for transporter mechanisms or low affinity for efflux pumps exhibit better CNS penetration.
based on pharmacodynamics and pharmacokinetic properties 3 important properties that greatly influence the frequency of dosing: Concentation dependent killing Time-dependent (conc. Independent) killing Post antibiotic effect [PAE]
i. Concentration-Dependent Killing
Drugs exhibiting concentration-dependent killing (e.g., aminoglycosides and daptomycin) show increased bacterial killing as concentration rises. àOnce-daily bolus infusions of these drugs achieve high peak levels, promoting rapid bacterial killing.
ii. Time-Dependent Killing
For time-dependent killing drugs (e.g., beta-lactams), clinical efficacy is best predicted by the percentage of time blood levels remain above the MIC. ß-lactams, Glycopeptides, Macrolides, Clindamycin Linezolid Dosing aims to keep drug levels above the MIC for a significant portion of the dosing interval (e.g., >50% for PCN, >60% for Cephalosporins). àExtended or continuous infusions can be used to maximize the time above the MIC.
iii. Postantibiotic Effect
The (PAE) is the persistent suppression of microbial growth after levels have fallen below the MIC. àDrugs with a PAE often require only one dose per day (aminoglycosides, fluoroquinolones) h. Antimicrobial Spectra and Combinations Chemotherapeutic spectra classify agents as narrow (single/limited microbes), extended (gram-positive and some gram-negative), or broad (wide variety of species). Generally, treating with a single, specific antibiotic is preferred to minimize superinfections, resistance, and toxicity. Combinations can be advantageous for synergy or treating infections with unknown or variable etiologies but can also lead to antagonism or promote resistance.
i. Drug Resistance Mechanisms Pathogens are resistant if the maximum tolerated drug level does not inhibit their growth. Resistance can be inherent or acquired through spontaneous mutation or genetic transfer. Genetic alterations , such as DNA mutation or movement between organisms, are key to acquired resistance. Resistance mechanisms include altered expression of proteins , such as modification of target sites, decreased drug accumulation (due to reduced uptake or increased efflux), and enzymatic inactivation of the antibiotic.
□ Practice:
- All of the following factors influence the penetration and concentration of an antibacterial agent in the CSF EXCEPT: □ Lipid solubility of the lung □ MIC □ Protein binding of the drug □ Molecular weight of the drug □MIC will affect the effectiveness of the drug against a given pathogen, it does not affect the ability of a drug to penetrate into the brain □Lipid solubility, protein binding, molecular weight all determine how likely a drug is to penetrate the blood brain barrier and concentrate in the brain
- 72 y/o patient presents with fever, cough, malaise and SOB. CXR shows bilateral infiltrates consistent with pneumonia. Cultures reveal Pseudomonas aeruginosa sensitive to a Cephalosporin. Which of the following dose scheme is best based on the drug’s time-dependent bactericidal activity? □ 1 gram every 6° given over 30” □ 2 grams every 12° given over 3° □ 4 grams every 24° given over 30” à□ 4 grams as continuous infusion over 24° □Clinical efficacy of Cephalosporins is based on percentage of time that the drug concentration remains above the MIC □A continuous infusion would allow for the most amount of time above the MIC compared to intermittent [30”] and prolonged infusions [3-4 hours]
2. Cell Wall Inhibitors (Ch 29)
a. Overview of Cell Wall Inhibitors
These antibiotics selectively interfere with the synthesis of the bacterial cell wall; a structure composed of peptidoglycan (type of polymer consists of glycan units joined together by peptide cross links). Cell wall inhibitors are most effective against actively proliferating microorganisms. Major classes include: Penicillins Cephalosporins Carbapenems Monobactams ß Lactam Inhibitor + Antibiotic Combinations Lipoglycopeptides Other Antibiotics
b. Penicillin
i. Mechanism, Spectrum, and Types
Penicillins feature a core four-membered beta-lactam ring, with variations in the R side chain affecting their spectrum, stability, and susceptibility to beta-lactamases. mechanism of action involves interfering with the final stage of cell wall synthesis by competing for and binding to penicillin-binding proteins (PBPs). Penicillins are bactericidal and operate via a time-dependent killing mechanism. Natural penicillins (Penicillin G, V) have activity against many gram-positive and some gram-negative organisms and spirochetes. PCN V- oral only. Acid stable can survive in stomach PCN G used IV and IM, less stable in acid. More potent and used for severe infection Obtained from fermented fungus of PCN chrysogenum □ PCN G [benzyl penicillin] has activity against many gram +, gram – and spirochetes. it is 5-10 times more potent than PCN V against Neisseria spp. and anaerobes □ Most streptococci are sensitive to PCN G BUT PCN-resistant viridians streptococci and Streptococcus pneumoniae isolates are emerging
□ More than 90% of Staphylococcus aureus are now penicillinase producing and
resistant to PCN G 52
*not effective with gram negative – bc microbes have outer lipololysaccharide membrane
iii. Pharmacokinetics and Adverse Effects Penicillins are administered via oral, IV, or IM routes, with some available as depot injections for prolonged release. Absorption can be affected by gastric acid and food intake decreases absorption Penicillins distribute widely throughout body fluids, but penetration into certain sites like the prostate is insufficient for treatment. All PCNs cross BBB-none are teratogenic Penetration in bone and CSF no therapeutic unless sites are inflamed Excretion is primarily via the kidneys, requiring dose reduction in renal disease, though some (Nafcillin, Oxacillin) are metabolized by the liver. Probenecid (gout prevention) inhibits secretion of PCN causing high levels in blood. Hold probenecid or lower PCN dose Adverse drug effects include hypersensitivity reactions (10% incidence) -cross allergy among the B-lactams diarrhea due to disruption of intestinal flora, and rarely acute interstitial nephritis neurotoxicity at high doses- PCN cause GABAergic inhibition. Not common but seen in epileptic pts Hematologic-Decreased coagulation can be seen with high doses of Piperacillin and Nafcillin and perhaps with PCN G -Cytopenias with therapy longer than 2 weeks—check CBCs weekly in these patients
ii. Pharmacokinetics and Adverse Effects Many cephalosporins require IV or IM administration due to poor oral absorption. Distribution is generally good, with some achieving adequate CSF levels for meningitis treatment. Elimination occurs via tubular secretion and/or glomerular filtration, necessitating dose reduction in renal disease, except for ceftriaxone which is excreted in bile. ADEs: Cephalosporins are generally well-tolerated, but caution is advised in patients with penicillin allergies due to a 5-10% cross-reactivity risk, particularly with 1st generation agents.
ii. Monobactams
disrupt bacterial cell wall synthesis and primarily cover gram-negative aerobic bacteria. Aztreonam (Azactam)- prototype Covers gram + or anaerobic bacteria, do not cover gram-positive or anaerobic bacteria. Given IV or IM Accumulates in CKD pts Aztreonam shows little cross-sensitivity with other beta-lactams, making it a viable option for patients with penicillin or cephalosporin allergies. Potential adverse effects include phlebitis, rash, and elevated liver function tests, relatively non toxic
e. Beta-Lactamase Inhibitors and Combinations
Beta-lactamase inhibitors (e.g., Clavulanic acid, Sulbactam, Tazobactam) inactivate beta- lactamases, protecting susceptible beta-lactam antibiotics. Hydrolysis of the ß-lactam ring—either by cleavage with a ß-lactamase or by acid, destroys the antimicrobial effect These inhibitors are combined with beta-lactamase-sensitive antibiotics like amoxicillin, ampicillin, and piperacillin. Combinations like Ceftolozane/Tazobactam (Zerbaxa) and Ceftazidime/Avibactam (Avycaz) are used to treat resistant gram-negative infections , including multidrug-
resistant Pseudomonas aeruginosa.
Also for intra-abd infx (w/flagyl) Carbapenem-beta-lactamase inhibitor combinations, such as Meropenem/Vaborbactam (VaBomere), are approved for complicated UTIs including pyelonephritis Has activity against enterobacteriacae producing a broad spectrum B-lactamases, except mettallo-B-lactamases
f. Other Cell Wall Inhibitors
i. Vancomycin Vancomycin is a glycopeptide active against aerobic and anaerobic gram +
pathogens , including MRSA, MRSE, Enterococcus spp., and Clostridium difficile.
It is bactericidal, and its dosing frequency depends on the Glomerular Filtration Rate (GFR), requiring monitoring of creatinine clearance. Therapeutic targets include trough levels of 10-20 mcg/mL (drawn before 4th^ or 5th^ dose)
AUC/MIC ratio >/= 400 for Staphylococcus aureus.
ADE : include nephrotoxicity, infusion-related reactions ("Red-Man" Syndrome), and ototoxicity.
Resistance is common in Streptococcus and Staphylococcus but emerging in
Enterococcus faecium due to altered binding affinity.
Oral vancomycin is primarily used for Clostridium difficile infection.
