aminoglycosides Flashcards
aminoglycosides
gentamicin, tobramycin, amikacin*, streptomycin
aminoglycoside chemistry
The aminoglycosides consist of 2 or more amino sugars linked to an aminocyclitol ring by glycosidic bonds, hence the name aminoglycosides.
The six-membered aminocyclitol ring of the aminoglycosides is either streptidine (streptomycin) or 2-deoxystreptamine (gentamicin, tobramycin, netilmicin, amikacin, kanamycin, and neomycin).
The aminoglycosides are very polar compounds that are polycationic, highly soluble in water (distribute primarily into extracellular fluid compartment; renally eliminated), and incapable of crossing lipid-containing cellular membranes (poor oral absorption; poor penetration through meninges, poor lung penetration).
aminoglycoside MOA
The mechanism of action of the aminoglycosides is multifactorial, but ultimately involves the inhibition of protein synthesis.
Aminoglycosides irreversibly** bind to the 30S ribosomal subunit (some to 50S subunits), which results in a disruption in the initiation of protein synthesis, a measurable decrease in protein synthesis, and misreading of messenger RNA.
-For Gram-negative bacteria, the aminoglycosides must first bind to and diffuse through the outer membrane through porin proteins. This is a passive and non-energy dependent process since the polycationic aminoglycosides bind to negatively charged residues in the lipopoly-saccharide polar heads of phospholipids in the outer membrane.
-Once in the periplasmic space, the aminoglycosides must then be transported across the cytoplasmic (inner) membrane → a process that is dependent upon a membrane potential, is energy-dependent, requires oxygen (why they are not useful against anaerobes), and is rate-limiting. The transfer across the cytoplasmic membrane can be impaired by hyperosmolarity, divalent cations, low pH, and anaerobiasis (all impair the membrane potential that drives transport), which lead to decreased transport and a reduction in antibacterial activity.
-Following transport across the cytoplasmic membrane, the aminoglycosides bind to polysomes and inhibit the synthesis of proteins, which disrupts the structure of the cytoplasmic membrane. This then accelerates the subsequent transport of aminoglycoside into the bacterial cell, and facilitates bacterial killing.
Aminoglycoside antibiotics are rapidly bactericidal in a concentration-dependent manner against Gram-negative aerobes, and only display bacteriostatic activity against Enterococcus spp.
aminoglycoside MOR
Alteration in aminoglycoside uptake**
-Chromosomal mutations that influence any part of the binding and/or electrochemical gradient that facilitates aminoglycoside uptake may lead to decreased penetration of aminoglycoside inside the bacteria.
Synthesis of aminoglycoside-modifying enzymes**
-Plasmid-mediated resistance factor that enables the resistant bacteria (usually Gram-negative) to enzymatically modify the structure of the aminoglycoside by acetylation, phosphorylation, or adenylation. The modified aminoglycoside displays poor uptake through the outer membrane and binds poorly to ribosomes, leading to high-level resistance.
-A large number of enzymes have been identified and cross-resistance may occur. Gentamicin and tobramycin are generally modified by the same enzymes, while amikacin is usually not affected.
Alteration in ribosomal binding sites**
-Ribosomal binding site alterations rarely occur as a mechanism of resistance to gentamicin, tobramycin, and amikacin because they bind to multiple sites on the 30S and 50S ribosomal subunits.
-May occur with some isolates to render streptomycin inactive (found in E. coli, N. gonorrhoeae, and Enterococcus spp.) since streptomycin only binds to a single site on the 30S ribosomal subunit.
aminoglycoside spectrum of activity
The aminoglycosides demonstrate concentration-dependent bactericidal** activity against aerobic Gram-negative bacteria, where the Peak:MIC ratio correlates best with clinical efficacy for infections due to Gram-negative aerobes (Peak:MIC ratio of 10 to 20:1 is optimal).
Gram-positive aerobes: (NEVER USED ALONE, always used in LOW DOSES with cell-wall active agents to provide synergy) – primarily gentamicin
-Viridans streptococci
-Enterococcus spp. (gentamicin or streptomycin)
-Most strains of Staphylococcus aureus* and coagulase-negative staphylococci
Gram-negative aerobes: gentamicin, tobramycin and amikacin (activity A>T>G; NOT streptomycin) are very active** against Gram-negative aerobes; often used with cell-wall active agents to provide synergy; HIGHER DOSES ARE USED
-PPPEEACKSSS**
-Acinetobacter spp.
-Proteus spp.
-Citrobacter spp.
-Providencia spp.
-E. coli
-Pseudomonas aeruginosa**
-Enterobacter spp.
-Salmonella spp.
-Klebsiella spp.
-Serratia marcescens
-Morganella morganii
-Shigella spp.
-Gentamicin and streptomycin are active against Brucella and Yersinia.
Anaerobes - aminoglycosides are INACTIVE
Mycobacteria
-Streptomycin is active against Mycobacterium tuberculosis, M. bovis, M. marinum, and some strains of M. kansasii and M. avium-intracellulare.
-Amikacin is active against most strains of M. chelonae, M. fortuitum, M. kansasii, and M. marinum.
Post-Antibiotic Effect (PAE)
-PAE is the persistent suppression of bacterial growth after the concentrations of the antibiotic have fallen below the minimum inhibitory concentration (MIC) for the infecting bacteria.
-Aminoglycosides display a post-antibiotic effect for most Gram-negative bacteria, as well as S. aureus. The PAE exists for a finite period of time; usually 2 to 4 hours against Gram-negative bacteria.
Synergy
-Synergy exists between the aminoglycosides and cell-wall active agents, such as the β-lactams and vancomycin. Synergy is demonstrated when the effect of the drugs in combination is greater than the anticipated results based on the effect of each individual drug; the effects are more than just additive.
-Thought to be due to enhanced uptake of aminoglycoside into bacteria whose cell walls have been damaged by cell wall synthesis inhibitors.
-Synergy has been demonstrated for:
—Enterococcus: with ampicillin, penicillin or vancomycin (gent or strep)
—S. aureus, viridans streptococci: with β-lactams or vancomycin (gent)
—P. aeruginosa and other Gram-negative aerobes: with β-lactams (gent-amicin, tobramycin or amikacin)
aminoglycoside pharmacology
Aminoglycosides are highly polar cations, which accounts for their lack of absorption after oral administration, their pattern of distribution throughout the body, and their elimination in the urine as unchanged drug. Interpatient variability exists in the pharmacokinetic parameters of volume of distribution and clearance**, which influences dosing of the aminoglycosides for each individual patient.
aminoglycoside absorption
Aminoglycosides are very poorly absorbed from the gastrointestinal tract. Therefore, for the treatment of systemic infections, they must be administered parenterally (intravenous-IV or intramuscular-IM).
Aminoglycosides are well absorbed after IM administration, with peak concentrations occurring 30 to 120 minutes after IM injection. Drug absorption after IM injection may be decreased in patients with hypotension and should not be used in critically ill patients.**
Intermittent intravenous infusion is the preferred* route of administration, with doses infused over 30 to 60 minutes.
aminoglycoside distribution
Aminoglycosides are distributed primarily in the extracellular fluid compartment, and are widely distributed into body fluids including ascites, pericardial, peritoneal, pleural, and synovial fluids as well as into the urinary tract.
Aminoglycosides distribute poorly into cerebrospinal fluid** (even in the presence of inflamed meninges), ocular tissue, bile, sputum, and adipose tissue. LEAN BODY WEIGHT (LBW)* should be used for aminoglycoside dosing, with an adjusted dosing weight (ADW) used for obese patients (over 130% of LBW). The lean body weight in kg for males and females can be calculated using the Devine method:
LBW males = 50 kg + {2.3 kg x (# of inches greater than 60)}
LBW females = 45.5 kg + {2.3 kg x (# of inches greater than 60)}
The physiologic space that accounts for aminoglycoside distribution is susceptible to volume-related changes that may occur in hospitalized patients or patients with certain medical conditions (e.g., ascites, pregnancy, congestive heart failure), as well as in patients of different ages (larger Vd in neonates and infants). These volume differences must be taken into account when calculating an aminoglycoside dose because the aminoglycosides are concentration-dependent bactericidal agents.
Vd normal = 0.25 L/kg
Vd dehydration = 0.15 - 0.20 L/kg
Vd edema = 0.30 - 0.35 L/kg
Neonates and infants tend to have a larger Vd than adults. The initial Vd is over 0.5 L/kg, and decreases from birth over the next year to the adult value of 0.25 L/kg.
aminoglycoside emilination
85 to 95% of an administered aminoglycoside dose is eliminated unchanged by the kidney* via glomerular filtration, resulting in high urinary concentrations.
In adults with normal renal function, the elimination half-life of the aminoglycosides is 2.5 to 4 hours. Decreases in renal function directly influence the elimination of the aminoglycosides, causing a prolongation of the half-life*.
Hemodialysis removes 30 to 50% of aminoglycoside present in the bloodstream, requiring supplemental dosing. Peritoneal dialysis removes 25% of serum concentrations over 48 to 72 hours.
aminoglycoside serum concentration monitoring
Clinical studies have demonstrated a relationship between aminoglycoside peak and trough concentrations with efficacy and toxicity. Because of interpatient variability in pharmacokinetic parameters and the narrow therapeutic index of the aminoglycosides, serum concentration monitoring is necessary in ALL patients.
The target peak and trough concentrations of aminoglycosides vary depending upon the dosing method used and the indication for use (see individual dosing methods for target serum concentrations).
Peak concentrations should be obtained 30 minutes after a 30 minute infusion for standard/traditional dosing, and 60 minutes after a 60 minute infusion for once-daily/extended interval dosing. Trough concentrations should be obtained anytime within 30 minutes prior to the next dose.
It is imperative to achieve “therapeutic” aminoglycoside concen-trations within 24 hours in patients with Gram-negative sepsis, as studies have demonstrated increased mortality with subtherapeutic levels in these patients.
aminoglycoside dosing
With either dosing method, differences in PK parameters must be considered when determining an aminoglycoside dose for each patient. Factors that should be considered include volume status, renal function, age, gender, weight, infection being treated, severity of infection, etc.
aminoglycoside standard or traditional dosing
Smaller doses (1 to 2.5 mg/kg/dose) are administered with the dosing interval dictated by the patient’s renal function; subsequent doses are based on peak and trough serum concentrations obtained at steady state Gram-positive synergy: 1 mg/kg gent – using LBW or ADW Gram-negative: -LD = 2 to 2.5 mg/kg (gent, tobra) – using LBW or ADW -MD = 1.5 to 2 mg/kg/dose (gent, tobra) – using LBW or ADW -Amikacin dose = 7.5 to 10 mg/kg/dose – using LBW or ADW Dosing interval - depends on renal function -Calculate k and half-life based on CrCl - typically dosed every 2 to 3 half-lives (every 8, 12, 18, 24 hours…choose practical interval) Subsequent dosing based on peak and trough concentrations
look at peak/trough on page 8 of lecture
once daily or extended interval aminoglycoside dosing
Dosing method based on the PD principles of concentration-dependent bactericidal activity and the post-antibiotic effect. Larger doses (5 to 7 mg/kg/dose) are administered every 24 hours to obtain high peak concentrations (better bacterial killing) and undetectable trough concentrations (less toxicity, rely on PAE).
Gent/Tobra: 5 to 7 mg/kg as a single daily dose* (use LBW or ADW)
Amikacin: 15 to 25 mg/kg as a single daily dose* (use LBW or ADW)
This dosing method should only be considered in patients with normal renal function (creatinine clearance > 40 to 50 ml/min), normal Vd, and in the treatment of one of the following infections: urosepsis, intraabdominal infection, skin and soft tissue infections. This method should be used with caution in immunocompromised patients, patients with large or small Vd, and patients with high clearance (young, burn) or low clearance.
**Some institutions employ this dosing method in patients with renal insufficiency (CrCl less than 40-50 ml/min), but prolong the dosing interval to every 36 or every 48 hours (AKA Extended Interval Dosing). **
* Subsequent doses are based on serum concentrations obtained at 2 and 10 hours after the end of infusion of the first dose OR using the Hartford dosing nomogram with a serum concentration drawn 8 to 12 hours after the first dose.*
**Actual peak and trough concentrations are rarely obtained with once daily/extended interval aminoglycoside dosing. In these rare instances, the desired target concentrations are:
-only used for gram-negative infections - intraabdominal, skin/soft tissue, complicated UTI
-gent, tobra: peak=13-20; trough=less than 0.5
-amikacin: peak=40-50; trough=less than 4
clinical uses of aminoglycosides
aminoglycosides are RARELY USED ALONE*
Amikacin, gentamicin, and tobramycin* are used for the treatment of serious infections due to Gram-negative aerobic bacteria* (including Pseudomonas aeruginosa) such as bacteremia, bone and joint infections, skin and soft tissue infections, respiratory tract infections, intraabdominal infections, and complicated urinary tract infections - usually with B-lactams
Gentamicin or streptomycin** may be used with appropriate cell wall active agents (ampicillin, vancomycin, etc) for the treatment of serious infections (endocarditis) due to enterococci, viridans streptococci, or staphylococci.**
Streptomycin or amikacin may be used in conjunction with other antituberculous medications in the treatment of active tuberculosis* or other mycobacterial infections.
Oral neomycin is used in conjunction with other oral antibiotics to sterilize the gastrointestinal tract prior to abdominal surgery.
aminoglycoside AEs
nephrotoxicity, ototoxicity, Other rare adverse effects of the aminoglycosides include neuromuscular blockade (neomycin), hypersensitivity, and sterile abscess formation with IM injection.
