Antimicrobials
What are the four primary drivers that reduce the incidence of C. difficile infections and the advent of antimicrobial resistance in health care environments.
1) Timely and appropriate initiation of antibiotics 2) Appropriate administration and deescalation of antibiotics 3) Data monitoring, transparency and stewardship infrastructure 4) Availability of expertise at the point of care
What are the key risk factors for the development of resistant infections?
1) Treatment with antimicrobial therapy in the previous 3 months 2) Hospitalization for > 5 days 3) An environment characterised by a high frequency of antimicrobial-resistant organisms, immunosuppressive disease or therapy 4) Evidence that the infection is related to health care (i.e. pneumonia in people) Others: - Potential for bacterial translocation from the GIT - Performance of invasive procedures - Interventions associated with the placement of foreign materials with surfaces conducive to bacterial colonisation (i.e. indwelling catheters) - Inappropriate dosing regimen
In dogs that have already been treated with antibiotics, what percentage has been reported to remain positive for growth (Black et al)?
44%
Aminoglycosides are bactericidal/bacteristatic?
Bactericidal
Are beta-lactams bacteriostatic or bactericidal?
Bactericidal but they require the cells to be actively growing to be efficacious.
Bacteriostatic/bacteriocidal drugs should be avoided in critically ill patients and MDR infections. Why should they not be combined with bactericidal drugs?
Bacteriostatic Because if these drugs are combined with drugs whose mechanism of action depends on protein synthesis, such as growth of the organism (beta-lactam) or formation of a target protein, the effectiveness of the latter drug will be reduced. I.e. Beta-lactams and fluoroquinolones depend on continued synthesis of bacterial proteins; there are antagonistic effects if they are mixed with inhibitors of ribosomal activity.
Are macrocodes bactericidal or bacteristatic?
Bacteristatic
Why does culture not necessarily confirm infection?
Because culture results may not discriminate between normal commensal flora, opportunistic agents or other pathogens. Vibrant and pure growth provides support but does not confirm that a cultured organism is the infecting isolate.
Why is amikacin preferred to gentamicin?
Because it is not degraded by the common enzymes that break down gentamicin and often shows broader antimicrobial spectrum.
Why are aminoglycosides not effective against anaerobes?
Because their uptake across bacterial cell membranes depends on energy derived from aerobic metabolism. NB: Thus, they also have markedly reduced activity in areas of low pH and low oxygen tension.
Why are colistin and polymixin generally considered unsafe?
Because they act on shared target structures such as cell membranes
Give an example of synergism between two antibiotics.
Beta-lactams and aminoglycosides. Aminoglycoside penetration into bacteria is facilitated by penicillin-induced cell wall fracture. --> Aminoglycoside activity against enterococcus and staphylococcus should be supported by being combined with a cell-wall active antibiotic such as beta-lactam and vancomycin.
An increase in the volume of distribution results in an increase/decrease in plasma drug concentration.
Decrease
What are the indications for use of aminoglycoside therapy?
Due to the existence of other agents with similar spectrums and better safety profiles, the aminoglycosides are used for short term (</= 7 d) treatment for infections caused by susceptible strains of gram-negative microorganisms that are resistant to less toxic antibiotics. Can also be used for empiric treatment of life-threatening infections in patients that have recently been hospitalised or recently received antibiotics.
The risk of which kind of concerning beta-lactam resistance was increased in the 3 month period before testing.
ESBL Also found in the feces of healthy cats and dogs in the community
What is the spectrum of macrolides?
Effective against gram positive organisms and mycoplasma species Fair efficacy against anaerobic organisms Often concentrated in macrophages which can lead to high drug concentrations at the site of infection.
What is the spectrum of the fifth generation cephalosporins?
Effective against methicillin-resistent staph
What is the spectrum of aminoglycosides?
Effective against most community acquired gram-negative aerobes and select gram-positive pathogens. Klebsiella, citrobacter, enterobacter, serratia, and most acinetobacter Frequently (not uniformly) effective against multidrug-resistant Pseudomonas and E. coli Aminoglycosides can be effective against many Staph however other gram positive organisms such as strep and many enterococci are relatively resistant. Also active against some myocobacteria and less common pathogens such as Yersinia, Brucella and Francisella.
What type of drug is erythromycin? What type of drug is azithromycin?
Erythromycin - A macrolide Azithromycin - An azide - Grouped with macrolides because it shares similar properties
What is the spectrum of the second generation cephalosporins?
Examples - Cefaclor, cefoxitin, cefotetan, cefuroxime Stable against beta-lactamase Broad spectrum Moderately efficacious against gm + (less s. aureus, NOT enterococci) Greater activity against gm - than 1st gen Cefoxitin and cefotetan have increased anaerobic coverage (bactericides)
What is the spectrum of the first generation cephalosporins?
Examples - Cefazolin, cephalothin, cephalexin Increased activity against some beta-lactamse producing organisms such as staphylococci Display high degree of activity against gm + (NOT enterococci) Moderate activity against gm - Minimal activity against anaerobes
What is the spectrum of the antipseudomonal penicillins?
Examples - Ticarcillin, piperacilin Broader spectrum Gram + strep, enterococci, and others Exhibit greater activity against Pseudomonas, Proteus and bacteroides species. Variable activity against some gram-negative bacteria such as acinetobacter. Combination of ticarcillin and clavulanic acid does provide greater coverage against beta-lactamase producing organisms
What is the spectrum of the aminopenicillins (described as extended-spectrum penicillins in S+H but inconsistent label)?
Examples - ampicillin, amoxicillin Less active against gram positive and anaerobes than penicillin G Greater efficacy against gram-negative species (many have plasmid mediated resistance) Resistance a growing problem Can be combined with beta-lactamase inhibitors (sulbactam and clavulanic acid) to improve efficacy against gram-negative organisms and some beta-lactamase producing gram-positive and anaerobic organisms
Use of which drug class is more likely to cause MDR bacteria including MDR methicillin resistance in staphylococci?
Fluoroquinolones Beta-lactams are likely to result in resistance to other beta-lactams; fluoroquinolones are more likely to cause MDR bacteria
The development of E. coli as an MDR organism is correlated with treatment with which antibiotic class?
Fluoroquinolones Administration of even a single dose of fluoroquinolone has been associated with changes in the resistance patterns of commensal coliforms in humans. Administration of amoxicillin or enrofloxacin in normal dogs was associated with expression of resistance by decal E. coli within 3-5 days of therapy initiation. Resistance was high level for both drugs. Resistance was multidrug for enrofloxacin.
Give 2 examples of aminoglycosides.
Gentamicin Amikacin
What is the spectrum of penicillin G?
Good against gram + (with the exception of some staphylococci) Good against anaerobes Poor against gram -ve rods Drug of choice for: streptococcal infections (necrotising fasciitis), clostridial infection, actinomycosis
What is the spectrum of the fourth generation cephalosporins?
Good gram positive and good gram negative spectrum Greater resistance to beta-lactamases Antipseudomonal activity
List some aminoglycosides.
Most commonly used: Gentamicin Amikacin Rarely used: Netilmicin Streptomycin Tobramycin
Is enrofloxacin a good choice for mycoplasma hemofelis? what about ehrlichia?
No - a study showed that therapeutic effect was only established at levels associated with retinal toxicity. Enrofloxacin was similarly not effective in treating ehrlichia in experimentally infected dogs. However - recently licensed pradofloxacin has efficacy against mycoplasma, rickettsia and mycobacteria.
What drugs are bacteriostatic - give mechanism and some examples?
Ones that inhibit ribosomes and microbial growth: Chloramphenicol Tetracyclines Erythromycin
What biomarker can be used to guide antimicrobial therapy in people with respiratory infections to effectively reduce antimicrobial use without increasing risk of mortality or risk of treatment failure (Cochrane review).
Procalcitonin
In a 2012 study in JVIM by Westropp, high-dose short duration enrofloxacin (20 mg/kg PO SID x 3d) was compared to a 14 day course of amoxicillin-clavulanate for the treatment of uncomplicated urinary tract infections in dogs. What was the main finding?
That the two approaches were non-inferior.
What is the significance of the post antibiotic effect of aminoglycosides?
The PAE indicates that bacterial replication is impeded even after serum concentrations have fallen below the MIC for the organism in question. PAE tends to be longer in vivo than in vitro. This permits extended drug-free intervals without compromising outcome and can be enhanced with synergistic drug administration (i.e. beta lactams).
What physical characteristic defines beta-lactam antimicrobials?
The beta-lactam ring - essential for the biological activity. Substitutions are made on the beta-lactam ring for specific purposes.
What antibiotic class acts synergistically with aminoglycosides?
The efficacy of the aminoglycosides is enhanced by increased cell permeability induced by the beta-lactams which accelerates uptake of the aminoglycoside into certain bacteria. gentamicin synergy is often reported by commercial labs for unasyn isolates of enterococcus faecium and enterococcus faecalis Synergy is also often taken advantage of for life-threatening gram-negative infections (i.e. with Pseudomonas or many enterobacteriaeace)
The relationship between what two factors are drugs classified as time dependent or concentration dependent?
The relationship between: 1) The MIC and 2) the magnitude and time course of the plasma drug concentration PDC
The therapeutic effectiveness of aminoglyosides is correlated with the Cmax/trough and adverse effects correlate with the Cmax/trough.
Therapeutic effectiveness - Cmax Adverse effects - trough
What is the mechanism of action of aminoglycosides?
They penetrate the bacterial cell wall and membrane and impair protein synthesis by binding to components of the prokaryotic 30s ribosomal subunit resulting in misreading of mRNA, production of nonfunctional proteins, detachment of ribosomes from mRNA and cell death.
What are the effects of fluoroquinolones on P-450 metabolism?
They slow down P-450 metabolism.
What is the mechanism of action of beta-lactams?
- Beta-lactams interfere with bacterial wall synthesis - Bind to and inhibit the transpeptidases and peptidoglycan-active enzymes collectively referred to as penicillin-binding proteins (PBPs) that catalyse the cross linking of the glycopeptides which form the bacterial cell wall
What adverse effects are associated with fluoroquinolones?
- GIT signs (mild, dosage related) - Seizures, tremors, abnormal EEG findings (suspected to be due to inhibition of GABA receptors and stimulation of NMDA receptors) - May increase hepatic transaminase levels or liver function test values --> should be used with caution in animals with hepatic disease - Can cause renal lesions from crystalline deposition in tubular lumens at high doses - Associated with cartilaginous defects in juvenile animals and humans (inhibit proteoglycan synthesis, chelation of magnesium, inhibition of mitochondrial dehydrogenase) - In humans, effects are reversible with discontinuation of therapy. In one study, cartilage defects in young dogs were exacerbated by exercise and prevented by exercise restriction. Use in dogs between 2 and 8 months and up to 18 months in large breed dogs is contraindicated. - Rapid administration IV can cause histamine release, and hypotension, bradycardia and QT prolongation at higher dosages - Blindness in cats appears to be dose related rather than idiosyncratic; causes retinal degeneration more prominent in the photoreceptor and outer nuclear cell layers; most cats have irreversible vision loss (most common with enrofloxacin but also with orbifloxacin and marbofloxacin)
Discuss resistance to macrolides.
- Resistance develops rather quickly - Occurs via a one-step mutation conferring a high level of resistance - This mutation can be unstable but can develop during treatment - Most low-level resistance is cause via an efflux pump - Widespread resistance occurs when a gene coding for methylation of the drug's target site is transferred via a plasmid
Describe an approach to deescalation therapy.
1) At 48-72 hours following start of treatment, there is both clinical reassessment and assessment of relevant microbiological data - if no clinical improvement has been observed, microbiologic data should be critically reassessed and therapy re-examined 2) If the patient has experienced clinical improvement despite microbial data that indicate an inappropriate antimicrobial choice, the clinician may choose to stay the course and monitor or, in a patient at risk, consider the addition of a second antimicrobial supported by the data 3) If the patient has shown clinical improvement and the data indicate that the choice is appropriate, deescalation to a drug with a narrower spectrum or total discontinuation should be considered
What are the most important pharmacodynamic parameters that most closely correlate with the success of fluoroquinolones?
1) Cmax/MIC 2) AUC/MIC Although pathogen or species-specific AUC/MIC targets have been established for veterinary patients but they are rarely applied to clinical patients.
What is the spectrum of the four different generations of fluoroquinolones? Give examples of each.
1) First generation - i.e. nalidixic acid; achieve minimal serum levels 2) Second generation - i.e. enrofloxacin, difloxacin, ofloxacin, marbofloxacin and ciprofloxacin - increased gram-negative and systemic activity, some atypical pathogens; Ciprofloxacin has activity against pseudomonas 3) Third-generation - i.e. pradofloxacin, levofloxacin; expanded activity against gram-positive bacteria (staph aureus), atypical pathogens and some anaerobes (many anaerobes not covered) 4) Fourth-generation - i.e. moxifloxacin (some references refer to it as a 3rd gen), trovafloxacin significant activity against gram positive organisms and anaerobes in addition to gram negative bacteria. Do not cover pseudomonas.
Describe the overall spectrum of fluoroquinolones as a class.
1) Highly effective against aerobic gram-negative bacteria (E. coli, Klebsiella, Pasteurella, Haemophilus somnus, Bordetella, Campylobacter). 2) Variable efficacy against Pseudomonas - Ciprofloxacin and levofloxacin are the only quinolines with suitable potency for sure in people 3) Some of the newer fluoroquinolones are active against gram-positive bacteria (staph aureus, staph epidermis, Neisseria) 4) Activity against strep is limited to a small subset of quinolines 5) Because they can penetrate cells, they have activity against many intracellular pathogens (mycoplasma, mycobacteria, chlamydia, brucella) --> In general, fluoroquinolones available for veterinary use have limited activity against gram-positive and anaerobic organisms.
List, in order of appearance, the problematic MDR species that have surfaced since the 1990's.
1) Methicillin-resistant Staphylococcus aureus (MRSA) 2) Vancomycin-resistant Enterococcus (VRE) 3) Fluoroquinolone-resistant Pseudomonas (FQRP) 4) Fluoroquinolone-resistant E. coli 5) Vancomycin-resistant S. aureus (VRSA) 6) Fluoroquinolone-resistant Clostridium difficile
Describe the three pronged approach to deescalation therapy.
1) Narrowing the antibacterial regimen through culture 2) Assessing the susceptibility for dosage determination 3) Choosing the shortest course of therapy clinically acceptable
List the 4 different groups of penicillins and give examples from each.
1) Natural penicillins - Pen G 2) Aminopenicillins (calle extended spectrum penicillins in S+H but not other sources) - ampicillin, amoxicillin 3) Anti-staphylococcal penicillins (penicillimase resistant penicillins) - Oxacillin, methicillin, naficillin 4) Antipseudomonal penicillins - Ticarcillin, piperacillin
List the three major groups of beta-lactam antimicrobials?
1) Penicillins 2) Cephalosporins 3) Carbapenems
What are the adverse effects associated with aminoglycosides?
1) Reversible neuromuscular parlaysis - uncommon; due to interference with the release and uptake of acetylcholine at the NM junction. May also inhibit calcium movement into nerve terminals during depolarisation. Unlikely to be clinically relevant beyond mild weakness at higher doses unless patients have NM disease or are receiving NM blockers. Effect can be reversed with injectable calcium or a cholinesterase inhibitor such as neostigmine. 2) Irreversible cochlear and vestibular toxicity - occurs because aminoglycosides accumulate in the affected tissue and destroy sensory hair cells. Scant reports of vestibulocochlear damage in dogs or cats receiving recommend therapeutic dosages of amikacin or gentamicin. In people, SSD does not appear to significantly change the risk of ototoxicity. Ototoxicity rather seems to be associated with the duration of aminoglycoside treatment. 3) Nonoliguric renal insufficiency - well known adverse effect; damage proximal tubular cells and reach maximal toxicity around day 9. Because cationic state of the aminoglycosides facilitates binding to tubular epithelial cells. Intracellular transport results in high concentrations of the aminoglycosides within lysosomes. Lysosomes eventually destabilise and rupture which disrupts the normal cell structure and function. The resulting decreased GFR likely results from both tubular and non tubular mechanisms. Gentamicin is more nephrotoxic than amikacin but both have the potential to cause tubular damage. Manifests as polyuric renal failure manifesting 5-7 days after starting therapy. SDD is associated with less nephrotoxicity than multiple daily doses. Nephrotoxicity is also reduced if it is administered during the day due to diurnal decreases in GFR (at night). Cannot use BUN/Creat to monitor as it is too late an indicator; as patients are on fluids cannot use USG; enzymuria can be used but not able to be done routinely, so examination of urine sediment for granular or cellular casts and dipstick evaluation to look for tubular proteinuria and glucosuria on a daily basis is recommended. Some reports state that aminoglycoside induced real toxicity is associated with a poor prognosis, but it is suspected that tubular lesions are often reversible and renal function can recover if tubular injury detected early and therapy promptly discontinued. Other risk factors include concurrent nephrotoxic drugs (cisplatin, NSAIDs, diuretics, ACE inhibitors), pre-existing renal disease, potassium and magnesium depletion.
What are the three levels of drug penetration that exist in normal tissues?
1) Sinusoidal capillaries - adrenal cortex, pituitary gland, liver, spleen = no barrier to bound or unbound drug movement 2) Fenestrated capillaries - kidneys, endocrine glands = pores that do not present a barrier to unbound drug 3) Continuous (non-fenestrated) capillaries - brain, CSF, testes, prostate, muscle, adipose tissue = present a barrier of endothelial cells with tight junctions that preclude drug movement
At what CFU levels should resistance to an antimicrobial drug be anticipated (regardless of whether it is a commensal resident or an infecting pathogen)?
10^6 to 10^8
In studies in people, what % of beta lactams or aminoglycosides reach bronchial secretions? How does this compare to lipid soluble drugs such as azithromycin? (Due to the blood-bronchus barrier)
2-30% of beta-lactams or aminoglycosides 30-80% of lipid soluble drugs Azithromycin concentrations in bronchial secretions are 17 x higher than in plasma concentrations
Minimum bactericidal concentrations of quinolines are usually within _____ fold of the MIC for many target organisms.
2-4 fold Exhibit a high degree of efficacy at relatively low serum concentrations.
If an organism has an MIC of 2 mcg/ml what Cmax is required to provide an appropriate inhibitory quotient of 10?
20 mcg/ml Achieved almost invariably with SDD but exceptions can occur particularly in critically ill patients.
In the study by Black et al, what percentage of dogs were reported to have MDR bacterial infections?
27%
What is the significance of the fact that fluoroquinolones have a marked post antibiotic effect (PAE)?
A PAE is the period of time after serum drug concentration falls below the MIC that bacterial growth continues to be inhibited It allows a low frequency of dosing because they continue to inhibit bacterial growth for up to 8 hours after elimination from the body.
What is a biofilm?
A virulence factor that facilitates microbe adaptation to new environments. A biofilm is a community that effectively allows a single-cell microbe to become a multi cell organism. It consists of micro colonies of both pathogenic and host microbes embedded in a polysaccharide produced by microbes adhering to flat surfaces (foreign bodies, wound surfaces or other tissues). This promotes symbiosis and survival through sophisticated communication and patterns of antimicrobial resistance as well as an ability to avoid the host immune response. Organisms in the community are often quiescent and non responsive to antimicrobial therapy. *** Organism growth in catheters does not necessarily lead to infection and isolates cultured from urinary catheter tips are not necessarily those causing infection
Describe the tissue penetration of fluoroquinolones.
Accumulate in urine, kidney, lung, prostatic tissue, stool, bile, macrophages and neutrophils (higher than serum levels) Due to effec ton white cells they reach higher concentrations in inflammatory sits. Also accumulate in saliva, prostatic fluid, bone and CSF at concentrations less than serum but at levels often adequate to kill susceptible organisms particularly in the presence of inflammation.
What is adaptive resistance with reference to aminoglycosides?
Adaptive resistance is a first-exposure effect most relevant for gram-negative organisms such as Pseudomonas. After the first dose there is down regulation of aminoglycoside uptake by bacteria following subsequent doses which results in less bacterial killing and shorter PAEs with subsequent doses. Most likely to occur when first doses provide low peak serum concentrations (Cmax). The down regulation can last for hours. SDD provides the high serum concentrations needed to prevent induction of a first-exposure effect, extends the interval between doses to overcome the onset of adaptive resistance, and decreases the incidence of nephrotoxicity.
Granulocytopenic or otherwise immunocompromised patients are more likely to be infected by (aerobic/anaerobic), gram (positive/negative) organisms.
Aerobic, gram-negative
True or false - Aerosolized gentamicin should be routinely incorporated into treatment for lower respiratory tract infections in animals.
Although intriguing, there is insufficient evidence to recommend its use routinely. Limited data support its used as adjunctive therapy in canine patients with B. bronchiseptica. Use should be reserved for select patients with pulmonary infections that are highly resistant or unresponsive to aggressive conventional therapies, recognising that it is unknown how well or to what extent nebulized agents will be distributed to affected tissues. Systemic absorption is usually negligible. Topical delivery is never adequate and systemic antimicrobials must be used simultaneously.
What are some water soluble antibiotics?
Aminoglycosides, beta lactams, glycopeptides
Define nosocomial infection.
An infection arising more than 48 hours after hospital admission. Generally opportunist.
What antibiotics exhibit synergism with fluoroquinolones?
Antispeudomonal penicillins Ceftazidime Impipenem Occasionally rifampin and the aminoglycosides
What is the inhibitory quotient?
Cmax/MIC
In what situation is combination therapy associated with increased efficacy?
Combination therapy is associated with increased efficacy in most critically ill patients, but an increased risk of death was found in low-risk patients. Suggests that combination therapy improves survival and clinical response in high-risk, life-threatening infections (particularly septic shock) but can be detrimental in low-risk infections.
Fluoroquinolones act via concentration/time-dependent bacterial killing.
Concentration High peak tissue concentrations and persistence of antibiotic concentrations above the MIC value for a given organism determines in vivo efficacy.
Are aminoglycosides time or concentration dependent? Discuss the implications of this.
Concentration dependent Current recommendations are for single daily dosing (SDD) where the 24 hour dose is administered as a single dose rather than several times. The rate and extent of bacterial killing increases with higher aminoglycoside concentrations are achieved with SDD resulting in more favourable outcomes with less resistance. Optimized by attaining a Cmax that exceeds the Mic by a factor of 8-10 (the inhibitory quotient).
What are the advantages of deescalation therapy?
Cost minimisation Reduction in adverse events Reduced risk of antimicrobial resistance Decrease in the incidence of infections related to antimicrobial use such as C diff diarrhea or superinfection with MDR isolates of Candida
What is the spectrum of the carbapenems?
Examples - imipenem, meropenem, ertapenem Truly broad spectrum as a sole agent - active against most gram +, gram -, anaerobes including pseudomonas INACTIVE against MRSA, enterococcus, C. difficile As with all beta lactams (apart from 5th gen cephalosporins), MRSA are resistant to treatment with carbapenems High activity of imipenem is attributed to stability against most beta-lactamases including ESBL and its ability to penetrate porin channels that usually exclude other drugs Imipenem can be nephrotoxic; administered with cilastatin to decrease renal tubular metabolism. Rapidly bactericidal - less likely to release endotoxin in gram negative sepsis than cephalosporins Meropenem has equal or greater antibacterial activity to imipenem and is otherwise similar to imipenem - more soluble and can be administered more rapidly and is less nephrotoxic Resistance to carbapenems has been very rare in vet med
True or false - oral aminoglycosides are readily absorbed.
FALSE - Oral aminoglycosides are poorly absorbed. Oral neomycin is prescribed to suppress bacterial overgrowth in the large bowel. Paromomycin is effective for enteric salmonellosis and protozoal enteritis in companion animals. It is possible that systemic absorption could occur when the intestinal barrier is diseased or compromised.
True or false - The use of mandated restrictive formularies is effective in reducing antimicrobial resistance.
FALSE - Such formularies may actually increase problems associated with antimicrobial resistance.
True or false - An increased Vd due to vascular leak syndromes, oedematous states, hypoalbuminemia, SIRs, mechanical ventilation, burn injury, trauma or aggressive intravenous fluid injury can cause dangerously increased aminoglycoside concentrations.
FALSE - These situations would increase Vd which could result in sub therapeutic aminoglyocisde serum levels.
True or false - Aminoglycoside mono therapy is a commonly prescribed protocol.
FALSE - mono therapy with aminoglycosides is seldom appropriate in critically ill patients because although they show in vitro activity against some staph and enterococci, effectiveness for treating these organisms clinically is unknown. Generally administered in combination with a beta-lactam, beta-lactam/beta-lactamase inhibitor or a carbapenem to enhance bactericidal activity and minimise resistance. Can also be prescribed with metrondiazole or clindamycin if there is confection with an anaerobic pathogen.
True or false - Fluoroquinolones can be safety administered with antacids.
False - Concurrent administrate of antacids decreases GI absorption; oral fluoroquinolones should be given 2 hours before or 6 hours after sucralfate and oral antacids containing polyvalent cations
Why does fluoroquinolone-induced retinal degeneration occur? Has retinal toxicity been reported for marbofloxacin, orbifloxacin and pradofloxacin?
Fluoroquinolone induced regional degeneration in case is due to an absence of a retinal efflux pump Marbofloxicin, orbifloxacin, pradofloxacin do not appear to cause retinal toxicity even at dosages exceeding the recommended dosages by severalfold *** One chapter states this in S+H but another states marbofloxacin and orbifloxacin have been reported to cause blindness.
The use of which antibiotic has been associated with streptococcal toxic shock syndrome and necrotising fasciitis when used to treat Staphylococcus pyogenes in people and Streptococcus canis in animals?
Fluoroquinolones
Describe the pharmacology of aminoglycosides.
Highly water soluble (do not readily cross biologic membranes) Largely confined to extracellular fluid Have a correspondingly small volume of distribution (Vd) Excreted unchanged in urine Minimal penetration into CSF, prostate, vitreous humour Therapeutic concentrations are generally achieved in nonexudative pleural and peritoneal effusions, bones and synovial fluid Adequate tissue levels are generally achieved in the pulmonary parenchyma but not in bronchial secretions Usually ineffective for treating intracellular pathogens
Why is protein binding significant with respect to C+S testing?
In vitro C+S testing presumes no protein; if highly protein bound the MIC may underestimate the total plasma concentration needed for effectiveness (i.e. doxycycline)
What is the mechanism of action of macrolide antibiotics? What is another name for the macrolides?
Mechanism of action - Reversibly bind the 50s ribosome which suppresses ribonucleic acid-dependent protein synthesis. Macrocyclic lactones (a biochemical characteristic)
What is the mechanism of action of fluoroquinolones?
Inhibition of two topoisomerases: 1) DNA gyrase (previously called topoisomerase II) 2) Topoisomerase IV Via interacting with the enzyme-bound DNA complexes, there are conformational changes that result in the inhibition of normal enzyme activity blocking the progression of the replication fork and inhibiting normal bacterial DNA synthesis. In general, inhibition of topoisomerase IV is responsible for the bactericidal effect on gram positive bacteria and DNA gyrase inhibition is responsible for the antibacterial effect in gram-negative organisms.
What is the significance of an isolate considered susceptible as per the CLSI but with MICs very close to the susceptible breakpoint?
It suggests that some level of resistance has begun to emerge in isolates classified as susceptible.
What is the most concerning adverse effect associated with aminoglycosides?
Predictably nephrotoxic with toxicity related to the duration of exposure Toxicity is minimised by SID dosing so that trough levels (and subsequently urine drug concentration) drops below a threshold of <1-2 mg/ml. It is also important toe nsure the patient is hydrated (may include treatment with Na+ containing fluids), avoiding nephroactive drugs and administration of the aminoglycoside in the morning in diurnal animals. If nephrotoxicity occurs, treatment with N-acetylcysteine may decrease damage.
Discuss developing resistance in fluoroquinolones.
Resistance has developed in recent years particularly in staphylococcus, pseudomonas and e. coli organisms. Chromosomal point mutations in DNA gyrase (gram negative) and topoisomerase IV (gram positive) are major mechanisms of resistance. Point mutations are observed in the "quinolone resistance-determining region" resulting in decreased drug affinity to the enzyme-DNA complex decreasing effectiveness. Later generations of fluroquinolones with equal activity against DNA gyrase and topoisomerase IV would require simultaneous mutations in the bacteria at both sites to be rendered ineffective. As double mutants are rare, this might restrict the development of resistance. Bacteria are able to increase the expression of efflux systems that actively pump quinolines out of the cell. Important in E coli and potentially also inSalmonella. Gram negative bacteria can also change levels of outer membrane porins responsible for passive diffusion. Reduced porin 1a reduces antibiotic accumulation in the cytoplasm. Plasmid-mediated resistance has also been reported. Typically confer low levels of resistance to fluroquinolones but they favour selection of bacteria with additional resistance mechanisms. This could select for proliferation of specific, drug-resistant mutant populations resulting in fluoroquinolone and MDR resistance.
Define multidrug resistance.
Resistance to three or more antimicrobial drugs to which the organism is generally considered susceptible.
What is the significance of detectable levels of aminoglycoside 2-4 hours before the next dose is due with SDD testing?
Suggests renal dysfunction and should prompt the clinician to discontinue the aminoglycoside and pursue treatment with another class.
True or false - The use of deescalation procedures has been associated with successful return to susceptibility to previously resistant antibiotics?
TRUE
What is the justification for the strongly encouraged use of combination therapy for treatment of organisms with MDR (Pseudomonas, Enterococcus, MRSA)?
That a population size of 10^14 or more CFUs must be reached before spontaneous mutations cause resistance to two drugs.
What is the difference between time dependent and dosage dependent drugs? Give examples.
Time dependent: - Often act reversibly and therefore must be present during most of the dosing interval - Efficacy best predicted by the % time that the PDC is above the MIC (T > MIC) - i.e. Beta-lactams: Must be present as long as the organism is making cell walls - Also: other cell wall inhibitors, folic acid inhibitors, drugs considered to be bacteriostatic - The duration of T > MIC varies with the drug: - First tier aminopenicillines - T > MIC ideally is 100% of the dosing interval; vs. third-fourth tier carbapenems, duration should be 25% of the dosing interval - If have a short half life (i.e. aminopenicillins), dosing intervals must be shortened - CRIs or slow release formulations might be ideal - The use of drugs with very long half-lives (cefovicin - convenia) complicates attempts at de-escalation Concentration dependent: - Tend to bind target irreversibly - Effectiveness depends on achieving sufficient concentration at the site so that all target microbial molecules are bound - Effectiveness is predicted by comparing Cmax with MIC of the infecting organism - Often demonstrate excellent post antibiotic effect which allows a longer dosing interval than might be expected based on the elimination half-life - Target Cmax:MIC should be 10-12 (higher for more difficult infections) - Effectiveness can also be predicted by the area under the inhibitory curve (AUIC) which is the ratio of the AUC for 24 hours based on dose and interval : MIC. - AUIC over 100-125 is generally associated with bacterial killing and decreased resistance - For some organisms, might target dosing regimen at maximising both Cmax:MIC (higher dosage) and AUC:MIC (shorter dosing interval) - i.e. might decide to dose fluoroquinolone BID if cannot reach target Cmax:MIC with a single dose to increase the AUC:MIC - Fluoroquinolones, aminoglycosides Dosing regimens that reach the mutant-prevention concentration rather than the MIC at the site of infection are most likely to be effective.
What is the goal of SDD therapy with aminoglycosides? Is TDM testing normally done with SDD dosing?
To obtain a high Cmax while maintaining a drug-free interval of at least 2-4 hours. Therapeutic drug monitoring (TDM) is not uniformly recommended with SDD unless treatment is required for >5-7 days or patients are at high risk of toxicity. Ideally, TDM are performed at peak levels (20-30 min after IV infusion), and 2 additional samples during elimination (2 and 4 hours after infusion) from which Vd, clearance and half-life are calculated. This is often impractical however and there can be day-to-day changes in critically ill patients. An alternative is to do peak level testing at 20-30 minutes and a trough level 2-4 hours before the next dose is due to ensure adequate renal clearance and a sufficient drug free period. Alternatively, a random sample can be obtained at 8-12 hours following administration in an effort to prevent a prolonged drug-free period. If levels are too high it could suggest impaired renal clearance. SDD may obviate the need for TDM in human patients but at this time, TDM is recommended in veterinary patients even intermittently because goal-oriented dosing of aminoglycosides should result in enhanced effectiveness and less toxicity.
What is the spectrum of the third generation cephalosporins?
Typical examples - cefotaxime, ceftriaxone, cefixime, ceftazidime High degree of specificity for and efficacy against gram - (*** Ceftiofur, cefpodoxime are exceptions - have a spectrum more similar to first generation drugs) Considered treatment of choice for empiric therapy for infections located within the CNS Note: Due to the variation in spectrum of action across this class, efficacy of one drug does not guarantee efficacy of another Cefotaxime - not effective against pseudomonas Ceftazidime - less gram + but effective against pseudomonas
How are genes imparting resistance shared among organisms facilitating rapid transfer of MDR?
Via integrins, plasmids, and transponsons
What factors influence drug elimination?
Volume of distribution (directly proportional) Clearance (inversely proportional)
Why does the volume of distribution impact water and lipid soluble drugs differently?
Water soluble drugs will distribute to interstitial and other extracellular fluids; therefore increased fluid in these compartments (including pleural and peritoneal cavity) will result in lower tissue antimicrobial exposure. Dosages should be increase in these situations and may require drug monitoring (i.e. for aminoglycosides) to check peak (for efficacy) and trough (for safety) levels. Hypoalbuminemia also decreases antimicrobial exposure even for drugs that are not protein bound probably due to peripheral fluid retention and increased volume of distribution. Usually doses should be increased 1.5-2X Lipid soluble drugs dosage is calculated on a milligram-per-kilogram basis.
Fill in the blanks: Black et al found that the use of antimicrobials before bacteriologic culture submission was appropriate in only ____a____ of critically ill canine patients. This increased to ____b____ after culture results were reported but before MICs were available.
a) 30% b) 75%
Fill in the blanks: In human patients with septic shock, the survival rate declined by ___a___% for each hour's delay in the administration of appropriate antimicrobial therapy after the onset of hypotension. However, only ____b____ % of patients received appropriate antimicrobial therapy within the first 5 hours.
a) 7.6% b) 50%
In 74 canine ICU patients for which culture specimens were collected prior to starting antimicrobial therapy, Black et al reported that empiric selection was appropriate what percent of the time (a)? Which antibiotic had the highest sensitivity %? (b) Which antibiotic had the lowest susceptibility %? (c) Which combination therapy had the highest % sensitivity? (d)
a) 75% b) Imipenem - 79% c) Ampicillin-sulbactam - 29% d) Imipenem + Gentamicin (89%)
