When you are choosing an agent to use, you are looking at what clinical symptoms the patient has, who is this patient, an immunocompromised or normal host. You are taking a little bit more of a detailed history to include infectious risks, and you are thinking about the antibiotic itself.
In a clinical syndrome, you are trying to identify what is the predominant symptom and signs. You are trying to see where the site of infection is. Is this infection in the joint? Is this infection in the bone? Where are we treating this infection? Does this patient have a central nervous system infection? Then, identify the disease process because if you identify that this is osteomyelitis, it is a little bit different than if you think that the patient has pyogenic arthritis. The causative organisms might change and then what you need do, is you need to think of what the disease is, what are the most likely pathogens associated with this disease and what is their susceptibility pattern in the area where you practice. This is essential. To pick a drug, you have to know what organism you are dealing with. Because if not, you are really doing it blindly. So you have to have an idea of what organisms cause what specific diseases so that then you can make a good choice about antibiotic therapy.
When you look at hosts, you need to know the age of the patient. A 10-year-old is different from a neonate. The pathogens are different. Think about underlying conditions. Is this a patient with cystic fibrosis with pneumonia, or is this a well child with pneumonia? Different pathogens. So you are thinking about that host. Does this patient have an indwelling catheter? Does the patient have a prosthetic heart valve? All these things make it a little different to know which antibiotic to choose. Then, is the patient malnourished because that might be a cause for immunodeficiency.
When you are looking at a focused history, you need to know if the patient you are seeing with fever for 10 days has just come back from a safari in Africa, or is this a patient who has just been in the community where there is a lot of influenza. So you are going to ask about travel, about exposure to people who have contagious diseases such as tuberculosis, or whether the child is exposed to more infections because he is in daycare. Are immunizations up to date? That is very important. That patient may have measles if they have never been immunized and there is an increase in your community of Hemophilus influenza type E,. which is now very rare but can occur. Is this adolescent an IV drug abuser? Unfortunately, this happens occasionally and it brings in another set of organisms and diseases we have to think about, and then sexual activity brings up another whole host of organisms and disease processes.
.... CLICK HERE TO DOWNLOAD FUL ARTICLE
Showing posts with label antibiotics. Show all posts
Showing posts with label antibiotics. Show all posts
Saturday, April 4, 2009
Antibiotic Toxicities Agents
Aminoglycosides. These are used for gram-negative infections.
Most of them have some gram-positive activity, but you would never use it for a gram-positive infection unless you're using it with other drugs. The most common that we still use in kids is gentamicin, also tobramycin, not much with kanamycin, even less with streptomycin. Pulmonologist are using inhaled tobra for some CS patients. The main type of toxicities that we see from aminoglycosides are ototoxicity and nephrotoxicity.
There are two kinds of toxicity to the ear. The direct ototoxicity is actually destruction of the cochlear hair cells and it produces a
high-frequency, irreversible hearing loss. This can occur early. It can occur late. It can occur after you've gone through you're
therapy. It's most commonly seen with amikacin and kanamycin. The vestibular dysfunction, which causes damage to the vestibular hair cells is most commonly seen with gentamicin and streptomycin. These can occur at any time during therapy.
Risk factors. The very young and the very old. Those may be some people to worry about. Ototoxicity is usually directly related to the peak level that you get. So, if you give 10 x the dose of
aminoglycoside, that's the kind of patient that I would worry about
their ears. If something could happen to their ears. Pre-existing renal disease, obviously if you are not getting rid of it and you're having high peaks for whatever reason you're not following them and you don't check peaks and troughs, there is a data suggesting that maybe we don't need to do that all the time anymore and maybe it doesn't really suggest efficiency of therapy. Let's say your patient had renal disease that you didn't pay attention, so you're getting too much of it producing high peaks. If you use other agents which also have Ototoxic potential in combination vancomycin and
other loop diuretics. Prior exposure to aminoglycosides or loud sound. Again, the very young, the very old. If you have a hereditary tendency for any ear problems you need to be concerned with
aminoglycosides and the exact amount of ototoxicity we always think is rare in infants but they're hard to evaluate, especially the premature infants. All premature infants should get their hearing screened usually before they leave the premature nursery and I talk about the micro-preemies. The 500 to 1000 gm infants, but if they have hearing loss was it to the multiple courses of aminoglycosides they got or the fact that they had intraventricular hemorrhage or a
brain abscess or was it the fact that they were exposed to multiple loud noises. So the exact mechanism is not well known.
Nephrotoxicity, I think of the patients who had high troughs. They're not clearing their aminoglycoside. They really need to be on it twice a day which is clearly just enough to get their peaks down but still
maintains a very high level which is hurting their kidneys as time
goes by. What we see is a gradual onset which could complete the kidney shut down. Usually we'll see elevations of BUN or creatine or hypertension and excessive urine protein. Risk for nephrotoxicity. Again, high doses or prolonged courses of therapy, especially for hemoglobin. Liver disease, concurrent use of other nephrotoxic medications, again, vancomycin, salt and water deprivation.
With each kind of drug we are going to talk about adverse effects and drug interactions. The interactions, mostly we worry about increased nephrotoxicity. Again, increased nephrotoxicity when you
use aminoglycosides in combination with all other potential
nephrotoxicity drugs. Cyclosporine, amphotericin B, some of the loop diuretics, indomethacin, most people don't realize that cephalothin is one of those. One of the interesting things aminoglycosides do or potentially potentiate is the respiratory suppression of nondepolarizing neuromuscular agents, but if you think about it too, in the old days before the cephalosporins when we used ampicillin and gentamicin exclusively when the newborn babies came in or you had the baby that presented with a little constipation, some cranial nerve findings, just kind of being floppy,
you put him on amp and gent and all of a sudden boom they got a lot worse, so it potentiates that neuromuscular blockade. I don't think anybody's going to use a lot of oral kanamycin, but oral
kanamycin and methotrexate can increase methotrexate toxicity.
.... CLICK HERE TO DOWNLOAD FULL ARTICLE
Most of them have some gram-positive activity, but you would never use it for a gram-positive infection unless you're using it with other drugs. The most common that we still use in kids is gentamicin, also tobramycin, not much with kanamycin, even less with streptomycin. Pulmonologist are using inhaled tobra for some CS patients. The main type of toxicities that we see from aminoglycosides are ototoxicity and nephrotoxicity.
There are two kinds of toxicity to the ear. The direct ototoxicity is actually destruction of the cochlear hair cells and it produces a
high-frequency, irreversible hearing loss. This can occur early. It can occur late. It can occur after you've gone through you're
therapy. It's most commonly seen with amikacin and kanamycin. The vestibular dysfunction, which causes damage to the vestibular hair cells is most commonly seen with gentamicin and streptomycin. These can occur at any time during therapy.
Risk factors. The very young and the very old. Those may be some people to worry about. Ototoxicity is usually directly related to the peak level that you get. So, if you give 10 x the dose of
aminoglycoside, that's the kind of patient that I would worry about
their ears. If something could happen to their ears. Pre-existing renal disease, obviously if you are not getting rid of it and you're having high peaks for whatever reason you're not following them and you don't check peaks and troughs, there is a data suggesting that maybe we don't need to do that all the time anymore and maybe it doesn't really suggest efficiency of therapy. Let's say your patient had renal disease that you didn't pay attention, so you're getting too much of it producing high peaks. If you use other agents which also have Ototoxic potential in combination vancomycin and
other loop diuretics. Prior exposure to aminoglycosides or loud sound. Again, the very young, the very old. If you have a hereditary tendency for any ear problems you need to be concerned with
aminoglycosides and the exact amount of ototoxicity we always think is rare in infants but they're hard to evaluate, especially the premature infants. All premature infants should get their hearing screened usually before they leave the premature nursery and I talk about the micro-preemies. The 500 to 1000 gm infants, but if they have hearing loss was it to the multiple courses of aminoglycosides they got or the fact that they had intraventricular hemorrhage or a
brain abscess or was it the fact that they were exposed to multiple loud noises. So the exact mechanism is not well known.
Nephrotoxicity, I think of the patients who had high troughs. They're not clearing their aminoglycoside. They really need to be on it twice a day which is clearly just enough to get their peaks down but still
maintains a very high level which is hurting their kidneys as time
goes by. What we see is a gradual onset which could complete the kidney shut down. Usually we'll see elevations of BUN or creatine or hypertension and excessive urine protein. Risk for nephrotoxicity. Again, high doses or prolonged courses of therapy, especially for hemoglobin. Liver disease, concurrent use of other nephrotoxic medications, again, vancomycin, salt and water deprivation.
With each kind of drug we are going to talk about adverse effects and drug interactions. The interactions, mostly we worry about increased nephrotoxicity. Again, increased nephrotoxicity when you
use aminoglycosides in combination with all other potential
nephrotoxicity drugs. Cyclosporine, amphotericin B, some of the loop diuretics, indomethacin, most people don't realize that cephalothin is one of those. One of the interesting things aminoglycosides do or potentially potentiate is the respiratory suppression of nondepolarizing neuromuscular agents, but if you think about it too, in the old days before the cephalosporins when we used ampicillin and gentamicin exclusively when the newborn babies came in or you had the baby that presented with a little constipation, some cranial nerve findings, just kind of being floppy,
you put him on amp and gent and all of a sudden boom they got a lot worse, so it potentiates that neuromuscular blockade. I don't think anybody's going to use a lot of oral kanamycin, but oral
kanamycin and methotrexate can increase methotrexate toxicity.
.... CLICK HERE TO DOWNLOAD FULL ARTICLE
Friday, April 3, 2009
Antibiotic Mechanisms
Antifungals
Binds to ergosterol in fungal membranes, disrupting membrane permeability and transport functions, thereby allowing cations and macromolecules to leak out of the cell
Aztreonam
Binds to PCP's, inhibits peptidoglycan synthesis and is bactericidal for gram negative (no effect on gram pos and anaerobes) B-lactam resistant
Cephalosporins
B-lactam Bactericidal...Binds to PCP's and inhibits murein synthesis and cell wall production
Clindamycin
Binds to 50s subunit of bacterial ribosomes and suppresses protein synthesis by disrupting formation of 70s initiation complex and inhibits translocation step of peptide bond synthesis...gram + cocci and most anaerobes
Erythromycin
Inhibits protein synthesis by binding reversibly to 50s ribosomal subunits ...specifically inhibits translocation step of protein synthesis, where tRNA/amino acid complex moves from the acceptor site to the peptidyl site on the ribososmes
Gentamicin
Aminoglycoside bactericidal...enters by oxygen dependent active transport, binds to 30s and inhibits protein synthesis...interferes with initiation complex, induces misreading of mRNA, and breaks up polysomes...synergistics with B-lactams
Imipenem
B-lactam, binds to PCP's (many of which are transpeptidases for murein wall synthesis)...autolytic enzyme activation..broadest spectrum of all antibiotics
INH
Inhibits mycobacterial cell wall synthesis (specifically mycolic acids)
Metronidazole
Bioactivation of drug's nitro base by ferridoxin leads to cytotoxic agents which are bacteriocidal
Nafcillin
Penicillinase-resistant PCN...binds to PCP's inhibits cell wall synthesis..bulky nature prevents B-lactamase function
Neomycin
Enters by oxygen dependent active transport, binds to 30s and inhibits protein synthesis by interfering with initiation complex, misreading mRNA, breaks up polysomes
Nitrofurantoin
Bacteriostatic...urinary antiseptic...best if urine is acidic
Penicillin
Binds to PCP's which inhibits cell wall synthesis...autolytic enzyme activation leads to bactericidal activity on dividing bacteria
Rifampin
Inhibits DNA-dependent RNA polymerase of Mycobacteria by interacting with its B subunit...this suppresses RNA chain initiation
Quinolones
Inhibits DNA topoisomerase II (DNA gyrase)...bactericidal
Sulfa
Bactriostatic, structural analog of PABA and a competetive antagonist for dihydropteroate synthetase
Tetracycline
Bacteriostatic, bacteriocidal only at high concentrations...passively diffuses through hydrophilic channels and then an energy dependent active transport pumps the drug through the inner cytoplasmic membrane. Humans lack active transport and therefore are protected...drug then binds to 30s and prevents access of the aminoacyl tRNA to its acceptor site on the mRNA
Trimethoprim
Inhibits dihydrofolate reductase, thus preventing folic acid synthesis and therfore decreased production of thymine, purines, and amino acids and interferes with nucleic acid production.
Vancomycin
Binds with high affinity to D-alanyl-D-alanine portion of cell wall precursors and prevents polymerization of peptidoglycans. Bactericidal for dividing gram positives
Binds to ergosterol in fungal membranes, disrupting membrane permeability and transport functions, thereby allowing cations and macromolecules to leak out of the cell
Aztreonam
Binds to PCP's, inhibits peptidoglycan synthesis and is bactericidal for gram negative (no effect on gram pos and anaerobes) B-lactam resistant
Cephalosporins
B-lactam Bactericidal...Binds to PCP's and inhibits murein synthesis and cell wall production
Clindamycin
Binds to 50s subunit of bacterial ribosomes and suppresses protein synthesis by disrupting formation of 70s initiation complex and inhibits translocation step of peptide bond synthesis...gram + cocci and most anaerobes
Erythromycin
Inhibits protein synthesis by binding reversibly to 50s ribosomal subunits ...specifically inhibits translocation step of protein synthesis, where tRNA/amino acid complex moves from the acceptor site to the peptidyl site on the ribososmes
Gentamicin
Aminoglycoside bactericidal...enters by oxygen dependent active transport, binds to 30s and inhibits protein synthesis...interferes with initiation complex, induces misreading of mRNA, and breaks up polysomes...synergistics with B-lactams
Imipenem
B-lactam, binds to PCP's (many of which are transpeptidases for murein wall synthesis)...autolytic enzyme activation..broadest spectrum of all antibiotics
INH
Inhibits mycobacterial cell wall synthesis (specifically mycolic acids)
Metronidazole
Bioactivation of drug's nitro base by ferridoxin leads to cytotoxic agents which are bacteriocidal
Nafcillin
Penicillinase-resistant PCN...binds to PCP's inhibits cell wall synthesis..bulky nature prevents B-lactamase function
Neomycin
Enters by oxygen dependent active transport, binds to 30s and inhibits protein synthesis by interfering with initiation complex, misreading mRNA, breaks up polysomes
Nitrofurantoin
Bacteriostatic...urinary antiseptic...best if urine is acidic
Penicillin
Binds to PCP's which inhibits cell wall synthesis...autolytic enzyme activation leads to bactericidal activity on dividing bacteria
Rifampin
Inhibits DNA-dependent RNA polymerase of Mycobacteria by interacting with its B subunit...this suppresses RNA chain initiation
Quinolones
Inhibits DNA topoisomerase II (DNA gyrase)...bactericidal
Sulfa
Bactriostatic, structural analog of PABA and a competetive antagonist for dihydropteroate synthetase
Tetracycline
Bacteriostatic, bacteriocidal only at high concentrations...passively diffuses through hydrophilic channels and then an energy dependent active transport pumps the drug through the inner cytoplasmic membrane. Humans lack active transport and therefore are protected...drug then binds to 30s and prevents access of the aminoacyl tRNA to its acceptor site on the mRNA
Trimethoprim
Inhibits dihydrofolate reductase, thus preventing folic acid synthesis and therfore decreased production of thymine, purines, and amino acids and interferes with nucleic acid production.
Vancomycin
Binds with high affinity to D-alanyl-D-alanine portion of cell wall precursors and prevents polymerization of peptidoglycans. Bactericidal for dividing gram positives
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