Pharm- Antibiotics

responsible for most resistance in an organism

occurs constantly in nature, unrelated to antibiotics

transfer of drug resistance gene from one cell to another via a phage

uptake of drug resistance plasmids (DNA), present in the immediate environment

transfer of resistance genes via direct contact through a sex pilus or bridge

involves resistance factor (RF) and resistance transfer factor (RTF)

a single plasmid can confer multiple drug resistance

minimal inhibatory concentration shows no growth in 24 hours

minimal bacteriocidal concentration (99.9% killed)

MIC usually sufficient in choosing dose, unless using a drug with low threapeutic index on a severe infection

must always have the MIC at the site of infection, since not all drugs penetrate equally into all parts of the body

most antimicrobials are excreted by the kidneys

impaired renal function = sustained blood levels

determined by properties of the drug and severity of infection

some drugs are not well absorbed after oral dosing, like vancomycin

pt w/ immune disorder not usually given bacteriostatic drug

all antimicrobial agents have the potential to cause a reaction

most common offenders are penicillins

THERE IS NO WAY TO ABSOLUTELY PREDICT WHETHER A PT WILL HAVE A REACTION

skin tests are not always diagnostic

• 1. Tx of mixed infections
• 2. Tx of severe infections when etiology is not known (CYA principle)
• 3. Enhancement of antimicrobial activity in treating a known infection (synergy)
• - penicillin and streptomycin in treating enterococcal endocarditits
• 4. Prevention of emergence of resistant organisms (often in TB Tx)

• 1. Drug antagonism (bacteriostatic drug used with a bacteriocidal drug)
• 2. Unnecessary patient exposure (toxic effects can also be synergistic)

prevention of wound infection during surgery

• 1. Treatment of untreatable infections (viral, etc)
• 2. Therapy of a fever of undetermined orgins
• 3. Improper dose (can be from lack of pt compliance)
• 4. Reliance on chemotherapy with omission of surgical drainage
• 5. Lack of adequate bacteriological information (ID of MO, sensitivity, etc)

emergence of resistant organisms, often in the GI tract, after reduction by antimicrobial agents of the more susceptable organisms

often from Clostridium difficile

CHANCES OF A SUPRAINFECTION IS DIRECTLY RELATED TO THE WIDTH OF ANTIMICROBIAL SPECTRUM OF THE DRUG

treatment of urinary tract infections due to susceptable bacteria

PABA, which is needed to make folic acid

inability to make folic acid

without folic acid, the cell has less tetrahydrofolate available

therefore, cell is unable to convert dUMP to TMP

therefore, inhibition of folic acid synthesis prevents bacteria from replicating DNA

BACTERIOSTATIC

therefore, sulfanomides have little or no effect without a competant immune system

can't be used with bacteriocidal drugs, b/c will reduce their effectiveness

microbes with greatly enhanced levels of PABA and folic acid

the increased levels of these substrates bypass the metabolic block caused by the drug

• 1. agranulocytosis (rare, usually can be reversed)
• 2. thrombocytopenia (mild)
• 3. aplastic anemia (very rare, can be fatal)
• 4. acute hemolytic anemia (assoc. w/ lack of erythrocyte glucose-6-phosphate dehydrogenase activity; most commonly seen in blacks)

Stevens-Johnson syndrome

trimethoprim

inhibits dihydrofolate reductase

the mammalian DHFR is only inhibited at concentrations over 10,000x higher than the bacterial enzymes, therefore safe in humans

mutant DHFR enzyme which will no longer bind the drug

uncomplicated lower urinary tract infections

GI infections

pneumocystis carnii infections (common in AIDS patients)

prophylaxis in neutropenic patients (organ transplant patients)

prevent the production of tetrahydrofolate-C1 and threfore inhibits synthesis of DNA

both are bacteriostatic

sulfa: overproduction of PABA

TMP: mutant DHFR enzyme will not bind the drug

inhibit cell-wall synthesis in bacteria

transpeptidase (inserts bridge in the last step in formation of the cell wall)

penicillin V (same action, but better absorbed in GI tract)

methicillin (these drugs should be used only when it is known that the infecting bacteria produces penicillinase)

ampicillin, amoxicillin

active against gram negative bacteria, but are destroyed by beta lactamases

all penicillins are excreted almost unchanged

through glomerular filtration

the exception is cloxacillin (metabolized in liver)

often mild, but can include anaphylaxis

major cause of hospital-acquired infections

do not produce penicillinases

resistant to other beta-lactam antibiotics as well as other antimicrobial agents of diverse structures and modes of action

can be acquired by mecA gene

identical to penicillins

very similar side effects

there is a high cross-over of penicillin allergic patients that are also allergic to cephalosporins

• 1. cephalothin (parenteral only, easily broken down by staphylococcal beta lactamase)
• 2. cefazolin (more susceptable to beta lactamase)

more active against gram negative than first generation

• 1. cefamandole (can't drink alcohol on this drug due to "disulfuram reaction")
• 2. cefuroxime (like the first, but longer acting)

ceftriaxone (long half life, very effective in treating gonorrhea)

prophylaxis during and after surgery

3rd generation groups are DOC for meningitis caused by gram negative bacteria

ceftriaxone used to treat gonorrhea, unless strain is tested to be sensitive to penicillin

sometimes used as penicillin alternative in patients that can't take PCN (although some are allergic to both)

hypersensitivity

"disulfuram" reaction with alcohol (cefamandole, cefoperazone)

clavulanic acid

has no bacteriostatic or cidal features

combined with amoxicillin to make Augmentin

inhibitors of cell-wall synthesis by inhibiting a phosphatase enzyme

very few side effects

inhibits MurA, which catalyzes the first step in making peptidoglycan

bacteriocidal

can be used as a single dose Tx for urinary tract infections

safe to use in pregnancy

binds to D-ALA-D-ALA, so cell wall can't polymerize

"red man syndrome" if given rapidly IV (anaphylaxis, fever, shock-like state)

very expensive

resistance is a growing problem

DOC for MRSA

DOC for antibiotic associated colitis (AAC)

peptidyl transferase

treatment of infections caused by aerobic gram negative bacteria

often given with beta lactam drug, but not in the same solution

• 1. streptomycin (interacts with the 30s subunit of the ribosome)
• - blocks protein synthesis at the level of initiation

ALL aminoglycosides are bacteriocidal

most important mechanism is "resistance caused by aminoglycoside modifying enzymes" which inactivate the drug

the genes for these enzymes are carried on plasmids which are conjugally transmitted

AMIKACIN AND NETILMICIN ARE UNIQUELY RESISTANT TO THE DRUG MODIFYING ENZYMES

• damage to 8th cranial nerve (irreversible)
• - loss of sensory cells in vestibulocochlear organs

very narrow