host organism's response to a pathogen, or a disease-causing substance

occures when tissue-destroying microorganisms enter & multiply in the body

to cause disease, microbial pathogens must adhere to cell surface, colonize & invade the host and proliferate inside 

viruses

bacteria 

microscopic genetic parasites that contain genetic material (DNA or RNA) but have no metabolic capability & need a host cell to replicate

(no cell walls, membranes, etc) 

single-celled microorganisms that have no true nucleus & reproduce by cell division

pathogenic bacteria contain cell-damaging proteins that cause infection; these proteins come in two forms:

exotoxins

endotoxins 

cell damaging proteins contained in pathogenic bacteria:

exotoxins 

cell-damaging proteins in pathogenic bacteria that cause infection:

endotoxins 

gram-positive bacteria

2 examples? 

these are everywhere; everything going on in the community

streptococcal organisms

staphylococcal organisms

(gram-positive rods are not commonly seen) 

encountered at the hospital

include gram-negative rods and cocci & gram-negative obligate intracellular parasites 

no cell wall

include mycoplasma and chlamydia 

single-celled or multicelled organisms that depend on a host for food & a protective environment

most common parasitic infections, such as tapeworm infestation, occur in the intestines 

substances produced by certain organisms which kill or inhibit the growth of other microorganisms

subset of antimicrobials

sulfa drugs: only ones that come from the lab

ability to kill an invading microorganism w/o harming the cells of the host

possibly b/c microbial pathogens difer in cellular structures or biochemical processes from human hosts

this is the most important quality aside from effectiveness

bactericidal-bacteriostatic actions

site of action/mechanisms of action 

arrest the growth & replication of bacteria, thus giving the body's immune system a chance to destroy & remove the pathogens

depend on the host having an intact immune status (so immune system can finish the job)

cannot be used in life-threatening situations; too slow to act

e.g. erythromycin, tetracyclines, sulfonamides 

drugs that kill microorganisms

less dependent on the host's defense mechanisms for their therapeutic effects (so, drug of choice for HIV pts, etc)

e.g. beta-lactam antibiotics, penicillins, vancomycin 

the dose used

causative organism being acted upon

site of action of the drug 

site of action/mechanisms of action

4 categories 

inhibitors of bacterial cell wall synthesis

inhibitors of  bacterial protein synthesis

inhibitors of bacterial metabolism (nucleic acid synthesis, energy metabolism)

disruptors of cell membrane permeability 

bactericidal

effective on "growing" bacteria that synthesize a peptidoglycan cell wall; should not be combined w/ bacteriostatic drugs 

 also inactive against organisms devoid of this structure (fungi, viruses, etc)

selectively interfere w/ the synthesis of the bacterial cell wall

bacterial cell walls are thicker & more rigid than the membranes of mammalian cells; they contain complex macromolecules that are formed via biosynthetic pathways which are absent from mammalian cells

block the cross-linking of peptidoglycan chains, which is the final step in bacterial cell wall synthesis, thereby producing deficiencies in the cell walls; interior of the cell is hypertonic, H20 enters the interior of the cell & causes lysis 

inhibitors of bacterial cell wall synthesis

examples: 

increase the permeability of the bacterial cell membrane thereby permitting leakage of intracellular components to take place

differing ratios btwn sterol & phospholipid contents in mammalian & microbial cell membrane appear to be the basis  for the selectivity of these agents

considered bactericidal in their action since interference w/ the cell membrane results in the immediate death of microbes 

disruptors of cell membrane permeability

examples: 

affect bacterial protein synthesis w/ relative selectivity

target the bacterial ribosome (smaller than the mammalian ribosome)

mammalian mitochondrial ribosome more closely resembles the bacterial chromosome; although drugs usually spare the host cells, high levels of drugs may cause toxic effects as a result of interaction w/ the mitochondrial ribosomes (relative selectivity)

inhibitors of bacterial protein synthesis

examples: 

nucleic acid synthesis

inhibitors of nucleic acid synthesis; bactericidal

(quinolones, fluoroquinolones)

foliate antagonists

inhibit folic acid synth; in the absence of folic acid, cells cannot grow or divide (folic acid coenzynes are required for the synth of purines & pyrimidines - precursors of RNA/DNA)

humans obtain folate in the diet, but many microorganisms must synthesize this substance by using PABA as substrate

function as competitive analogues of PABA

bacteriostatic alone & bactericidal in combo

(sulfonamides, trimethaprim, bactrim) 

refers to the ability of a microorganism to withstand a drug that was previously toxic to it

many orgainisms have adopted, through spontaneous mutation or acquired resistance & selection & developed more virulent stains many of which are more resistant to multiple abx

cross resistance can occur btwn antimicrobial drugs, especially if they are chemically related & have similar mechanisms of action

production of drug-inactivation enzymes

e.g. B-lactamases destroy many penicillins/cephalosporins

changes in drug penetration

microbes may adopt to become impermeable to the abx or increase their ability to excrete the abx; aminoglycosides, tetracyclines

changes in receptor structure

abx such as erythromycin bind to certain receptors; microorganisms can cause these receptors to mutate so that they have very little affinity for abx

alterations of metabolic pathways

bacteria may acquire the ability to use performed folic acid, bypassing the inhibitory actions of sulfonamides

bacteria may alter the target of the abx (e.g. altered forms of the enzymes that make cell walls) 

drugs w/ structure containing a beta-lactam ring that is essential for antimicrobial activity

include PCNs & cephalosporins

bactericidal drugs

exhibit some cross-sensitivity (i.e. PCN allergy may translate into a cephalosporin allergy 5-10% of pts) 

most widely effective & extensively used abx

among the least toxic drugs known

derived from cultures of molds or manufactured semisynthetically

natural PCNs are potent gram-pos. killers; they have little to no coverage against gram-neg. organisms 

bactericidal; interfere w/ cell wall synth. by inhibiting biosynthesis of cell wall mucopeptides

most effective on rapidly growing organisms

have virtually no untoward effec on human cells; safe in children, elderly, and during pregnancy (cat. B)

do not cross the BBB except when the meninges are inflamed 

Subclass of PCNs:

natural PCNs/narrow spectrum 

penicillin G (prototype drug, PO/IV/IM)

penicillin V (penVeeK) (PO only, less potent)

penicillin G procaine (crysticillin A.S.) (IM only, releases PCN over period of 4-24 hrs; used for desensitizing allergic pts)

penicillin G benzathine (bicillin L-A) (IM only; long-acting repository form; produces low, but sustained blood levels of PCN for as long as 4 wks)

all natural PCNs work the same way but differ in route of  admin & stability to gastric acid

broad spectrum: gram pos organisms the most (strep, staph)-the most effective; gram neg; gram pos anerobes

susceptible to inactivation of B-lactamases (penicillinases) 

subclass of PCNs:

penicillinase-resistant PCNs (antistaphylococcal) 

resistant to penicillinase (bacterial enzyle that hydrolyzes the amide bond of the B-lactam ring)

SPECTRUM-use restricted to the tx of infections caused by penicillinase producing staphylococci 

MRSA-Methicillin Resistant Staphylococcus Aureus

• major source of nosocomial or community-acquired infections; usually susceptible only to vancomycin 

subclass of PCNs:

broad spectrum PCNs (aminopenicillins) 

not resistant to penicillinase

SPECTRUM-all of the organisms affected by the natural PCNs, plus are more effective against gram-neg bacilli (salmonella, shigella, etc) 

resistance to these abx is a major clinical problem b/c of inactivation by plasmoid-mediated penicillinase; frequently resistant: E.coli, H.influenzae (30-40%), M. catarrhalis (70%)

important toxicities of ampicillin: incidence of rash is extremely high in pts w/ mono; ampicillin-induced psuedomembraneous colitis is another potential side-effect

amoxicillin (Amoxil) PO

ampicillin (Omnipen) PO/IV/IM 

subclass of PCNs:

extended-spectrum PCNs (antipseudomonal) 

SPECTRUM: less effective against the typical Pen G spectrum & ineffective against staphylococci; gram-neg coverage includes: pseudomonas, enterobacter, klebsiella

important in treating serious gram-neg bacteria; often used in combo w/ aminoglycosides 

have the same specgrum as the original PCNs + coverage against penicillinase-producing bacgteria such as staph, etc.

B-lactamase inhibitors inhibit the enzyme by binding to it & thus protecting the accompanying abx; on their own, B-lactamase inhibitors are not effective in eliminating bacteria 

amoxicillin + clavulanic acid = augmentin

piperacillin + tazobactam = zosyn 

hypersensitivity & allergy

caution with severe renal insufficiency; doses should be adjusted 

deep into large muscle mass

shake med well before injection & massage the site prior to injection

mostly unchanged drug appears in the urine

positive

negative 

cephalosporins are organized into four generations based on their order of  development & general features of antimicrobial activity

from 1st generation to 4th generation, there is:

(4) 

decrease in gram-positive coverage

increase in gram-negative coverage

increase in CNS penetration

increase in resistance to B-lactamase 

cefazolin (Ancef, Kefzol) prototype: IV/IM (most commonly used)

cephalexin (Keflex) PO (#1 PO) 

uncomplicated, community-acquired infections of the skin & soft tissue & urinary tract (E.coli)

useful for respiratory infections caused by PCN-sensitive streptococcus pneumoniae

parenteral 1st generation agents (Ancef) are used  for surgical would prophylaxis

cefazolin (Ancef) remains the more popular parenteral "1st generation" agent due to its superior blood & tissue conc., low cost, low toxicity 

community acquired URIs (H.influencae, M. catarrhalis, S. pneumoniae) & uncomplicated UTIs (E.coli)

useful in mixed aerobic/anaerobic infections of the skin  & soft tissue, intra-abdominal infections, gynecological infections, surgical prophylaxis 

for infections involving gram-neg bacteria, particularly hospital-acquired infections or complicated community-acquired infections of the respiratory tract, blood, intra-abdominal, skin & soft tissue, urinary tract

third-generation may be an alternative to aminoglycosides, esp in some pts w/ renal dysfunction b/c of their activity against gram-neg bacteria 

fourth-generation cephalosporins

very expensive

possess the gram-neg coverage of the third-generation & gram pos coverage of the first-generation cephalosporins

usually tolerated well and are the safest type of abx

other B-lactam antibiotics:

Carbapenems 

n/v/d

seizures in high doses (b/c stays as metabolite in kidney-but cilastatin helps neutralize this problem) --> so, you're safe as long as dose is right 

other B-lactam antibiotics:

Monobactams 

other agents affecting the cell wall:

vancomycin (Vancocin) 

other agents affecting the cell wall:

bacitracin 

bacterial protein synthesis inhibitors:

tetracyclines 

tetracycline (Sumycin) - generic/cheap but short 1/2 life and must be on empty stomach (1-2 hrs after food)

doxycycline (Vibramycin)

minocycline (Minocin) - better 1/2 life 

bacterial protein synthesis inhibitors:

aminoglycosides 

must useful in treating infections cased by aerobic gram-neg bacilli and serious nosocomial infections such as gram-neg bacteremia or sepsis; tx of TB

often given in combo w/ PCN to encourage facilitation of the aminoglycoside into the cell 

no absolute contradications except in lactation

promote adequate fluid intake (2L/day) to maintain adequate renal function

admin IV aminoglycosides & PCNs at least 2 hrs apart 

bacterial protein synthesis inhibitors:

macrolides 

erythromycin (prototype) **comes in different preparations

azithromyxin (Zithromax) 

bacterial protein synthesis inhibitors:

lincosamine 

clindamycin (Cleocin)

#1topical acne drug; also prophylaxis w/ mitral valve, etc when there's PCN allergy 

usually used to treat severe infections by anaerobic bacteria such as Bacterioides fragilis

topical preparations-acne vulgaris, affective against Propionobacterium acnes 

foliate antagonists:

sulfonamides 

sulfasalazine (Azulfidine) - frequent use in autoimmune conditions

mafenide (Sulfamylon) 

foliate antagonists:

sulfamethoxazole/trimethroprim