disrupt the microbial ecology

select for resistant microorganisms

can have adverse effects on other patients

what is the therapeutic index and why is a high one prefered?

TI: the ratio of the drug concentration that causes toxicity to the drug concentration that is effective/therapeutic

ideally, the difference between these concentrations should be great (high TI) so that the risk of overdose and other adverse effects is low

the range of bacteria susceptible to the antimicrobial agent

broad spectrum: active against many species/strains; good in polymicrobial infections or when causative microbe is unknown

narrow spectrum: target a small number of species, strains; cultures are important in determining the causative agent so that you can treat with specificity

broad ≠ better

why is killing microorganisms not responsible for the disease under treatment bad?

leads to colonization of the patient with highly resistant microbes and increased antimicrobial resistance in the community

minimum concentration (mcg/ml) of an antimicrobial agent that can prevent the growth of a particular micoorganism

minimum concentration (mcg/ml) of an antimicrobial agent that can REDUCE by 99.9% the NUMBER of a particular strain of bacteria; similar terms for fungus (MFC), etc.

only a few instances when bactericidal agents are strongly indicated over bacteriostatic ones: ENDOCARDITIS; T-cell depleted leukemia patient on chemotherapy..

• interfere with delivery: reduce penetration rate of agent or increase rate of agent removal from target
• modify the antimicrobial: either destroy the agent or chemically modify it so that it is no longer active
• change the target: mutations in the target or acquisition of alternative pathways that are not susceptible to the agent

what is difference between "antibiotics" and "antimicrobial"?

antibiotics are a specific sub-category of antimicrobials; they are derived from other living organisms, particularly bacteria and fungi that have evolved quite effective ways of waging war against other microorganisms

• intrinsic: usually a property of poor antimicrobial delivery or ineffective binding to the target
• acquired: can occur through mutation of existing genes, or the acquisition of new genes; can employ any previously discussed strategies (don't let it in, change/destroy the agent, change the target)
  • selected by (over) use
  • theoretically reversible

what drugs block folate synthesis and why are they effective for bacteria, while sparing humans?

• sulfonamides (first step) mimic PABA and are a competitive inhibitor of the enzyme DIHYDROPTEROATE SYNTHETASE
• trimethoprim (last step) is a potent inhibitor of DHFR (DIHYDROFOLATE REDUCTASE)

Humans ingest folic acid, which is reduced first to DHF and then to THF (tetrahydrofolate).  THF is required for synthesis of purines and thymidine.

Bacteria and some fungi and parasies are unable to transport folate and therefore synthesize it, starting with PABA.

how are sulfonamides (sulfamethoxasole) and trimethoprim usually used?

usually used together in SYNERGY

trimethoprim usually combined with sulfamethoxazole in a fixed 1:5 ratio

greater activity, lower potential for emerging resistance

quite inexpensive

• broad combination active against GRAM + and GRAM - bacteria
  • used against some protozoa and at least one fungus
• excellent bioavailability
• excellent tissue penetration
• USED FOR INFECTIONS IN:
  • GI
    • bacterial diarrhea
  • URINARY
  • RESPIRATORY
    • sinusitis
    • otitis media

• can be due to chromosomal mutation
• acquisition of a plasmid encoding alternative alleles of gene encoding alternative alleles of gene encoding DHPS (dihydropteroate synthetase)
• plasmids may confer resistance to both TMP and Sulfa

common

• nausea
• vomiting
• headache
• rashes

less common

• hyperK* high doses/renal insufficiency*
• hepatitis, pancreatitis

rare (but severe)

• hematological toxicities
  • anemia, aplastic anemia, thrombocytopenia
  • hemolytic anemia (G6PD deficiency)
• severe cutaneous reactions
  
  • Stevens Johnson Syndrome
  • toxic epidermal necrolysis (3/100,000)

pregnancy/drug interactions

• sulfonamides displace bilirubin and some drugs (warfarin/phenytoin/others) from albumin --> kernicterus (infants) and drug toxicities (others taking above drugs)

• form complexes with DNA and topoisomerase II (dna gyrase) and IV
• quinolones stabilize the complex that includes the double strand breaks (interfering with RNA transcription/DNA replication) --> CELL DEATH

quinolones are BACTERICIDAL

topoisomerases II and IV!

Topo II: introduces the super coils

Topo IV: de-concatenates intertwined chromosomes

• efficacy determined by the relative affinity of each agent for topo II and IV
• all have broad activity for gram negative
• gram + activity requires Topo IV affinity
• gram - activity requires gyrase/Topo II affinity
• active against "atypical" bacteria (mycoplasma, chlamydia, legionella) and Mycobacteria

good oral bioavailability, except in presence of divalent cations (antacids, Fe, Zn)

good tissue penetration

half lives are long, allowing bid or qd dosing

most excreted in urine, expect for moxifloxacin

BACTERICIDAL

• CIPROFLOXACIN
  • DNA gyrase = primary target
  • poor streptococci activity
  • good penetration of urinary tract
• MOXIFLOXACIN
  • gram positive and anaerobic bacteria
  • poor penetration of urinary tract

• can evolve rapidly in some organisms due to one+ mutations
  • common sites: gyrA; parC; efflux pumps
• mutatations may pre-exist in infections w/ large organism burdens
• efflux pumps implicated
  • de-repression of MDR efflux pumps

common

• nausea
• vomiting
• abdominal pain
• dizziness
• headache

uncommon/severe

• prolonged QT interval when used w certain other drugs
• arthropathy in children
• tendon rupture

what are some serious adverse effects associated with some types of fluoroquinolones?

• trovofloxacin withdrawal
  • hepatitis
  • liver failure
• gatifloxacin
  • hyperglycemia and hypoglycemia
  • withdrawn from market

bind to beta-subunit of RNA polymerase and block transcription

bacteriostatic

resistance due to mutations in binding pocket and occurs at 10^-8

at any given time in the course of infection, a few bacteria are naturally (ie: randomly) resistance due to sheer probability among all organism burden

drug interactions are VERY important with rifamycins. what are some notable details of rifamycin metabolism?

• metabolised via CYP450 3A4
• rifampin
  • potent inducer
  • can increase metabolism of many drugs
• rifabutin
  • less of an inducer
  • increased levels can result from inhibition of CYP450 3A4
• rifamimin is not absorbed
  • serves as a topical coating in the GI tract for infections; only given orally for topical effects

• very broad, including Gm+/Gm-, anaerobic and Mycobacteria
• prophylaxis
  • Neisseria menegitidis
  • Staph aureus
• in combination with other antimicrobials
  • Mycobacterial infections (Tb)
• GI tract infections
  • rifaximin only
  • travelers' diarrhea, C. dificile infection

• rifampin secretions turn orange
• GI
  • pain, nausea, vomiting, diarrhea
• hematological
  • usually mild thrombocytopenia, leukopenia, anemia
• hepatitis
  • more likely with co-administration of other agents; pre-exisiting liver disease