Micro Lecture 6 Antimicrobial Therapy

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Empiric therapy

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initiated based on clinical signs, symptoms and lab info.

therapy based in site of infection, etiology of infection, anticipated antimicrobial susceptibility

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prophylactic prescribing

give an example

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utilized to prevent infection in at risk patients

pt with damaged heart valves who undergo dental manipulations are treated with penicillin becuase they are at risk for developing endocarditis with oral streptococci

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Therapeutic prescribing

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specific therapy directed at a KNOWN etiologic agent with a known antimicrobial susceptibility.

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give an ex of empiric changed to therapeutic prescribing

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patient started on empiric levofloxacin for comm acquired pneumonia. after sputum and blood cultures reveal it is penicillin susceptible strep pneumoniae treatment is changed to penicillin

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what microbes are resistant to peptidoglycan synthesis inhibitors

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mycoplasma, rikettsia, chlamydia becuase they either have altered or no cell walls.

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3 main types of beta lactam antibiotics

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they have a beta lactam ring that is broken down by beta lactamase

penicillins
cephalosporins
carbapenems

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what is non beta lactam peptidoclycan synthesis inhibitor

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glycopeptides (vancomycin)

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3 types of penicillins and some info on them as a group

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penicillin, ampicillin, amoxicillin
very narow spectrum of activity
destroyed by beta-lactamase

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penicillin is active against

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syphilis
beta-hemolytic strep and some other streps
neisseria meningitidis
and beta lactamase negative strains of Neiseria gonorrhoeae

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ampicillin and amoxicillin are active against

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some gram negatives (more so than penicillin) and agains wimpy enterobacteriacea that are resistant to penicillin. so these 2 are stronger than penicliin

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nafcillin and methicillin

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beta-lactamase stable
good against staph becuase 95% of staph has beta lactamase that makes them resistant to penicillin, ampicillin and amoxicillin

* good verses staph and strep, but not agains gram negative

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MRSA
(methicillin-resistant staph aureus)

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These are staph that have overcome beta-lactamase stable drugs.

Resistance mediated by altered penicillin binding protein (PBP-2) that are not involved in PG synthesis

*are resistnt to ALL beta lactam antibiotics
represent 40-60% of staph aureus

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how do you treat MRSA

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treat with vancomycin, but some resistant ones have been recovered, those are treated with synercid (quinupristin/dalfopristin) or linezolid

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Synercid and linezolid

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used to treat vancomycin resistant MRSA act by inhibiting protein synthesis.

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examples of extended spectrum (anti-pseudomonal) penicillins

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ticarcillin, piperacillin, carbenicillin

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what is special about extended spectrum penicillins

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designed to have broad sprectrum against gram negative bacilli. but some of the gram negative bacilli have developed different beta-lactamase enzymes.

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penicillin/penicillinase inhibitor combinations examples and what they do

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clavulanate, sulbactam, tazobactam
inhibit beta-lactamase

can be added to variety beta lactam antibiotics with activity against gram negative

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ticarcillin/clavulanate and pipercillin/tazobactam

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active against ALL orgainsims that break down ticarcillin and pipercillin and against some organisms that can break down ticar and piper

this combo has braod activity against gram negative and anaerobes

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imipenem and mirimipenem

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they are carbapenems a class of beta-lactam drugs with different struture than penicillin and cephalosporin

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imipenems mechanism of action

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its one of smallest beta lactam antibiotics and is a zwiterion so it can pass through porin channels and outer membrane of gram negatives which gives it a broad range of activity. binds to penicillin binding proteins of a variety of bacteria and resistant to many different beta lactamases

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Cephalosporins

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have activity against bela-lactamase positive staphlococci.
No activity against enterococcus.

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widespread used of cephalosporin led to

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emergence of enterococci as nosocomial pathogens because they are not killed by cephalosporins

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the first generation cephalosporins are

and they're used for

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cephalexin and cefazolin

used for surgical procedures where wound infections tend to be staph aureus or staph pyogenes

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in general what can we say about the cephalosporin generations

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the higher the number the more activity against gram negative bact.

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the 2nd generation cephalosporins are

they're used for

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cefuroxime and cefotetan

like first generation cephalosporin has activity against staph but is also
reasonably active against some enterobacteriacae, but not against gram negative bacilli

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the 3rd generation cephalosporins are

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ceftazidime, cefoperazone, cefotaxime, and ceftriaxone

3rd generation has broad activity against gram negative bacilli

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Ceftazidime and cefoperazone

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more effective than other 3rd gen cephlosporins against pseudomonas aeruginosa

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4th generation cephalosporins

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one ex is cefepime and has good activity against pseudomonas aeruginosa

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aztreonam

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it is a monobactam meaning its beta lactam ring is not attached to another.

Binds to PBP of gram neg and pos. just like other beta lactams

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what is aztreonam used for

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active against gran neg facultative anaerobes,

no activity against anaerobes, pos or neg

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vancomycin

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Acts trans peptidation and on GlcNac addition to MurNac
active against almost all gram positives both anaerobes and aerobes

no activity against gream negative

*does not cross bbb so not good for meningitis

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what are at risk of developing resistance to vancomycin

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E. faecium and staphylococci

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acts on protein 50s ribosomal unit

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macrolides (erythromycin/azithromycin)
clindamycin
linezolid
streptogramins (ex synercid)

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acts on the 30s ribosomal unit

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tetracyclines
aminoglycosides (binds to 50s tooo)

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erythromycin

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a macrolide, and binds to 50 s ribosomal unit.
good substitute for pts allergic to pennicillin

good against mycoplasma, legionella, and chlamydia
NOT good against strep

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azithromycin

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also a macrolide. broader spectrum than erythromycin also binds to 50 s

inhibits erythromycin bact as well as H. influenzae, M. catarrhalis, and N. gonorrheae

good agent for empiric treatment of sinusitis, otitis media, and pneumonia

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clindamycin

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binds to 50s ribosome
good against MSSA and many streptococci
good against most anaerobes both pos and neg
ineffective against enterococci and gram neg aerobes

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linezolid and synercid

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good for enterococcus faecium and staphylococcus aureus that are resisistant to vancomycin

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tetracycline and doxicycline

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good against chlamydia, mycoplasma, rickettsia and legionella

so same as erythromycin but with rickettsia added

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aminoglycosides

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gentamycins, amikacin, tobramycin
treats aerobic gram neg
no anaerobic activity
poor versus gram pos by them sleves but my be synergistic with penicillins ex vs enterococcus

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side effects of aminoglycosides

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potential for renal toxicity and ototoxicity. not much clinical use becuase its very toxic

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DNA gyrase inhibitors

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quinolones (ex ciprofloxacin, levofloxacin)
broad spectrum of activity against aerobes, and facultative anaerobes
poor vs anaerobes and MRSA

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how do quinolones work?

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inhibit DNA synthesis --> cell death

quinolones target 2 enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV

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levofloxacin

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active against most aerobes except MRSA and E. Faecium

good vs S. pneumoniae, moraxella catarrhalis, H. influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella

*favorite for treating community acquired pneumoniae

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ciproflaxacin

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good vs gram negative aerobes and MSSA

One of the few oral agents with activity against pseudomonas

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metronidazole

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used for treatment of protozoal infections
also good for obligate anaerobes
good for anaerobic gram neg and clostridium variable vs anaerobic gram positive cocci

inactive vs actinomyces and P. acnes

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how does metronidazole work

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works by entering cell by diffusion and activated by reductive process and produces short lived metabolites damaging bacterial DNA --> cell death

this process requires low O2 levels thus its effectives vs anaerobes

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clinica uses of metronidazole

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useful for most anaerobic infections except actinomycosis and acne

penetrates into all tissue well including CNS so good for brain abscess, clostridum difficile colitis and abdomina abscess

*because most anaerobci infections are polymicrobial including facultative anaerobes metronidazole is used in combination treatment

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Bactrim

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Also known as trimethoprim (TMP) and Sufamethoxazole (SMX)

broad spectrum agent with activity against aerobic bacteria and some protozoans

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mechanism of action of bactrim

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TMP and SMX inhibit folic acid biosynthesis

SMX like all other sulfonamides is a P-aminobenzoic acid analoge and blocks the first step prevents PABA to dihidrofolate

TMP- competitively inhibits dihidrofolate to tetrahydrofolate needed for sythesis if purines and pyrimidines of DNA

more effective for bact than human's enzyme

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bactrim's spectrum of activity

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good vs aerobic gram pos and gram neg

inactive vs most obligate anaerobes

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what are resistant to bactrim

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pseudomonas aeruginosa, cacteroides fragilis, (anaerobes)
mycobacterium tuberculosis, camplyobacter, treponema pallidium and rickettsiae

MRSA is variably resistant
Penicillin resisntat strep is usually resistnat

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clinical uses of bactrim

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UTI
otitis media
pneumocysitic pneumonia (fungus)
travelers's diarrhea
acute exacerbation of chronic bronchitis

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daptomycin

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class of lipopeptides
binds to cytoplasmic membrane of gram positive bacteria, disrupting membrane potential, but can not penetrate outer membrane of gram negative bact.

good activity against most gram pos including MRSA and VISA and VRE

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what types of infections is daptomycin used for

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primarily used for skin and soft tissue infections.
should not be used for pneumonia

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nitrofurantoin

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only used for uncomplicated cystitis

good against E. coli, Staph saprophyticus, Group B strep, and enterococci and some Vancomycin resistant enterococcus