antimicrobial chemotherapy Flashcards
<p>define bactericidal</p>
<p>antimicrobial that kills bacteria
| e.g. penicillin</p>
<p>define bacteriostatic</p>
<p>antimicrobial that inhibits the growth of bacteria
| e.g. erythromycin</p>
<p>define sensitive</p>
<p>an organism is considered sensitive if it is inhibited or killed by levels of the antimicrobial that are available at the site of infection</p>
<p>define resistant</p>
<p>an organism is considered resistant if it isn't killed or inhibited by levels of the antimicrobial that are available at the site of the infection</p>
<p>define MIC</p>
<p>minimal inhibitory concentration
| the minimum concentration of antimicrobial needed to inhibit visible growth of a given organism</p>
<p>define MBC</p>
<p>Minimum bactericidal concentration
| the minimum concentration of the antimicrobial needed to kill a given organism</p>
<p>what are the 3 routes of administration</p>
<p>topical
systemic
parenteral (IV/IM)</p>
<p>3 sites of antibiotic action</p>
<p>inhibition of cell wall synthesis
inhibition of protein synthesis
inhibition of nucleic acid synthesis</p>
<p>antibiotics that inhibit cell wall synthesis</p>
<p>- penicillins and cephalosporins (beta lactams)
| - glycopeptides</p>
<p>penicillins and cephalosporins</p>
<p>- beta lactam antibiotics
- disrupt peptidoglycan synthesis by inhibiting the enzymes (PBPs) responsible for cross-linking the carbohydrate chains</p>
<p>benzyl penicillin resistance</p>
<p>many gram -ve are resistant to benzyl penicillin due to the relative impermeability of the gram -ve cell wall</p>
<p>beta lactamas are effective against mostly gram</p>
<p>+ve bacteria</p>
<p>glycopeptides</p>
<p>work on gram +ve only
vancomycin and teicoplanin
inhibit assembly of a peptidoglycan precursor
can't penetrate the gram -ve cell wall
vancomycin and teicoplanin arent absorbed from the GI tract so are only given parenterally</p>
<p>vancomycin toxicity</p>
<p>local tissue damage can occur if it leaks from the veins
side effects: ototoxicity, nephrotoxicity, skin rashes
important to measure levels
teicoplanin appears to be less toxic</p>
<p>antibiotics that inhibit protein synthesis</p>
<p>aminoglycosides
macrolides and tetracyclines
oxazolidinones
cyclic lipopeptide</p>
<p>Aminoglycosides</p>
<p>e.g. gentamicin
concentration dependent bactericidal
gram -ve resistance is unusual - main use is to treat gram -ve infections
most staphylococci are sensitive, streptococci aren't
gentamicin is toxic and requires careful dosing regime</p>
<p>macrolides and tetracyclines</p>
<p>macrolides are useful alternatives to penicillin when treating gram +ve infections in patients who are allergic to penicillin
>10% of Staph aureus, strep pyogenes and strep pneumonia strains are resistant</p>
<p>oxazolidinones</p>
<p>bacteriostatic/bactericidal depending on the bacteria
linezolid - good activity against MRSA, orally</p>
<p>cyclic lipopeptide</p>
<p>strong bactericidal
daptomycin - activity against gram +ve, particularly MRSA
last resource</p>
<p>antibiotics that inhibit nucleic acid synthesis</p>
<p>trimethoprim and sulphamethoxazole
| fluoroquinolones</p>
<p>trimethoprim and sulphamethoxazole</p>
<p>both inhibit different steps in purine synthesis
used in a combined form - co-trimoxazole
less likely than other broad spectrum agents to cause C. diff infections</p>
<p>fluoroquinolones</p>
<p>e.g. ciproflaxin inhibit DNA synth more directly given orally and parenterally effective against gram -ve can't be used in children - interference with cartilage growth
levofloxacin has more activity against gram +ve</p>
<p>what are the 2 types of antibiotic resistance</p>
<p>inherit/intrinsic resistance
| acquired resistance</p>
<p>inherit/intrinsic resistance</p>
<p>- all strains of a given species are naturally resistant to an antibiotic
- usually due to the inability of the drug to penetrate the bacterial cell wall to exert its action
e. g. streptococci resistance to amino-glycosides, gram -ve resistance to vancomycin</p>
<p>acquired resistance</p>
resistance may be present in some strains of the species but not others
lab sensitivity testing is essential to establish the likely sensitivity of any individual isolate from a patient
mechanisms of acquired resistance
- spontaneous mutation during multiplication of the bacterial DNA, can result in change in structure/function
- genes that code for resistance can spread from organism to organism or from species to species (commonest method)
widespread use of antibiotics causes …
selective pressure and encourages new resistant organisms to outgrow sensitive strains (natural selection)
mechanisms of resistance to beta lactams
- beta lactamase production
- alteration of PBP target site
beta lactamase production
- bacterial enzymes that cleave the beta lactam ring of the antibiotic and make it inactive
- common is hospital strains of S aureus and most gram -ve bacteria
- extended spectrum beta lactamases (ESBLs) are produced by some gram -ve organisms can break down 3rd generation cephalosporins as well as penicillin and render the organism resistant to all beta lactam antibiotics
combating beta lactamase production
- introduce a 2nd component to the antibiotic (beta lactamase inhibitor) - protects the antibiotic from enzymatic degradation e.g. co-amoxiclav
- modify the antibiotic side chain to produce an antibiotic that is resistant to beta lactamase action e.g. flucoxacillin
carbapenemase producing enterobacteriaciae
group of extremely resistant gram -ve organisms
resistant to carbapenems
usually also resistant to multiple other classes of antibiotics - often leaves no antimicrobial options for therapy
carbapanems
highly effective antibiotics
used for severe/high risk bacterial infections
member of beta lactam class
reserved for multi-drug resistant infections
alteration of PBP target site
- results in a modified target site to which all beta lactams will no longer bind
these organisms are resistant to all beta lactam agents
addition of beta lactamase inhibitor makes no difference
e.g. MRSA - resistant to all penicillins and cephalosporins
treatment of MRSA
- flucloxacillin: beta lactamase resistant, treats beta lactamase producing s aureus (NOT MRSA)
- vancomycin and linezolid - MRSA treatment
glycopeptide resistance
- vancomycin resistant enterococci - peptidoglycan precursor to which vancomycin normally binds has an altered target site
these types of bacteria have appeared very recently
vancomycin resistance is unusual in gram +ve organisms
penicillins (examples of drugs)
benzyl penicillin (penicillin G) amoxicillin, ampicillin co-amoxiclav flucloxacillin piperacillin imipenem, meropenem
spectrum of benzyl penicillin
largely acts against gram +ve organisms
best choice for IV treatment of serious pneumococcla, meningococcla and S pyogenes infection
phenoxymethylpenicillin has slightly better absorption when taken orally
amoxicillin, ampicillin spectrum
better oral absorption that benzylpenicillin
originally better gram -ve activity
20-30% of coliform organisms are now resistant due to beta lactamase production
covers streptococci, enterococci and some coliforms
co-amoxiclav spectrum
amoxicillin + beta lactamase inhibitor clavulanic acid
extends the spectrum to cover beta lactamase producing coliforms
flucloxacillin spectrum
resistant to staphylococcal beta lactamase
first choice of treatment for staph infections
methicillin is a similar agent, used to represent flucloxacillin in lab testing - resistant organisms are termed MRSA
piperacillin spectrum
broad spectrum penicillin
extended gram -ve cover
anti-anaerobic activity
imipenem, meropenem spectrum
carbapenems
widest spectrum - used against most bacteria
cephalosporin spectrum
often divided into generations
activity against gram -ve organisms increases from 1st to 3rd generation
only ceftazidime has any activity against pseudomonas
gram +ve activity decreases from 1st to 3rd generation
aminoglycosides spectrum
parenteral use only
noted for use against gram -ve organisms
most staphylococci are sensitive (not streptococci)
gentamicin is the cheapest and most commonly used - BUT IS TOXIC
Glycopeptide spectrum
parenteral use only
vancomycin and teicoplanin
activity against gram +ve only - anaerobic and aerobic
vancomycin - toxicity
macrolide spectrum
clarithomycin or erythromycin
activity against mostly gram +ve
alternative to penicillin (for allergic patients)
azithromycin -newer, useful for single dose treatment of chlamydia
quinolone spectrum
newer generations have wider specturm and are active against nearly all gram -ve (including pseudomonas)
only possibility for oral treatment of pseudomonas
streptococci activity is generally poor but levofloxacin is active against pneumococci
metronidazole spectrum
effective against gram +ve and -ve anaerobes
no useful activity against aerobes
fusidic acid spectrum
anti-staphylococcal drug
should always be used in combination with other anti-staphylococcal drugs to prevent resistance developing
diffuses well into bone and tissues
trimethoprim spectrum
urinary infection treatment
co-trimoxazole = trimethoprim + sulfamethoxazole
- used for a few specialised conditions and sometimes the treatment of chest infections (as long as it doesnt predispose to C diff infection)
tetracyclines spectrum
broad spectrum
inhibit protein synthesis
few limited applications
some genital tract and respiratory tract infections
shouldn’t be given to pregnant women or young children - deposited in teeth and bones (toxic)
clindamycin spectrum
only lincosamide antibiotic in common use
good gram +ve activity e.g. staphylococci and streptococci
good activity against anaerobes
very good tissue penetration
can be taken orally
linezolid spectrum
good MRSA activity
can be given orally
can cause bone marrow suppression
daptomycin spectrum
gram +ve only
serious MRSA infections
fidaxomicin
new macrocyclic antibiotic
bactericidal against C diff
urinary tract agents
used only in the treatment of lower UTI (cystitis)
nalidixic acid - urinary antiseptic, gram -ve aerobes only
nitrofurantoin - urinary antiseptic, most gram -ve (not proteus and pseudomonas spp), also effective against some gram +ve
allergic reactions
most commonly associated with beta lactams
true penicillin hypersensitivity is rare
10% of truly penicillin allergic patients will also be allergic to cephalosporins
types of allergic reactions
immediate hypersensitivity
delayed hypersensitivity
GI side effects
immediate hypersensitivity
anaphylactic shock - usually follows parenteral administration
IgE mediated
occurs within minutes of administration
itching, urticaria, nausea, vomiting, wheezing, shock, laryngeal oedema
delayed hypersensitivity
hours or days to develop
immune complex or cell mediated mechanism
drug rashes (most common), drug fever, serum sickness, erythema nodosum
rashes are usually maculopapular, restricted to the skin
Steven’s johnson syndrome: severe and sometimes fatal, associated with sulphonamides, skin and mucous membranes are involved
GI side effects
commonly encountered with anti-microbial usage
nausea and vomiting are common
diarrhoea associated with toxin production by C diff is a major problem with HAI
C diff appears to overgrow normal flora during antibiotic therapy and produces toxins - can develop to pseudomonas colitis
treated with oral metronidazole or oral vancomycin - other antibiotic use is discontinued if clinically appropriate
relapses are common and further courses of treatment may be required
thrush
suppression of normal flora, overgrowth of resistant orhanisms
therapy with broad spectrum penicillins or cephalosporins may be complicated by the overgrowth of C albicans (yeast)
results in oral and/or vaginal candidiasis
liver toxicity
more common in patients with pre-existing liver disease and in pregnancy
tetracyclines, flucloxacillin and anti TB drugs (isoniazid and rifampicin) have been associated with hepatotoxicity
renal toxicity
dose related and more common in patients with pre-existing renal disease
most commonly seen with aminoglycosides or vancomycin
usually reversible but can be permenant
neurological toxicity
ototoxicty - aminoglycoside or vancomycin use
optic neuropathy - ethambutol associated with dose related optic nerve damage
encephalopathy and convulsions - high dose penicillin and cephalosporin use or with aciclovar, especially if the dose isnt reduced in the presence of renal impairment
peripheral neuropathy - metronidazole and nitrofurantoin, may produce reversible peripheral neuropathy of uncertain mechanisms; anti TB drug isoniazid may also induce peripheral neuropathy
haematological toxcity
- toxic effect on bone marrow resulting in selective depression of one cell line or unselective depression of all bone marrow elements
co-trimoxazole may result in folate deficiency which can cause megaloblastic anaemia after prolonged therapy
toxicity of some antivirals requires close monitoring of blood count
linezolid also causes bone marrow suppression and may lower platelet counts
prevention of adverse reactions
antimicrobials should be used only when indicated and in the minimum dose and duration necessary to achieve efficacy
exercise care when administering to susceptible groups
carefully monitor antimicrobials with a low therapeutic margin to ensure maximal efficacy and minimal toxicity
report all adverse reactions
preventing resistance
antibiotics should only be prescribed when absolutely necessary
use narrow spectrum antibiotics targeted at the likely infecting organism
patient characteristics
age: certain drugs are contraindicated in children
renal function: antimicrobials tend to accumulate in the body in the case of renal failure due to the reduced ability of the kidneys to excrete the drug, in this case dose will need to be reduced
liver function: dose should be decreased in hepatic insufficiency or chose an alternative drug
pregnancy: some drugs are contraindicated in pregnancy (mutagenic, teratogenic or both), many other drugs are contraindicated because their effects on the unborn foetus are unknown
prophylaxis
administration of antimicrobias to prevent the future occurrence of infection
dosage should cover the period of risk only and shouldnt be extended beyond this to avoid selecting out resistant organisms
therapy
when the organisms causing infection aren’t known, empirical antimicrobial therapy may have to be commenced if urgent treatment is required
this takes into account the site and type of infection and the likely causative agent
the treatment prescribed should always be reviewed once the results of culture and antibiotic sensitivity tests become available
drug related considerations
spectrum of antimicrobial agent monotherapy vs combination penetration to the site of infection additive/synergistic/antagonistic effects monitoring dose and duration of therapy
spectrum of the antimicrobial agent
antibiotic chosen should normally be effective against the known or likely causative agents
monotherapy vs combination
simplest approach (monotherapy) is generally best but sometimes it is necessary to use a combination
- to cover mixed infection by more than one organism
- 2 antimicrobials that have an enhanced effect (synergy)
- minimise the development of resistant strains to any one agent
what are the 3 possible outcomes when using antibiotics in combination
- their effects are additive
- they are antagonistic and their combined effect is less than the sum of their individual contributions
- they are synergistic and their combined effect is more than the sum of their individual contributions e.g. penicillin and gentamicin in the treatment of streptococcal endocarditis
combined effects of antibiotics (general rules)
two cidal/two static = additive/synergistic
one static + one cidal = may result in antagonism
penetration to the site of infection
antibiotics must be able to penetrate to the site of infection in order to have effective use in clinical practice
monitoring
certain antimicrobials have a low therapeutic index and the serum levels of these should be monitored careully to prevent toxicity
dose and duration of therapy
- consult BNF for appropriate dosage schedules
- patients with serious infections often require much higher doses than normal
- combination of drugs may further influence dosage
- children and patients with renal failure may require reduced dosage
- standard course for many infections is 7 days (some are longer and some are shorter)
what are the 2 main reasons for monitoring serum levels of an antimicrobial
- to ensure that therapeutic levels have been reached
- to ensure that levels aren’t high enough to be toxic
- most commonly measured are gentamicin and vancomycin
suceptibility testing
automated methods: growth of individual isolates is measured in the presence of different concentrations of each antibiotic and the likely MIC of the antibiotic for that organism is calculated. In vitro lab testing only gives a prediction of whether the infection is likely to be cured by the antibiotic
E test: simplest way to measure the MIC of one antibiotic, gradient of antibiotic concentrations on the strip, MIC of the organism can be read directly from the point where organism growth intersects the strip
antifungal drugs
polyenes
azoles
allylamines
echinocandins
polyenes
bind to ergosterol in the fungal cell wall - increases permeability of the cell wall
active against yeasts and filamentous fungi
toxic as they bind to other sterols in our cell walls
Amphotericin B - only drug available for IV use, for the treatment of serious systemic fungal infection
lipid complexed formulations of the drug reduce incidence of side effects
Nystatin - only available for topical use and in oral suspension
azoles
inhibit ergosterol synthesis
older: miconazole, ketoconazole
newer: fluconazole, itraconazole, voriconazole
fluconazole: oral and parenteral treatment of yeast infections, no activity against filamentous fungi, no apparent toxicity problems, resistance among some candida species
itraconazole: active against yeasts and filamentous fungi
voriconazole: treatment of aspergillosis
allyamines
suppress ergosterol synthesis
terbinafine: active primarily against dermatophytes (clinical use is restricted to infections of the skin and nails), mild infections are treated topically and serious infections are treated orally
echinocandins
inhibit glucan polysaccharide synthesis
caspofungin, mycafungin, anidulafungin
fungicidal against candida spp, inhibit growth of several aspergillus spp (used for serious infections)
antiviral drugs
antibiotics have no action against viruses
there are no virucidal agents (only virustatic)
many anti-viral drugs are nucleoside analogues which interfere w/ nucleic acid synthesis
anti herpes virus drugs
HSV, VZV, EBV CMV - not all are equally sensitive to anti-viral treatment
treatment is most effective if started early but doesnt eradicate the virus
Aciclovir - nucleoside analogue, specific for virus infected cells, low toxicity for uninfected host cells, extremely active against HSV and VZV, IV form is given to treat severe infections , cold sores can be treated orally or with the topical preparation
in the case of renal impairment, dose may need to be reduced to avoid neurological toxicity
famiclovir, valaciclovir: oral, better oral bioavailability than aciclovir, HSV and shingles treatment
ganciclovir: CMV treatment, toxic and given by IV injection, treatment of life-threatening infections or immunocompromised patients
Valganciclovir: pro-drug of ganciclovir, oral alternative for some CMV infections
foscarnet: some HSV, VZV and CMV infections resistant to the above drugs, highly nephrotoxic, IV only
cidofovir: CMV retinitis
anti HIV drugs
first treatment: zidovudine (AZT, ZDV), nucleoside analogue, slows viral replication, high incidence of side effects
combination therapy with 3 drugs is now common practice: drugs are selected that are active on at least 2 different stages of HIV replication
e.g. two nucleoside analogue reverse transcriptase inhibitors + non-nucleoside reverse transcriptase inhibitor (nevirapine, efavirenz) or a protease inhibitor (saquinavir, darunavir)
these drugs are used for prophylaxis also following occupational/sexual exposure to HIV +ve blood or body fluids
drugs for chronic hep B/C
interferon - alpha: treats selected chronic hep B and C infections , low response rates and serious side effects
combination therapy with ribavarin is now common
drugs for viral respiratory infections
zanamavir, osteltamivir: influenza A/B treatment within 48 hrs of symptom onset and also for post-exposure prophylaxis
influenza immunisation remains the first line of protection
ribavarin: nucleoside analogue, treatment of severe respiratory syncytial virus infections, must be inhaled as a fine spray to reach the site of infection - difficult administration
anti-viral resistance
genotypic analysis may help in choosing rational treatment in selected patients
anti-viral drug levels
available only for a few drugs
ensures therapeutic, but not toxic, serum levels are achieved
how long is antimicrobial treatment of osteomyelitis or endocarditis
several weeks
how long is treatment for S aureus bacteraemia
at least 14 days of IV therapy
how long is treatment of a simple UTI infection
3 days of trimethoprim
standard length of an antimicrobial course
7 days
what length of course is recommended for Staph aureus bacteraemia
14 days IV
