Antimicrobial Part I Flashcards
1
Q
Bacteriostatic
A
• Thought to arrest growth and replication of bacteria at drug levels achieved • Most of these agents are able to effectively kill pathogens, but they are unable to meet the arbitrary cut-off value in the bacterial definition
2
Q
Bactericidal
A
• Able to effectively kill
>/=99% within 18-24° of
incubation
3
Q
True or False: It is possible for a drug to be bacteriostatic for one microbe and bactericidal for another
A
TRUE
4
Q
MBC—Minimum Bactericidal Concentration
A
Lowest concentration of antimicrobial agent that
results in a 99.9% decline in colony count after
overnight broth dilution incubations
MBC is rarely determined in clinical practice
5
Q
What abx should you not give children?
A
Young children should not receive
Tetracyclines or Quinolones which can
affect teeth, bones and joints
*congenital abnormalities have
been seen after pregnant women have
taken tetracyclines—so should not be
prescribed
6
Q
When do you use parental route for abx?
A
Parenteral route is used when the med is poorly absorbed from the GI tract and for those with serious infections that need high serum concentrations of the antibiotic
7
Q
Name to abx poorly absorbed in the gut and do not achieve high enough serum levels via oral ingestion
A
vanc and aminoglycosides
8
Q
three important properties that greatly
influence the frequency of dosing;
A
Concentration-dependent killing
Time-dependent [concentration-
independent] killing
Postantibiotic effect [PAE]
9
Q
Concentration Dependent Killing
A
Certain drugs—such as aminoglycosides and Daptomycin show a large increase in the rate of bacterial killing as the concentration of the drug increases from 4 to 64 times the MIC of the drug for the causative pathogen
Giving drugs that exhibit this concentration-killing by a once a day bolus infusion obtains high peak levels—that cause rapid killing of the bug
10
Q
Postantibiotic Effect [PAE]
A
Persistent suppression of microbial growth that occurs after levels of the drug have fallen below the MIC
Drugs that have a PAE often require one dose per day—especially against gram negative bacteria
[aminoglycosides, fluoroquinolones]
11
Q
Narrow Spectrum
A
• Agents acting on a single or limited group of microbes • An example—INH is active only against Mycobacterium tuberculosis
12
Q
Extended Spectrum
A
• Drugs that are modified to be effective against gram + organisms and also against
a number of gram –bacteria
• An example—Ampicillin
13
Q
Broad Spectrum
A
• Drugs affect a wide variety of microbe
species
• These drugs can alter the nature of the
normal bacterial flora and lead to
superinfection from pathogens such as
C. difficile [the growth of which is normally kept in check by other colonizing bacteria]
• Examples—Tetracyclines,
Fluoroquinolones, Carbapenems
14
Q
Advantages of combination antimicrobial drugs
A
Some combinations show synergy [ß-lactams + aminoglycosides]
Because synergism is pretty rare, we use these combinations in special cases—enterococcal endocarditis
Combinations often used when infection is of unknown etiology or several organisms with variable sensitivities—such as TB
15
Q
Disadvantages of Combinations
of Antimicrobial Drugs
A
Many drugs work only when pathogens are multiplying, so when combinations are given, where one is bactericidal and other is bacteriostatic—the 1st drug may interfere with the action of the 2ndagent
For example—bacteriostatic tetracyclines interfere with the bactericidal effects of PCN and cephalosporins
Another concern is development of resistance from giving unneeded combinations
16
Q
Genetic Alterations Leading to Drug Resistance
A
Acquired antibiotic resistance requires the
temporary or permanent gain or alteration of
bacterial genetic information
Resistance occurs due to the ability of DNA to change/mutate or to move from one organism to another
17
Q
Red man syndrome
A
Some reactions related to rate of infusion
ex: from rapid infusion of Vancomycin
18
Q
Patients with history of Stevens-Johnson syndrome or Toxic Epidermal Necrosis from an antibiotic should NEVER_____
A
be rechallenged, not even for antibiotic desensitization
19
Q
Direct Toxicity
A
High serum drug levels can cause toxicity by directly affecting cellular processes in the patient
Aminoglycosides can cause ototoxicity by interfering with membrane function in the auditory hair cells
Chloramphenicol can be toxic to mitochondria leading to bone marrow suppression
Fluoroquinolones can have effects on cartilage and tendons
Tetracyclines can directly affect bones
Many antibiotics can cause photosensitivity
20
Q
Superinfections
A
Antimicrobials—especially those with broad spectrums or combinations can cause altered normal bacterial flora in respiratory tract, mouth, GI and GU tracts—
thus allowing overgrowth of opportunistic agents, fungi or resistant bacteria
These infections will then require secondary therapy
21
Q
Antimicrobials are classified by:
A
Chemical structure
Mechanism of action
Activity against particular types
of pathogens
22
Q
Cell Wall Inhibitors
A
These antibiotics selectively interfere with synthesis of the bacterial cell wall
The cell wall is made of polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links
The antibiotics that inhibit cell walls require actively proliferating microorganisms
23
Q
Families of cell wall inhibitors
A
Penicillins
Cephalosporins
Carbapenems
24
Q
Penicillins
A
Consist of a core 4 membered ß-lactam ring—which is attached to a thiazolidine ring and an R side chain
Drugs in this family differ from each other in the R substitute attached to the 6-aminopenicillanic acid residue—this side chain affects the drugs spectrum, stability in the stomach acid, cross-sensitivity and susceptibility to bacterial degradation enzymes—better known as ß-lactamases
25
PCN: MOA
Interfere with final stage of cell wall synthesis known as transpeptidation
PCNs compete for & bind to enzymes called penicillin binding proteins [PBPs] which catalyze transpeptidase and facilitate cross-linking of the cell wall
Downstream effect is a weak cell wall and cell death
PCNs are bactericidal and work in a time-dependent mode
26
PCN: antibacterial spectrum
Gram + microbes have a cell wall easily transversed by PCNs—so unless resistance is present, they are susceptible
Gram –microbes have an outer lipopolysaccharide membrane surrounding their cell wall that acts as a barrier to PCNs
However, gram –pathogens do have proteins inserted into this barrier membrane that behave as a water lined channel [porins] that allow some PCNs to enter via this transmembrane canal
27
Natural Penicillins
Penicillin G and Penicillin V are obtained from fermented fungus of PCN
chrysogenum
PCN G [benzyl penicillin] has activity against many gram +, gram –and
spirochetes; it is 5-10 times more potent than PCN V against Neisseria spp. and
anaerobes
Most streptococci are sensitive to PCN G, BUT PCN-resistant viridians
streptococci and Streptococcus pneumoniae isolates are emerging
More than 90% of Staphylococcus aureus are now penicillinase producing and
resistant to PCN G
PCN is DOC for gas gangrene [Clostridium perfringens] and syphilis [Treponema pallidum]
PCN V is only available oral, with a spectrum similar to that of PCN G—not used for severe infections due to limited oral absorption
PCN V more acid stable than PCN G and is oral agent used in less severe infections
28
Semisynthetic Penicillins
Ampicillin and Amoxicillin
Aminopenicillins or extended spectrum penicillins
Created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus—this extends the gram –coverage to include Haemophilus influenzae, E. coli and Proteus mirabilis
Ampicillin [+/- Gentamicin]—DOC for Listeria
monocytogenes and some enterococcal species
Extended spectrum agents used in URIs
Ampicillin used by dentists to prevent bacterial endocarditis in high risk patients
These drugs are combined with ß-lactamase inhibitors such as clavulanic acid or sulbactam to treat infections from ß-lactamase producing pathogens
Without B-lactamase inhibitor, RSSA is resistant to Ampicillin and Amoxicillin
Resistance from plasmid-mediated penicillinases are a problem—this limits the use of these agents with gram - bugs
29
Antistaphylococcal Penicillins examples
Methicillin [only used in lab testing in US]
Nafcillin
Oxacillin
Dicloxacillin
ß-lactamase [penicillinase]-resistant penicillins
They are used for infections caused by penicillinase-producing staphylococci, including MRSA
30
Antistaphylococcal Penicillins
MRSA—source of serious community acquired and nosocomial infections and is resistant to most commercially available ß-lactam antibiotics
Penicillinase-resistant penicillins have minimal to no activity against gram - infections
31
Antipseudomonal Penicillins
Piperacillin
Active against Pseudomonas aeruginosa
When combined with Tazobactam [Zosyn] extends the antimicrobial spectrum to cover penicillinase-producing organisms [Enterobacteriaceae and Bacteroides spp.]
32
Antipseudomonal Penicillins: Resistance
```
Survival in spite of a ß-lactam antibiotic
can occur by one of three ways—ß-
lactamase production, decreased
permeability of the drug or altered
penicillin binding proteins [PBPs]
```
33
Antipseudomonal Penicillins: ß-Lactamase Production
```
This family of enzymes breaks
down the amide bond of the ß-lactam ring, which causes loss of bactericidal activity—they are the MAJOR cause of resistance to PCNs and are becoming more and more of an issue
Some ß-lactam antibiotics are poor
substrates for ß-lactamases and
resist hydrolysis, thus keeping their
power over ß-lactamase producing bugs
Gram + organisms secret ß-lactamases
extracellularly
Gram –organisms inactivate ß-lactam
drugs in the periplasmic space
```
34
Antipseudomonal Penicillins: Decreased Permeability of the Drug
Reduced penetration of the drug into gram –bugs is more of a problem—they have a complex cell wall that includes aqueous channels [porins]
Pseudomonas aeruginosa lacks high permeability porins
Presence of an efflux pump, actively removes the drug from the site of action can also reduce amount of intracellular drug [Klebsiella pneumoniae]
35
Antipseudomonal Penicillins: Altered Penicillin Binding Proteins [PBPs]
Antibiotic exposure can prevent cell wall synthesis and lead to changes or lysis of susceptible bacteria
Modified PBPs have lower affinity for ß-lactam antibiotics—requiring unobtainable levels of the drug to be present to kill the bug—this mechanism explains MRSA resistance to most available ß-lactams
36
Antipseudomonal Penicillins: Pharmacokinetics
Administration:
Determined by stability of the drug in gastric acid and severity of infection
Routes:
• Ampicillin + sulbactam [Unasyn]; Piperacillin + tazobactam [Zosyn];
Nafcillin and Oxacillin given IV or IM
• PCN V, Amoxicillin, Dicloxacillin are given PO
• All others are available PO, IV or IM
• Amoxicillin + Clavulanic acid is only oral in the US
Depot Forms:
Procaine PCN G and Benzathine PCN G are given IM as depot
injections—they are slowly absorbed and persist at low levels over long periods
```
Absorption:
• Acidity of the GI tract interferes
with absorption of PCNs
• Only 1/3 of PCN V is absorbed
orally
• Food decreases absorption of
penicillinase-resistant penicillin
Dicloxacillin—as gastric emptying
time increases, the drug is
destroyed by HCl, so should be
taken on empty stomach
• Amoxicillin is stable in acid
environment
```
37
Antipseudomonal Penicillins: Distribution
• ß-lactam antibiotics distribute
throughout body
• All PCNs cross the blood-brain barrier—none are teratogenic
• Penetration into bone and CSF not enough for therapy unless these sites are inflamed—inflamed meninges more
permeable to PCNs—resulting in higher levels in CSF than in serum
• PCN levels in prostate too low to use for treatment
38
Antipseudomonal Penicillins: Metabolism
• Host metabolism of the ß-lactam antibiotics usually insignificant; metabolism
of PCN G may occur in those with CKD
• Exceptions—Nafcillin and Oxacillin metabolized by liver
39
Antipseudomonal Penicillins: Excretion
• Primary route is organic acid [tubular]
secretory system in the kidney and GFR
• Those with CKD must have dosages reduced
• Nafcillin and oxacillin metabolized in liver
and do not require dose reductions in CKD
• Probenecid [gout prevention drug] inhibits
secretion of PCNs by competing for active
tubular secretion via the organic acid
transporter and can increase blood levels of
PCNs
• PCNs excreted in breast milk
40
Antipseudomonal Penicillins: ADes
- hypersensitivity
- diarrhea
-nephritis: PCNs—especially
Methicillin [no longer available in US because of this] have the potential to
cause acute interstitial nephritis
-neurotoxicity: Irritating to neuronal tissue and can provoke seizures if injected
intrathecally or if very high dose blood levels are reached—epileptics at risk as PCNs can cause GABAergic inhibition--
-hematologic effects: Decreased
coagulation can be seen with high doses
of Piperacillin and Nafcillin and perhaps
with PCN G
41
Cephalosporins
ß-lactam drugs related structurally and functionally to PCNs
Most Cephalosporins are semisynthetic by attaching side chains to 7-aminocephalosporanic acid
Changes on the acyl side chain at the 7 position effects the antibacterial power; variations at the 3-position change the pharmacokinetic profile
Same MOA as PCNs and affected by same resistance mechanisms
Tend to be more resistant than PCNs to certain ß-lactams
42
Cephalosporins 1st Generation Antibacterial spectrum
* Like PCN G substitute except they cover MSSA; isolates of Strep pneumoniae resistant to PCN G will be resistant to these drugs
* Modest activity against:
* Proteus mirabilis
* E. coli
* Klebsiella pneumoniae
* Oral cavity anaerobes, such as Peptostreptococcus
* Bacteroides fragilis is resistant to these drugs
GRAM POSITIVE COVERAGE
43
Cephalosporins 2nd Generation Antibacterial spectrum
• M. catarrhalis
• Gram + coverage is less than 1st generation drugs
• Cefotetan [Cefotan] and Cefoxitin [Mefoxin] covers anaerobes [Bacteroides fragilis]—only cephalosporins with good activity against gram –anaerobes; however neither is 1st line for B. fragilis—currently, a
lot of resistance
GRAM NEGATIVE COVERAGE
44
Cephalosporins 3rd Generation Antibacterial spectrum
* Important players in treating ID
* Yet, they are less potent against 1st generation drugs when treating MSSA
* Enhanced coverage of gram –bacilli, including ß-lactamase producing H. influenzae and Neisseria gonorrhea
* Covers Serratia marcescens and Providencia spp.
* Ceftriaxone [Rocephin] and Cefotaxime [Claforan] are DOC in meningitis
* Ceftazidime [Fortaz] covers Pseudomonas aeruginosa [resistance is increasing]
* Use these drugs cautiously—they can foster bacterial resistance and cause C. difficile infection
GRAM -/+ COVERAGE WITH SOME LOSS OF gram + coverage
45
Cephalosporins 4th Generation Antibacterial spectrum
• Cefepime [Maxipime]
• Must be given parenterally
• Wide spectrum with coverage of Staph and
Strep [that are methicillin sensitive]
• Also covers aerobic gram negative bugs—
Enterobacter spp., E. coli, K. pneumoniae, P.
mirabilis and Pseudomonas [refer to local
antibiograms to assess coverage of
Pseudomonas]
EXPANDED COVERAGE
46
Cephalosporins Advanced Generation Antibacterial spectrum
• Broad spectrum—only ß-lactam in the US that covers MRSA
• Indicated to treat complicated skin and skin structure infections and CAP
• It binds to PBPs in MRSA and Penicillin resistant Streptococcus pneumoniae
• Covers gram + pathogens and gram –coverage similar to 3rd generation Ceftriaxone
• Does not cover—P. aeruginosa, certain strains of Enterobacteriaceae and Acinetobacter baumannii
• Ceftaroline [Teflaro]
• Twice day dosing limits its use outside
of a hospital setting
47
Pearls for Practice for Cephalosporins.
Sanford Guide is your bible to assist in learning what drugs cover what bugs—and it is updated yearly based on resistance patterns and CDC recommendations...
1st generation drugs—gram + bugs*****
2nd generation drugs—gram –bugs****
3rd generation drugs—covers both but you
lose some gram + coverage*****
4th generation—broader coverage and
covers some aerobes and Pseudomonas*****
48
Cephalosporins: resistance
Develops from:
-Hydrolysis of the beta-lactam ring by
ß-lactamases
-Reduced affinity for PBPs
49
Cephalosporins: administration
Many have to be given IV or
| IM because of poor oral absorption
50
Cephalosporins: Distribution
• Distributes well in body fluids
• Adequate levels in the CSF, regardless of inflammation, are obtained with only a few
of these drugs
• Ceftriaxone [Rocephin] and Cefotaxime [Claforan] used in treating neonatal and childhood meningitis from H. influenzae
• Cefazolin [Ancef; Kefzol] used for surgery prevention due to its coverage of
penicillinase-producing S. aureus getting good tissue and fluid penetration
51
Cephalosporins: Elimination
```
• Through tubular secretion and/or GFR
• Dose reduction in renal disease
• Ceftriaxone is excreted through the
bile into the feces, no dose reduction on
those with CKD
```
52
Cephalosporins: ADEs
• Generally well-tolerated
• Those who have had anaphylaxis, Stevens-
Johnson Syndrome or Toxic Epidermal Necrolysis
to PCNs should not be prescribed a Cephalosporin
• Use with caution in those with PCN allergy
• Cross-reactivity between Cephalosporins and
PCNs is 5-10%
• Highest chance of cross-sensitivity between PCN
is with 1st generation Cephalosporins
53
Carbapenems
```
Synthetic ß-lactam antibiotics that
differ from PCNs in that sulfur atom
of the thiazolidine ring has be
externalized and replaced by a
carbon atom
Imipenem [Primaxin] is prototype drug
Meropenem [Merrem]
Doripenem [Doribax]
Ertapenem [Invanz]
```
54
Imipenem [Primaxin] is prototype drug
• Resists breakdown by ß-lactamases, but
not metallo-ß-lactamases
• Can be used empirically as it is active against gram + and gram –ß-lactamase producing pathogens, anaerobes and
Pseudomonas
55
Meropenem [Merrem]
• Bacterial coverage similar to Imipenem
56
Doripenem [Doribax]
• Bacterial coverage similar to Imipenem
• May be active against resistant strains of
Pseudomonas
57
Ertapenem [Invanz]
• Does not cover Pseudomonas, Enterococcus spp. or Acinetobacter spp.
58
Carbapenems : Pharmacokinetics
• Imipenem, Meropenem and Doripenem penetrate well into tissues, fluids and CSF [when meninges are inflamed]
• Meropenem reaches therapeutic levels in the meninges even without inflammation
• Excreted by glomerular filtration
• Because Imipenem is cleaved by a dehydropeptidase in the brush border of the proximal tubule, it is combined with cilastin to protect the drug from this cleavage
• Other Carbapenems do not require co-
administration
• Ertapenem is given once per day [IV]
• All of these agents must be dose reduced
in CKD
59
Carbapenems : ADE
• Nausea, Vomiting and Diarrhea can be seen with Imipenem
• Eosinophilia and neutropenia are less than with other ß-lactams
• High levels of Imipenem can cause seizures [less chance with other
carbapenems]
• Because carbapenems and PCNs share a common bicyclic core cross
sensitivity may occur
• Use carbapenems cautiously in those with PCN allergy [cross sensitivity
rate is <1%]
60
Monobactams
Disrupt bacterial cell wall synthesis—
unique because ß-lactam ring is not fused
to another ring
Aztreonam [Azactam] is the prototype
drug
Aztreonam mainly covers gram –bugs—Enterobacteriaceae and Pseudomonas
Does not cover gram + or anaerobic bacteria
Given IV or IM
Can accumulate in those with CKD
Relatively non-toxic, but can cause phlebitis, rash and elevated LFTs [rare]
Shows little cross-sensitivity with other ß-lactams—so can be used in those allergic to PCN, Cephalosporins or Carbapenems
61
ß-Lactamase Inhibitors
Hydrolysis of the ß-lactam ring—either by cleavage with a ß-lactamase or by acid, destroys the antimicrobial effect
ß-lactamase inhibitors, such as Clavulanic acid, Sulbactam and Tazobactam contain a ß-lactam ring, but alone have not antimicrobial effects or cause any S
Avibactam and Vaborbactam are also ß-lactamase inhibitors, but they lack the core ß-lactam ring
ß-lactamase inhibitors function by inactivating ß-lactamases, and protecting the antibiotics that are normal substrates for these enzymes
ß-lactamase inhibitors are combined with ß-lactamase-sensitive antibiotics, such as Amoxicillin, Ampicillin and Piperacillin
62
Cephalosporin + ß-lactamase Inhibitor Combinations
Ceftolozane + Tazobactam [Zerbaxa]
Ceftolozane + Tazobactam [Zerbaxa]
3rd generation cephalosporin + ß-lactamase inhibitor
IV medication used to treat resistant Enterobacteriaceae and multi-drug resistant Pseudomonas aeruginosa
It has some activity against some ß-lactamase-producing bacteria [select strains of extended spectrum ß-lactamases; ESBLs]
This agent has narrow gram + and limited anaerobic activity
63
Cephalosporin + ß-lactamase Inhibitor Combinations
Ceftazidime + Avibactam [Avycaz]
Ceftazidime + Avibactam [Avycaz]
3rd generation cephalosporin + ß-lactamase inhibitor
IV medication with broad gram –activity including Enterobacteriaceae and Pseudomonas aeruginosa
Adding Avibactam allows the drug to resist hydrolysis against broad spectrum ß-lactamases
Little activity against Acinetobacter, anaerobes and gram + bugs
64
Cephalosporin + ß-lactamase Inhibitor Combinations
```
Both of these drugs are used to treat
intra-abdominal infections [with
Metronidazole] and for management
of complicated UTIs
These agents are reserved for the
treatment of infections due to
multiple-drug resistant pathogens
```
65
Carbapenem + ß-lactamase Inhibitor Combinations
Meropenem + Vaborbactam [VaBomere]
Carbapenem + ß-lactamase Inhibitor
Approved for the treatment of complicated UTIs including pyelonephritis
Drug has activity against Enterobacteriaceae producing a broad spectrum of ß-lactamases, except mettallo- ß-lactamases
66
Vancomycin
Tricyclic glycopeptide active against aerobic and anaerobic gram + pathogens—MRSA, MRSE, Enterococcus spp., Clostridium difficile
The drug is bactericidal
Used in skin and soft tissue infections,
infective endocarditis, nosocomial
pneumonia
Dosing frequency depends on GFR—
monitoring creatinine clearance is needed
to optimize exposure while minimizing
toxicity
Best cure rates occur when trough is 10-20 mcg/mL
For activity against Staph aureus—AUC/MIC ratio is used—this ratio should be >/= 400
Initial trough levels are drawn before the 4th or 5th dose to ensure proper dosing
67
Vancomyocin ADEs
nephrotoxicity, infusion related reactions [“Red-Man” Syndrome and phlebitis], ototoxicity
68
Oral vancomycin is limited to the management of ____
c diff
69
Lipoglycopeptides
```
Telavancin [Vibativ]
Oritavancin [Orbactiv]
Dalbavancin [Dalvance]
Bactericidal concentration-dependent
semi-synthetic lipoglycopeptide drugs
active against gram + pathogens
Spectrum is similar to Vancomycin—
staphylococcus, streptococcus and
enterococcus
Agents are MORE potent than
Vancomycin and may cover VR isolates
```
70
Lipoglycopeptides
These drugs inhibit bacterial cell wall synthesis; lipid tail is essential to anchor the drug to the cell walls to improve target site binding Telavancin is an alternative to Vancomycin for acute bacterial skin and skin structure infections [ABSSSIs], hospital acquired pneumonia from resistant gram + organisms, including MRSA
Use of Telavancin may be limited by ADEs—nephrotoxicity, risk of fetal harm, interactions with drugs that prolong the QTc interval [Quinolones, Macrolides]—renal function and pregnancy test must the evaluated before prescribing this drug
Oritavancin and Dalbavancin have long ½ lives [245° and 187° respectively]—can be used as single doses for managing ABSSSs as outpatients
As with other glycopeptides—infusion reactions may occur; Oritavancin and Telavancin are known to interfere with phospholipid reagents used in managing coagulation—so other agents should be prescribed if patient is on heparin or other anti-coagulants that must have blood monitoring
71
Examples of Lipoglycopeptides
Telavancin and Oritavancin
72
Daptomycin
Bactericidal concentration-dependent cyclic lipopeptide antibiotic that is an alternative to other agents, such as Vancomycin or Linezolid, to treat infections caused by resistant gram + organisms, such as MRSA and VRE
Used to treat complicated SSSIs and bacteremia from S. aureus, including those with right sided infective endocarditis [not used for left sided BE]
This drug is inactivated by pulmonary surfactants—so it cannot be used to treat pneumonia
Given IV once a day
73
Fosfomycin
-Bactericidal synthetic derivative of phosphonic acid—blocks cell
wall synthesis by inhibiting a key step in peptidoglycan synthesis
-Used for UTIs from E. coli or E. faecalis—and is considered 1st line
for acute cystitis
-Cross resistance is not likely because of its unique MOA
-Rapidly absorbed after oral ingestion—distributes well into kidneys,
bladder and prostate
-Excreted in active form in urine and maintains high levels for days—
allowing for one time dosing
-ADEs—diarrhea, vaginitis, nausea and headache
74
Polymyxins
```
Polymyxin B—prototype drug
🔽
Colistin[Coly-Mycin M]
🔽
Cation polypeptides that bind to
phospholipids on bacterial cell membrane of
gram –pathogens
🔽
Detergent like effects that disrupt cell
membrane and cause cell death
🔽
Concentration dependent bactericidal
agents
```
75
Polymyxins
Active against Pseudomonas aeruginosa, E.
coli, K. pneumoniae, Acinetobacter spp.,
Enterobacter spp.
Proteus and Serratia are resistant
Polymyxin B is available parenteral, ophthalmic, otic and topical
Colistin is available as a prodrug, colistimethate sodium, given IV or nebulized
Use of these drugs is limited due to renal and neurotoxicity [when used systemically]
However, with increasing gram –resistance, these agents are now used as salvage therapy for multi-drug resistant infections
76
Vancomyocin
MOA: inhibits bacterial cell wall synthesis
Pharmacodynamics: combination of time and concentration time dependent. Bactericidal
Common antibacterial spectrum: Activity limited to gram positive organisms. Staph aureus (including MRSA) Strep Pyogenes, S. agalactiae, pencillin-resistant S. pnejmooniae, corynebacterium jeikeium, vancomyocin susceptible enterococcus
Unique antibacterial Spectrum: c diff (oral only)
Route: IV/PO
Adim. Time: 60-90 min IV infusion
Pharmacokinetics: renal elimination. half life 6-10 hrs. Dose is adjusted based on renal function and serum trough levels
Unique AE: Infusion-related reactions due to histamine release: fever, chills, phlebitis, flushing (red man); dose related to ototoxicity, and nephrotoxicity
Key Learning Points: Drug of choice for severe MRSA infections; oral form only used for C. diff infection; monitor serum trough concentrations for safety and efficacy
77
Daptoymycin
MOA: causes rapid depolarization of the cell membrane, inhibits intracellular synthesis of DNA,RNA,and protein
Pharmacodynamics: concentration dependent
Common antibacterial spectrum: Activity limited to gram positive organisms. Staph aureus (including MRSA) Strep Pyogenes, S. agalactiae, pencillin-resistant S. pnejmooniae, corynebacterium jeikeium, vancomyocin susceptible enterococcus
Unique antibacterial Spectrum: vancomyocin-resistant E. faecalis and E. faecium (VRE)
Route: IV
Adim. Time: 2 min IVP or 30 min IV infusion
Pharmacokinetics: renal elimination. Half life 7-8 hrs. Dose is adjusted based on renal function
Unique AE: Elevated hepatic transaminases and creatine phosphokinase (check weekly), myalgias, and rhabdomyolysis (consider holding HMG-CoA reductase inhibitors (statins) while receiving therapy
Key Learning Points: Daptomyocin is inactivated by pulmonary surfactants and should never be used in the treatment of pneumonia
78
Telavancin
MOA: inhibits bacterial cell wall synthesis; disrupts cell membrnae
Pharmacodynamics: concentration dependent; Bactericidal
Common antibacterial spectrum: Activity limited to gram positive organisms. Staph aureus (including MRSA) Strep Pyogenes, S. agalactiae, pencillin-resistant S. pnejmooniae, corynebacterium jeikeium, vancomyocin susceptible enterococcus
Route: IV
Unique antibacterial Spectrum: some isolated vancomyocin resistant enterococci
Adim. Time: 60 min IV infusion
Pharmacokinetics:
Unique AE: taste disturbances, foamy urine, QTc prolongation, interferes with coagulation labs (PT/INR, aPTT, ACT), not recommended in pregnancy (box warning recommends pregnancy test prior to initiation)
Key Learning Points: Use with caution in patients with baseline renal dysfunction (CrCl<50 mL/min) due to higher rates of treatment failure and mortality in clinical studies; any necessary coagulation labs should be drawn just prior to the telavancin dose to avoid interaction
