Chapter 24 Flashcards
Week 2
What year and by who were penicillins discovered
1928, Alexander Flemming
What are 4 ways abx resistance is mediated?
1.Production and excretion of an enzyme that hydrolyzes the antimicrobial
2.Genetic alteration of the microbial site where antimicrobial binds
3.Alteration in cellular membrane proteins that prevent antimicrobials from penetrating into microbial cells
4.Transmembrane efflux pumps that transport antimicrobials from interior to exterior of the microbial cells
What is VRE and when did it emerge
vancomycin-resistant enterococci - emerged in 1980
What is CRE and when did it emerge
carbapenem-resistant enterobacterales - emerged in 2000s
Leading Risk Factors for having a drug-resistant pathogen:
Recent use of antimicrobials
Multiple medical comorbidities
Recent hospitalization or other skilled healthcare contact
Antibiotic Stewardship Strategies
Treatment for specific infectious disease
Formulary restrictions
Dose optimization
Prospective audits
Continuing education for prescribers
Define Antimicrobials:
The entire arsenal of drugs that have the activity to inhibit or kill microbes.
Define Antibiotic or Antibacterial
Specifically refers to antimicrobials that target bacteria
Define Bactericidal
Refers to 99.9% eradication of a bacterial colony in vitro in 24 hrs by an antimicrobial.
-No clinical utility in the designation. Not to be used for clinical decision-making.
Define Bacteriostatic:
Refers to an abx that kills bacteria but the result is less than 99.9% eradication in a 24hr period.
-No clinical utility in the designation. Not to be used for clinical decision-making.
What are Beta Lactams and what are they most effective at treating
Super class of abx and contains the most abx’s of any class. Most effective against rapidly replicating organisms.
What are the 4 major groups of abx within beta-lactams
Penicillins
Cephalosporins
Carbapenems
Monobactams
What is the active part of the beta-lactam abx
a 4-member ring known as the beta-lactam ring
What is the MOA of all beta-lactam abxs
B-lactams inhibit the biosynthesis of the bacterial cell wall by binding to bacterial enzymes, specifically the peptidoglycan structure, and leading to cell lysis.
What are three bacterial enzymes that help create cell wall/peptidoglycan synthesis
Transpeptidase
Carboxypeptidase
Endopeptidase
What is peptidoglycan?
a rigid envelope surrounding the cytoplasmic membrane of most bacterial species
What is minimum inhibitory concentration (MIC)?
the lowest concentration of an antimicrobial agent that will inhibit the visible growth of a microorganism after overnight incubation.
What are the 4 penicillin subclasses?
- Natural penicillins
- Aminopenicillins
- Antistaphylococcal penicillins
- Antipseudomonal or Extended-Spectrum penicillins
What are the four natural penicillins and how are they administered
Penicillin V - administered PO
Procaine penicillin - administered IM
Benzathine penicillin - administered IM
Penicillin G - administered IV
Penicillin G is reliable for treating which bacteria
reliable for treating Listeria monocytogenes
Natural penicillins are active against which organisms
active against aerobic, gram-positive organisms, including:
Streptococcus species such as S. pneumoniae and group A beta-hemolytic Streptococcus (GABHS)
Some Enterococcus strains
Some non–penicillinase-producing staphylococci
What is penicillinase?
the vast majority of organisms produce and excrete an enzyme called penicillinase. this enzyme hydrolyzes the beta-lactam ring of natural penicillins rendering them completely ineffective
Why has Penicillin-resistant Streptococcus pneumoniae has decreased in prevalence ?
widespread vaccination for Streptococcus pneumoniae (PCV-13, -15, -20)
Why do only 5% to 15% of community-acquired Staphylococcus aureus remain susceptible to natural penicillins?
the vast majority of organisms produce and excrete an enzyme commonly known as penicillinase
A Penicillin-resistant s. pneumoniae is also likely to be resistant to?
cephalosporins, macrolides, and sulfonamides, and, to a lesser extent, clindamycin; therefore, they are commonly called drug-resistant S. pneumoniae (DRSP)
What kind of organisms do Aminopenicillins target?
Have greater activity against gram-negative bacteria because of their enhanced ability to penetrate the outer cell membrane of these organisms.
(Like penicillins, they also have reliable activity against gram-positive organisms, including Streptococcus and Enterococcus species.)
What are the two most common aminopenicllins?
Ampicillin
Amoxicillin
Aminopenicllins are often paired with what to increase their effectiveness
Often paired with beta-lactamase inhibitors to prevent the destruction of beta-lactam antibiotics by serving as a competitive inhibitor of beta-lactamase. (sulbactam and clavulanate)
Ampicillin/sulbactam and amoxicillin/clavulanate have excellent activity against?
Staphylococcus aureus (MSSA), Streptococcus and Enterococcus species
Haemophilus influenzae, Neisseria meningitidis, Salmonella, some Shigella species
What are three Antistaphylococcal Penicillins and how are they administered?
Nafcillin (only available IV)
oxacillin (only available IV)
dicloxacillin (only available PO)
Are Antistaphylococcal penicillins stable in the presence of penicillinase produced by staphylococci?
yes
What is the difference between penicillinase and beta-lactamase?
Penicillinase is a specific subtype of β-lactamase, showing specificity to pencillins
Antistaphylococcal Penicillins are active against which organisms?
They are active against Streptococcus species, MSSA, and Peptostreptococcus.
What is the Antipseudomonal Penicillin abx
Piperacillin/tazobactam
comprised of a single combination product: piperacillin and a beta-lactamase inhibitor, tazobactam.
Piperacillin/tazobactam is active against?
Pseudomonas aeruginosa, Enterobacter, Escherichia coli, Klebsiella species.
What is the the most common mechanism of resistance to penicillins?
Beta-lactamase production. large group of enzymes with diverse ability to inactivate beta-lactams
Which bacteria are considered extended-spectrum beta-lactamases (ESBLs)? What is the consequence of this.
Enterobacterales such as E. coli, Klebsiella species, and Enterobacter produce ESBLs that have broader activity and not generally inhibited by beta-lactamase inhibitors.
Which natural penicillin can be given PO
Penicillin V
Which antistaphylococcal penicillin can be given PO
dicloxacillin
Which penicillins should be given IM, with a long half life
Penicillin G procaine and penicillin G benzathine
What could cause a cardiac arrest regarding penicillin administration
IM administration of Penicillin G procaine and penicillin G benzathine near a vein or artery
How are penicillins distributed throughout body
Varying degrees of plasma protein bonding
Can penicillins cross the placenta or be in breast milk?
Yes and Yes
Do penicillins readily cross the BBB?
No
What percent of renal excretion of penicillins is by active tubular secretion
90%
How readily are penicillins metabolized?
Excluding nafcillin and oxacillin, penicillins undergo negligible metabolism and are excreted primarily as unchanged drugs in the urine, achieving high urinary concentrations.
How should you treat C.Diff? What is the criteria for stool sampling?
if definitive diagnosis is made, treatment with oral vancomycin or fidaxomicin is required.
more than three watery, unformed stools per day or blood in the stool warrant stool testing to detect C. difficile toxin.
Piperacillin/tazobactam, when combined with vancomycin, leads to higher-than-expected rates of?
nephrotoxicity
the most commonly prescribed antibiotic in the United States
Amoxacillin
cross-sensitivity between penicillins and cephalosporins, carbapenems, or beta-lactamase inhibitors was thought to be much higher, data suggest that the rate is closer to?
1%
less than what percent of patients are truly allergic to penicillins?
1%
Type 1 rxns of penicillins usually occur within how much time post administration
2-30min
4 steps for Abx selection
Make clinical diagnosis
Obtain culture/specimens if able
Make microbial dx
Select drug based on sensitivity or usual susceptibility
Which 6 drugs are known to interact with penicillins
Diuretics
Methotrexate
Oral contraceptives
Probenecid
Tetracyclines
Warfarin
Ampicillin can interact with which two drugs
beta blockers and allopurinol
a rapid strep test, is testing for which organism
Group A Streptococcus Bacteria
How do cephalosporins compare chemically and structurally to penicillins?
Chemically and structurally similar to penicillins
What two drugs are included in the cephalosporin class but technically cephamycins?
Cefoxitin and cefotetan
What is the MOA of cephalosporins?
inhibit mucopeptide synthesis in the bacterial cell wall, making the bacterium osmotically unstable. Like penicillins, cephalosporins inhibit PBPs involved in cross-linking peptidoglycans in the cell wall
What are Penicillin Binding Proteins (PBPs)?
subgroup of enzymes of transpeptidases. Essential for bacterial cell wall synthesis. involved in the final stages of synthesizing peptidoglycan.
Inhibition of PBPs leads to defects in cell wall structure and irregularities in cell shape
What are cephalosporins most effective against?
They are most effective against rapidly growing organisms forming cell walls and when antibiotic concentrations exceed the pathogen’s MIC for at least 50% of the dosing interval
What is the only intravenous first-generation cephalosporin?
Cefazolin
What are the most commonly used first-generation cephalosporins?
cephalexin & cefadroxil
What organisms do 1st gen cephalosporins target?
active against gram-positive cocci, including S. aureus and S. epidermidis (excluding methicillin-resistant strains), and most streptococci.
What species are intrinsically resistant to cephalosporins?
Enterococcus species
Do 1st gen cephalosporins readily enter the CSF?
No
What are the three 2nd gen. cephalosporins?
cefaclor, cefprozil, and cefuroxime
2nd gen cephalosporins are active against?
active against the same organisms as the first generation but with increased activity against H. influenzae
Cephamycins are included in what generation of cephalosporins?
2nd generation
What are the two cephamycins?
cefotetan and cefoxitin
Cephamycins have what sort of activity?
activity similar to 1st gen. W/ limited activity against anaerobes including Bacteroides fragilis
What needs to be performed before ordering a second gen. cephalosporin?
2nd gens have variable activity, so susceptibility tests need to be performed
What are three 3rd gen. cephalosporin abx?
Cefotaxime, Ceftazidime, and Ceftriaxone
Third Generation Cephalosporins have activity against?
streptococcal species, Streptococcus pneumoniae, MSSA, H. influenzae (including beta-lactamase–producing strains), Moraxella, N. gonorrhoeae, N. meningitidis, E. coli, Klebsiella, Proteus, and Salmonella
What kind of activity do 3rd gen. cephalosporins have? What is the exception?
Similar spectrum of activity to other generations
*except for ceftazidime.
Ceftazidime - reduced gram-positive but increased gram-negative activity such as Pseudomonas aeruginosa
Do 3rd gen. cephalosporins have reliable activity against anaerobes?
None of the third-generation cephalosporins have reliable activity against anaerobes other than Peptostreptococcus
What generation of cephalosporins are used to treat meningitis?
Because they cross the blood-brain barrier, third-generation parenteral cephalosporins are used to treat meningitis
What is the 4th gen. cephalosporin?
cefepime
What is the 5th gen. cephalosporin?
ceftaroline
What are two nongenerational cephalosporins and how are they available?
ceftolozane/tazobactam and ceftazidime/avibactam are only available for IV administration.
What are the most common mechanisms of resistance to cephalosporins?
that bacteria express against cephalosporins are beta-lactamase production and altered target sites.
are cephalosporins stable in the presence of penicillinases produced by S. aureus?
yes
Which generation(s) are the most stable in the presence of most beta-lactamases produced by enteric gram-negative bacteria?
Third- and fourth generation cephalosporins
How well are cephalosporins absorbed through GI?
oral formulations are well-absorbed from the GI tract
How are cephalosporins distributed? What needs to be considered with ceftriaxone?
Protein binding varies, but ceftriaxone is so highly bound to albumin that it should be avoided in neonates at risk for hyperbilirubinemia, especially preterm infants
What generations of cephalosporins readily enter the CSF in the presence of meningeal inflammation
Third and fourth-generation drugs and cefuroxime
How significant is hepatic metabolism for cephalosporins?
Hepatic metabolism is not significant for cephalosporin drug elimination.
How are most cephalosporins excreted? What is one exception?
Most cephalosporins are excreted via the kidney in varying degrees as unchanged drug. Renal impairment significantly extends the half-life of these drugs.
Ceftriaxone elimination is mainly extrarenal, via biliary, making its half-life stable to changes in renal function
What lab value signifies a renal dosing adjustment is needed for cephalosporins?
Dosage adjustments are recommended for most oral agents when the glomerular filtration rate reaches less than 30 mL/min
How does renal impairment affect cephalosporin elimination?
Renal function impairment significantly affects the half-life of most cephalosporins
Are cephalosporins safe in pregnancy?
Generally safe in pregnancy. Does cross placenta and small portions into breast milk.
Are cephalosporins recommended for those who have had a type 1 (immediate, anaphylactic) reaction to any penicillin?
Despite this low cross-reactivity (1%), cephalosporins are still generally not recommended
What adverse event has occurred when renal impairment is not adjusted for when administering cephalosporins?
Several parenteral cephalosporins have been associated with induction of seizure activity, especially in the presence of renal impairment when the dose was not adjusted
Who are at risk for coagulation abnormalities from cephalosporin administration?
those with impaired renal function, cancer, impaired vitamin K synthesis, low vitamin K stores, or malnutrition.
Is C. diff development a possible sequela of cephalosporin admin?
yes
What are some clinical uses for cephalosporins?
Active against many respiratory pathogens, including those that cause acute otitis media, sinusitis and group A streptococcal pharyngitis, pneumonia, and chronic bronchitis
Active against most UTI pathogens
What cephalosporin is used to treat gonorrhea?
Ceftriaxone (IM) is the recommended treatment for gonorrhea - resistant to others
Staphylococcal skin infections often respond to which generation of cephalosporins?
first-generation cephalosporins such as cephalexin.
What is the drug of choice for surgical prophylaxis?
Parenteral cefazolin
What is the “definitive approach” to drug selection?
the microbial diagnosis is based on valid and reliable tests such as culture or antigen assays, and drug selection is based on laboratory and susceptibility results. The goal of susceptibility testing is to identify the most effective antibiotics.
What is the “empirical approach” to drug selection?
the microbial diagnosis and drug regimen are determined with epidemiological studies. These references identify the drug with the narrowest spectrum that covers the most likely microbiological pathogens for a specific clinical diagnosis.
What goes into the drug selection process of cephalosporin selection?
Selection of cephalosporins, like selection of any antimicrobial, is based on the organism that is present (in the definitive approach) or most likely present (in the empirical approach), site of infection, resistance patterns, adverse effects, pharmacokinetics, cost, and convenience
Which generation of cephalosporins is the preferred empirical treatment for skin and tissue infections?
Second-generation oral cephalosporins are slightly less active against gram-positive cocci than first-generation oral cephalosporins, so the latter are the preferred empirical treatment
What cephalosporins are effective against the most resistant strains of pneumococcus
Parenteral ceftriaxone and cefotaxime are used empirically in serious infections presumed to be caused by these strains.
What is Clindamycin and does it have much utility?
Derivative of Lincomycin and only drug of its class
Limited indications due to potential for severe diarrhea/CDI, resistance, and better-tolerated alternatives
MOA of Clindamycin
Binds to 50S subunit of bacterial ribosome; Suppresses protein synthesis
What kind of organisms does Clindamycin affect?
Primarily Gram-Positive and select anaerobic organisms
How well is Clindamycin absorbed?
PO: Complete absorption, not affected by gastric acid or food
How is Clindamycin distributed?
Distributes to pleural/peritoneal fluids w/high conc in bile/bone
Highly protein bound
What is Clindamycin’s presence in CSF, placenta, and breast milk?
Poor CSF penetration
Crosses placenta and found in breast milk
How is Clindamycin metabolized and eliminated?
metabolized by the liver to active and inactive metabolites
Excreted in bile/urine(10%)
Clinical uses of Clindamycin
Bacterial Vaginosis
first-line therapy to treat odontogenic infections including dental abscesses
Bacterial Endocarditis prophy as alternative for penicillin allergic pt
Drug-Resistant Penumococcal Infections
Does Clindamycin need to have renal or hepatic dosage adjustments?
No dosage modification unless severe renal/hepatic impairment
What are three known drug interactions with Clindamycin?
Erythromycin: Antagonist effects
Kaolin-pectin: Delays GI absorption
NMB: Severe respiratory depression
What makes Clindamycin a treatment option in septic shock?
Its inhibition of protein synthesis, clindamycin can decrease toxin production in the setting of septic shock caused by Streptococcus, susceptible Staphylococcus, and Clostridium
What is the mechanism of resistance against Clindamycin?
Mechanisms of resistance include mutation or modification of the ribosomal receptor site and enzymatic inactivation of clindamycin. Modification of the ribosomal receptor site also confers macrolide resistance as these two classes of antibiotics have overlapping binding sites on the 50S ribosomal subunits
What are a few adverse reactions due to Clindamycin
GI-related, including nausea, vomiting, and a bitter or metallic taste. GI intolerance is dose-limiting. The most serious is the risk for CDI.
What is an anesthesia consideration of Clindamycin?
If surgery or general anesthesia is planned during or within a day or so after therapy, the anesthetist or anesthesiologist must be advised because clindamycin can intensify neuromuscular blockade.
What kind of antibiotics are fluoroquinolones?
synthetic, broad-spectrum antibiotics
Fluoroquinolones are divided into two groups. What are the older fluoroquinolones?
ciprofloxacin [Cipro]
ofloxacin [Floxin]
Fluoroquinolones are divided into two groups. What are the newer fluoroquinolones? What are they often referred to as?
(often referred to as the respiratory fluoroquinolones because of their activity against S. pneumoniae)
levofloxacin [Levaquin]
moxifloxacin [Avelox]
delafloxacin [Baxdela]
What is the MOA of fluoroquinolones?
bactericidal through interference with enzymes required for the synthesis and repair of bacterial deoxyribonucleic acid (DNA)
extra info: inhibit bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication
What effect does the fluorine molecule have on fluoroquinolone activity?
Fluorine molecule added to create the fluoroquinolones provides increased potency against gram-negative organisms and broadens the spectrum to include gram-positive organisms as well.
What are the two fluoroquinolones that have activity against P. Aeruginosa?
Only ciprofloxacin and levofloxacin
Fluoroquinolones have notable activity against?
notable for their extensive gram-negative activity
Ex: E. Coli, Klebsiella, +more
How is resistance mediated against fluoroquinolones?
Resistance is mediated by mutations in the quinolone-binding region of the target enzyme or by a change in the permeability of the organism. Overuse of these agents has already eroded the utility of this group of drugs.
How well are fluoroquinolones absorbed PO?
All drugs in this class are well-absorbed after oral administration
How are fluoroquinolones distributed?
All drugs in this class are widely distributed, with high tissue and urinary levels.
Tissue concentrations > than plasma concentrations
Do fluoroquinolones readily cross BBB and placenta?
Minimal BBB crossing. All apear to cross to placenta.
How much are fluoroquinolones metabolized?
Very minimal metabolism
How are fluoroquinolones excreted?
Predominant route of elimination varies widely between fluoroquinolones.
Ofloxacin and levofloxacin have predominant renal excretion with minimal (less than 10%) metabolism
At what CrCl level should fluoroquinolones be renally dosed?
For patients with CrCl of 50 mL/min or less, dosage adjustments are necessary for all fluoroquinolones, except for moxifloxacin
What is the boxed warning for fluoroquinolones?
All fluoroquinolones have a boxed warning regarding the risk of tendon rupture and tendonitis. The risk is increased in older patients, patients taking corticosteroids, and patients immunosuppressed. An additional boxed warning has been issued to avoid all fluoroquinolones in patients with myasthenia gravis.
What is the age recommendations for fluoroquinolones?
Fluoroquinolones are not recommended for children younger than 18 years.
What are three possible adverse effects of fluoroquinolones?
C. Diff
Serious and occasionally fatal hypersensitivity reactions, including Stevens–Johnson syndrome and anaphylaxis
Phototoxicity has been observed with all fluoroquinolones
Fluoroquinolones are first-line therapy in the treatment of?
traveler’s diarrhea and severe diarrhea not associated with antibiotic therapy.
Which respiratory fluoroquinolones are used for community-acquired pneumonia?
levofloxacin and moxifloxacin
What drug is termed an OXAZOLIDINONE?
Linezolid (Zyvox)
approved in the United States in 2000, is the first drug in a new class of antibiotics,
a unique class of synthetic antibiotics.
MOA of Linezolid (Zyvox)
inhibitors of bacterial ribosomal protein synthesis, but unlike other antibiotics, they stop the first step in synthesis in which bacteria assemble ribosomes from their dissociated subunits.
(Linezolid does this by binding to the 50S ribosomal subunit, thus preventing the formation of a 70S initiation complex required for protein synthesis. No other known antibiotic uses this process.)
What is Linezolid (Zyvox) active against?
most effective against aerobic gram-positive bacteria.
group A and B Streptococcus, S. aureus (both MSSA and MRSA.
retains activity against the most resistant forms of Enterococcus including VRE
What is the resistance activity against Linezolid (Zyvox)
resistance is not widespread and considered uncommon
What is the absorption of Linezolid (Zyvox)
Linezolid is rapidly and completely absorbed after oral administration
What is the distribution of Linezolid (Zyvox)
only 31% protein bound and the binding is dependent on concentration. High drug concentrations are found in the skin and other well-perfused tissues. Peripheral tissue concentrations far exceed plasma concentrations
How do Linezolid (zyvox) concentrations compare between maternal plasma and placenta?
Breast milk concentrations are similar to those in the maternal plasma
What is the metabolism of Linezolid (Zyvox)
two inactive metabolites of linezolid created by oxidation of the morpholine ring. Because this is a nonenzymatic oxidation, this drug does not induce the CYP system
What is the excretion of Linezolid (Zyvox)? Is renal or hepatic dosing needed?
Nonrenal excretion accounts for 65% of the total clearance; of the remainder, 30% is excreted unchanged in urine. No dosage adjustments are required for impaired hepatic or renal function
When is Linezolid (Zyvox) contraindicated?
Concomitant use or use within 2 weeks of a monoamine oxidase inhibitor (MAOI) with linezolid is contraindicated.
Serotonin syndrome or hypertension
What are the recommendations for children using Linezolid (Zyvox)?
Linezolid is approved for use in children from birth. Preterm infants and neonates require reduced dosing because of slower clearance.
What is a unique precaution clinicians need to be aware of before prescribing Linezolid (Zyvox) ?
Bone marrow activity suppression AKA Myelosuppression (anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid
What kind of food must be avoided when receiving Linezolid (Zyvox)?
Because significantly elevated blood pressure may occur if taken with tyramine-rich foods, the amount of tyramine consumed at any one meal should be limited (less than 100 mg/meal).
The most common adverse effect of Linezolid (Zyvox)?
most common adverse reactions reported were diarrhea, headache, and nausea.
C diff.
What drug interactions does Linezolid (Zyvox) have?
Because linezolid is a reversible, nonselective inhibitor of monoamine oxidase, it also has potential interactions with serotonergics such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, ondansetron, meperidine, buspirone, methadone, and tramadol
Watch for s/s of serotonin syndrome
Clinical use of Linezolid (Zyvox)?
Shown to have greater clinical cure rates for MRSA pneumonia compared with vancomycin.
one of only several agents that are first line for treating VRE infections
Drug Selection Rationale for Linezolid (Zyvox)?
Linezolid’s use should be reserved for moderate to severe infections in which alternative antibiotics are less desirable secondary to efficacy, resistance, safety, route, or $$cost.
Why has the use of sulfonamides decreased?
Use of sulfonamides has decreased due to resistance and the incidence of allergic reactions to sulfa drugs.
What are two sulfonamide topical agents used to prevent infection in patients with burns?
Mafenide (Sulfamylon) and silver sulfadiazine (Silvadene)
MOA of Sulfonamides
Competitive inhibition synthesis enzymes. Inhibition of this pathway prevents folic acid synthesis, which is required by susceptible organisms for the production of purines and nucleic acids.
If a bacteria doesn’t require folic acid, sulfa is ineffective.
Activity of Sulfonamides
inhibit both gram-positive and gram-negative bacteria.
Protazoa - Toxoplasma gondii
Resistance to sulfonamides is mediated by?
Mutations that result in excessive production of PABA cause organisms to develop resistance.
MOA of Trimethoprim
inhibits bacterial dihydrofolic acid reductase. Dihydrofolic acid reductases convert dihydrofolic acid to tetrahydrofolic acid, a stage leading to the synthesis of purines and ultimately to DNA
What happens when a Sulfonamide and Trimethoprim are giving together?
results in synergistic activity of both drugs
Activity of Trimethoprim
active against both gram-positive and gram-negative organisms
Resistance of Trimethoprim
results from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with less drug-binding ability
most common cause is plasmid-encoded resistant reductases
Nitrofurantoin use is limited to? Is it a sulfonamide?
UTIs, Not a sulfonamide
MOA of Nitrofurantoin
Ultimately, protein synthesis, aerobic energy metabolism, DNA and RNA synthesis, and cell wall synthesis are inhibited
Activity of Nitrofurantoin
Active against most gram-positive cocci and gram-negative bacilli that cause UTIs
Many bacteria including E.Coli
Resisitance of Nitrofurantoin
Resistant mutants are rare
What is Fosfomycin and is it a sulfonamide?
a bactericidal antibiotic available in the United States only as an oral formulation for the treatment of UTIs
Not a sulfanamide
MOA of Fosfomycin
ultimately leads to inhibition of cell wall synthesis. beneficial in the treatment of UTIs because it reduces adherence of bacteria to the epithelial cells in the urinary tract.
Activity of Fosfomycin
activity against most urinary pathogens
Resistance of Fosfomycin
uncommon but has been reported. The bacterial mechanisms of resistance most commonly described are enzymatic modification of fosfomycin.
Absorption of Sulfonamides
Oral sulfonamides are absorbed readily from the GI tract.
Distribution of Sulfonamides
They are distributed widely throughout the body and found in all body tissues. They readily enter the CSF, pleura, synovial fluids, and the eye. They cross the placenta and enter breast milk.
Absorption of Trimethoprim
well-absorbed following oral administration. .
Distribution of Trimethoprim
It is widely distributed in body tissues, including prostatic tissues, and crosses the placenta. Distribution into breast milk occurs with high concentrations.
Absorption of Nitrofurantoin
readily absorbed via oral administration.
Absorption of Fosfomycin
oral bioavailability of 34% to 58%
Distribution of Fosfomycin
Very little drug is protein-bound. Fosfomycin distributes into the kidneys, bladder wall, prostate, and CSF fluid if the meninges are inflamed.
Metabolism of Sulfinamide
Metabolism in the liver by conjugation and acetylation to inactive metabolites
Excretion of Sulfinamide
Renal excretion is mainly by glomerular filtration
Metabolism of Nitrofurantoin
Approximately 50% to 70% is rapidly metabolized by body tissues to inactive metabolites.
Excretion of Nitrofurantoin
Renal excretion is via glomerular filtration and tubular secretion. Needs renal dosing for CrCl <30
Excretion of Fosfomycin
eliminated as unchanged drug primarily through renal excretion (up to 60% of an oral dose) and in feces (18%)
What abx should be used with caution for patients with folate deficiency.
Trimethoprim
What electrolyte should be monitored when using Trimethoprim
Potassium. risk for hyperkalemia
What are tetracyclines?
broad-spectrum antibiotics that are used extensively throughout the world.
What drugs are in the tetracycline group
tetracycline, demeclocycline, doxycycline (Doxy, Doxychel, Vibramycin), and minocycline (Minocin)
which tetracycline is used primarily for syndrome of inappropriate antidiuretic hormone.
Demeclocycline
MOA of tetracyclines
inhibit protein synthesis by reversibly binding to the 30S subunit of the bacterial ribosome and preventing the addition of amino acids to growing peptides.
Activity of tetracyclines
good activity against gram-positive organisms, activity against some gram-negative bacteria
mechanism of resistance to tetracyclines
The mechanisms of resistance to tetracyclines are (1) decreased intracellular accumulation due to impaired influx or increased efflux of an active transport protein pump, (2) ribosome protection by proteins that interfere with drug binding, and (3) enzymatic inactivation. Resistance to tetracycline generally predicts resistance to the entire class
Absorption of tetracyclines
adequately. The percentage of oral dose absorbed is highest for doxycycline and minocycline (95% to 100%) and intermediate for tetracycline (60% to 70%)
Distribution of tetracyclines
Doxycycline and minocycline are highly lipid soluble. found in tissues
Which tetracycline needs to be renally dosed? Which does not?
Tetracycline needs renal dosing. doxycycline and minocycline do not significantly accumulate or require dosage reductions for renal impairment.
Metabolism of tetracyclines
liver metabolism
Excretion of tetracyclines
Tetracyclines are eliminated by the kidney via glomerular filtration and undergo enterohepatic recirculation with excretion in the bile and feces
Can tetracyclines be used during pregnancy and breastfeeding?
Doxycycline and other tetracyclines should not be used in pregnancy.
Short term breastfeeding ok
Can children use tetracyclines
Children younger than 8 years generally should not use tetracyclines. These drugs form a stable calcium complex in any bone-forming tissue, decreasing bone growth.
Besides GI upset, what adverse reactions are related tot tetracycline use
GI Symptoms including C. Diff
Pseudotumor cerebri (benign intracranial hypertension) has also been associated with tetracyclines. Symptoms are headache and blurred vision
Photosensivity, SJS
What drug interactions do tetracyclines have?
Mainly with elements.
with divalent and trivalent cations that are found in antacids, iron salts, sevelamer, magnesium-containing laxatives, and zinc supplements.
Clinical use of tetracylines
STIs, Acne, H. Pylori
Doxycycline is the primary drug choice for which conditions/infections
ehrlichiosis and rickettsial infections (e.g., Rocky Mountain spotted fever, typhus, Q fever, and trench fever caused by B. quintana)
What drug level should be closely monitored when taking a tetracycline
digoxin
What is the primary glycopeptide
Vancomycin
When are glycopeptide abx’s used?
group of antibiotics is used for gram-positive infections that are resistant to first-line antibiotics.
MOA of vancomycin
inhibits cell wall synthesis by binding firmly to a portion of peptidoglycan synthesis enzymes.
result is a weakened cell wall susceptible to lysis
Activity of Vanco
bactericidal for gram-positive organisms
Resistance to Vanco
Resistance is due to a modification of the binding site of the peptidoglycan building block
Absorption of vanco
Poor PO absorption.
Oral bioavailability is approximately 1%
When vanco is given IV, how quickly is onset? What influences the duration?
When administered intravenously, onset of action is rapid, with peak concentrations in 1 hour and a duration of effect that is highly variable and directly correlated to renal clearance
Distribution of Vanco
It is 52% to 56% protein bound. Distribution is wide, with 20% to 30% penetration of the CSF. The drug crosses the placenta.
Excretion of Vanco
Because minimal oral absorption occurs, most oral doses of vancomycin are excreted in feces. Intravenously administered vancomycin is eliminated renally, with more than 90% via glomerular filtration
Precautions using vanco
nephrotoxic and should be used with caution in patients with impaired renal function or patients receiving other nephrotoxic agents
What is Vancomycin Infusion Syndrome
includes potentially severe hypotension, and red man syndrome, has been associated with rapid intravenous administration of vancomycin
When can vancomycin be used in pregnancy
Oral vancomycin is generally considered safe in pregnancy, whereas the IV form should only be used if the benefits outweigh the risk.
What drug, when administered with Vanco, leads to a three-fold higher risk of AKI
Pip/Taz aka Zosyn
Clinical use of Vanco
Oral vancomycin is used to treat CDI
IV dosing of vancomycin is complex and extremely patient specific.
