Antibiotics Flashcards
What are the beta-lactam antibiotics?
Penicillins
Cephalosporins
Carbepenems
Monobactam
Beta-lactams inhibit transpeptidation of NAG and NAMs in bacterial cell walls
β-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall.
Beta-lactam - routes and general uses
Given Oral, IV, IM
Intrathecally is contraindicated
Poor CSF penetration, can reach therapeutic levels when meninges are inflamed.
T>MIC
Renally excreted - OAT
which beta-lactam antibiotics can treat CNS infections regardless of meningeal inflammation?
3rd generation cephalosporins - ceftriaxone and cefotaxime
2nd gen cephalosporin - cefuroxime
Mechanisms of resistance to β-lactam antibiotics
1 - penetration (intracellular organisms)
2 - Porins (like in gram-neg, need to get through porins in outermembrane to get to the peptidoglycan)
3 - pumps - drug efflux
4 - PBPs with low affinity for drug (penicillian binding protein)
5 - Penicillinases - hydrolyze (inactivate) drug
6 - peptidoglycan - organisms without cell wall (mycoplasma)
beta lactam resistant bacteria come in different classes,
Class A - Extended Spectrum Beta-lactamases - through several genes: TEM, SHV, CTX-M and KPC (klebsiella) Carbapenemase
Class A is passed by conjugation, expressed by gram-neg species especially
Class C – with genes AmpC and CMY organism displays resistance to broad and extended-spectrum beta-lactams
Class D – OXA-type: ESBLs and Carbapenemases
Class B -- genes: IMP, VIM, GIM, SPM, SIM: Carbapenemases. New Delhi (NDM-1): Carbapenemases (class B type metallo-beta-lactamases)
How do bacterial biofilms affect therapy?
bacteria in biofilms are much less sensitive to antibiotics and tend to have decreased rates of growth
Hypersensitivity reactions to penicillins
Anaphylaxis: Rapidly progressive, life-threatening
-hypotension, bronchonstriction
angioedema, serum sickness (delayed, type III), immune hemolysis, rash or SJS
Fever; interstitial nephritis; vasculitis; neutropenia and
thrombocytopenia
Rx – Airway management, epinephrine followed by respiratory and cardiovascular support. Antihistamines or GCs as needed.
Name the non-immunologic side effects of beta-lactams
GI: mild to severe diarrhea; nausea; vomiting
Clostridium difficile infection - significant, pseudomembranous colitis
candidiasis infection
IM - pain, sterile imflammatory rxn at inj site, IV - phlebitis or thrombophlebitis
Intrathecal use is CONTRAINDICATED It can cause arachnoiditis or severe, fatal encephalitis
c. diff - gram pos, spore-forming, anaerobic bacillus
phlebitis - inflammation of vein wall
Drug Interactions of beta lactams
inhibition of OAT messes with probenecid and methotraxate
decreases effectiveness of oral contraceptives by decreasing estrogen recycling
interacts with gastric acid suppressors which increases c diff risk
tetracycline - reduce beta-lactam efficacy
decreases thyphoid vaccine efficacy
Natural Penicillin - What organisms do they treat?
useful for gram positive aerobes and anaerobes, N. meningitidis; H. influenzae; spirochetes
How are the different forms of natural penicillins administrured?
Penicillin G - IV and IM
Penicillin V - oral
repository Penicillin G - IM
- Penicillin G procaine
- Penicillin G benzathine
- Penicillin G benzathine / procaine combo
poor penetration of CSF, inflamed meninges increases penetration
Resistance and cautions to Natural Penicillins
Beta-lactamases — s. aureus and gram-neg bacilli
PBPs with low affinity for beta-lactams —- s. pneumoniae, s. aureus, enterococcus faecium
gram-neg bacilli - drug cant pass through porins and have beta-lactamases
cautions - hypersensitivity, seizures, electrolyte distrurbances
jarisch-herxheimer reaction - complication of treatment of syphilis, thought to be a response to lipoproteins released by dying treponema pallidum
Penicillinase-Resistant Penicillins - name the drugs
Nafcillin
Oxacillin
Dicloxacillin
Cloxacillin
methicillin was the first in the class
Activity and therapeutic uses of penicillinase-resistant penicillins
activity against penicillinase-producing, methicillin-sensitive Staph aureus and Staph epidermidis
used for MSSA and MSSE
should not be used when penicillin can do the job
Resistance to penicillinase-resistant peniceillin and Adverse Effects
resistance - alteration of PBPs, expression of PBP2a (MecA gene) and inherent resistance (enterococci and listeria)
adverse effects special to these drugs are hepatitis and interstitial nephritis
hepatitis is through direct toxicity and hypersensitive rxn
Aminopenicillins - what are they?
extended spectrum penicillins
ampicillin (sometimes given with sulbactam)
amoxicillin (sometimes given with clavulanate)
Activity of Penicillin G plus Extended spectrum: gram-negative
Resistance to aminopenicillins
Class A TEM-1/SHV-1 β-lactamases found in H. influenza, N gonorrhoeae, E coli and klebsiella
Altered PBPs found in MRSA, pneumoniae, enterococcus
bacteroided fragilis - can be overridden with beta-lactamase inhibitor
Pseudomonas aeruginosa: inherently resistant
Adverse Effects of Aminopenicillins
non-allergic rash – pruritic maculopapular rash
viral infection - mononucleosis (EBV)
hypersensitivity reaction
Ampicillin-sulbactam: Broad use
parenteral only
includes repiratory, intra-abdominal, UTI and endocarditis
Amoxicillin-clavulanate Use
oral only
Respiratory, skin/skin structure, bite wounds and UTIs
Antipseudomonal Penicillins
Extended-spectrum penicillins
Piperacillin- tazobactam
Piperacillin-tazobactam
able to pass through porins in outer membrane because of polar side chains – pseudomonas aeruginosa and Enterobacteriaceae
broadest antibacterial spectrum of penicillins
Used for resistant gram-negative bacteria
-P. aeruginosa, indole-positive Proteus, Enterobacter
monotherapy is not recommended for p. aeruginosa - give with tobramycin or ciprofloxacin
Adverse Effects of Piperacillin-tazobactam
special effects of drugs:
exacerbation of CHF - drugs are manufactured as Na+ salts
abnormal platelet aggregation, thrombocytopenia
leukopenia and neutropenia with long-term use
seizure disorders
rash - especially in piperacillin use
β-Lactamase Inhibitors
Clavulanic acid Sulbactam Tazobactam Avibactam Vaborbactam
Mechanism of β-Lactamase Inhibitors
suicide inhibitors - molecules bind irreversibly to and inhibit bacterial beta-lactamases
They are not antibiotics
Most active against Ambler class A beta lactamases
staphylococci N gonorrhoeae E coli
H influenzae K pneumoniae
M catarrhalis salmonella
B fragilis shigella
Cephalosporins
First-generation - Cefazolin, Cephalexin
Second-generation - Cefuroxime, Cefoxitin
Third-generation - Ceftriaxone, Cefotaxime, Cefdinir, Ceftazidime, Ceftazidime-avibactam, Ceftolozanetazobactam
Fourth-generation - Cefepime
“Fifth”-generation - Ceftaroline
First Generation Cephalosprorins - drug names
Cefazolin*
Cephalexin*
Cefadroxil
Second-generation Cephalosporins - drug names
Cefuroxime
Cefoxitin
Others - cefaclor, cefprozil, loracarbef, cefotetan
Third - Generation Cephalosporins - drug names
Ceftriaxone
Cefotaxime
Cefdinir
Ceftazidime (alone or with avibactam or tazobactam)
others - ceftizoxime, cefpodoxime proxetil, cefditoren, ceftibuten, ceftixime
Fourth - Generation Cephalosporins - drug names
Cefepime
“Fifth”-generation Cephalosporins - drug names
Ceftaroline
General Properties of Cephalosporins
given IM, IV or oral with poor CSF penetration unless meningeal inflammation (with some exceptions)
cross placenta and enters breast milk
renal excretion of unchanged drug
half life ranges from hour to 8 hours
Ceftriaxone
third generation cephalosporin
biliary excretion
1st Generation Cephalosporin Spectra of Activity and Uses
Gram-positive – MSSA and Streptococci
Gram-negative – PEcK (Proteus, E coli, Klebsiella) and respiratory bacteria
Uses - skin and soft tissue infections(s. pyogenes, MSSA), otitis media, GU tract infections
cefazoline
1st generation cephalosporin - surgical propholaxis
2nd Generation Cephalosporin Spectra of Activity and Uses
Streptococci and MSSA (staph)
Expanded gram-negative
HeNPEcK (H.influenzae & PEcK - Proteus, E coli, Klebsiella)
Cephamycins: B. fragilis
uses - Uncomplicated skin / soft tissue, respiratory, GU infection
How is bacteroides fragilis treated?
resistant to all cephalosporins except:
cefoxitin and cefotetan (cephamycins)
3rd Generation Cephalosporin Spectra of Activity and Uses
Activity of Penicillin G – useful for gram positive aerobes and anaerobes, N. meningitidis; H. influenzae; spirochetes
expanded gram negative spectrum
ceftazidime has anti-pseudomonas activity
4th Generation Cephalosporin Spectra of Activity and Uses
Activity of Ampicillin
(Ampicillin is Pen G plus extended spectrum gram negative)
Extended spectrum gram negative + anti-pseudomonas
Uses - reserved for treatment of severe infections
5th Generation Cephalosporin Spectra of Activity and Uses
Gram-positive aerobes and
anti-MRSA with the gram negative activity of ceftriaxone (gram negative bacilli, some enterobaster, H. influenza, and Moraxella catarrhalis.)
Uses - Skin/skin structure infections (including MRSA) and community-acquired pneumonia
What are the cephalosporins that can penetrate into CSF without meningeal inflammation?
cefuroxime
cefotaxime
ceftriaxone
ceftazidime
ceftriaxone
third generation cephalosporin
drug of choice for Gonorrhea and Lyme Disease infections
also can be used for s. pneumonia (penicillin-sensitive), MSSA, gram negative bacilli, some enterobaster, H. influenza, and Moraxella catarrhalis
what drug options are available against Pseudomonas?
Piperacillin-tazobactam
Ceftaroline (5th Gen)
Cefepime (4th Gen)
ceftazidime (2nd Gen)
Carbapenems - except ertapenem
What types of infections are cephalosporins not good for?
penicillin-resistact S. pneumoniae, MRSA, MRSE (with exceptions), enterococcus, listeria monocytogenes, C. Diff
KPC-producing enterobacteriacease, campylobacter jejuni, stenotrophomonas maltophillia, acinetobacter
atypicals – myoplasma, legionella pneumophila, chlamydia
Adverse effects of 3rd-Generation Cephalosporins
I.M. painful injection; I.V. thrombophlebitis
Rare - renal tubular necrosis or interstitial nephritis
Adverse effects of Ceftriaxone
(third gen)
biliary statis and cholestatic hepatitis
in neonates - hyperbilirubinemia (with potential kernicterus) and lung and kidkey damage from precipitation of Ca2+
(give cefotaxime to neonates instead)
Adverse effects of Cefotetan
Hypoprothrombinemia by inhibition of Vit K activation
Disulfiram-like reaction (alcohol consumption)
Carbapenems
Imipenem-cilastatin*
Meropenem*
Ertapenem*
Doripenem
Characteristics and spectrum of Carbapenems
parentarel only, penetrates CSF
short half life
Broad Spectrum:
gram-positive and gram-negative, aerobic and anaerobic
Penicillin-resistant S. pneumonia
Penicillin-sensitive Enterococcus faecalis
Not affected by beta-lactamases but are suspectible to carbapenemases or metallo-β-lactamases (Klebsiella)
treatment of choice for: − ESBL-expressing Enterobacteriaceae − Pseudomonas aeruginosa, (may acquire resistance) • except ertapenem − Anaerobes, including B. fragilis
Resistance to Carbapenems
Acquired
- Class A serine protease - Klebsiella pneumoniase carbapenemase
- Class B metallo-β-lactamases AKA carbapenemases
Intrinsic - MRSA, Enterococcus faecium, Clostridium difficile, Stenotrophomonas maltophilia
what do carbapenemases do?
They hydrolyze penicillins, cephalosporins, and carpenems
They are not inhibited by beta-lactamase inhibitors
Therapeutic uses of Carbapenems
Empiric treatment of serious infections of hospitalized patients who have already recieved beta-lactam therapy – lower respiratory, intra-abdominal, gynecological, skin, soft tissue, bone or joint infections
Intra-abdominal and pelvic infections caused by gram-positive bacteria, enterobacteriaceae and anaerobes
Adverse effects of carbapenems
hypersensitivity reactions’
Common side effects
Seizures - greatest risk with imipenem and patients with renal insufficiency
hematologic - bleeding, agranulocytosis, leukopenia
GI - nausea, vomiting, diarrhea
C. diff superinfection
Aztreonam - PK, Spectrum, Resistance
Monobactam - IV, IM; widely distributed; renal excretion
gram-negative aerobes only - esp. aerobic cocci and bacilli, including P. aeruginosa
Resistance:
• Gram-positive bacteria
• ESBLs; AmpC β-lactamase hydrolyze aztreonam
• Some strains of Enterobacteriaceae and Pseudomonas
(PBPs with low affinity for aztreonam)
Therapeutic Uses of Aztreonam
Infections by susceptible gram-negative bacilli - UTI’s, LRT infections, septicemia, skin/skin structure infections, intra-abdominal infections, and gynecological infections
aztreonam inhalation - in Cystic Fibrosis Patients with Pseudomonas aeruginosa
Aztreonam should not be used alone for empiric therapy
Adverse Effects of Aztreonam
cross-reactivity with beta-lactams is limited, so hypersensitivity reactions are less common
- Exception, ceftazidime
Nausea/vomiting/diarrhea
Thrombophlebitis and pain at injection site
C. difficile superinfection reported - and can occur more than two months after treatment
Vancomycin - MOA and PK
glycopeptide - inhibit
peptidoglycan polymerization - D-ala-D-ala
poor absorption from gut so oral is only for local gut action,
IV for systemic with slow infusion bc of red man syndrome
only penetrates CSF with meningeal inflammation
6 hours half life, 24-h AUC/MIC and bacteriocidal
(efficacy depends on the total amount of drug given in a 24 hour period)
Vancomycin - spectrum
Gram-positive pathogens only - Penicillin-resistant S. pneumoniae, MRSA and MRSE
Enterococcus faecalis and E. faecium - bacteriostatic
Clinical Uses of vancomycin
MRSA / MRSE infections- - bacteremia, pneumonia, empyema, endocarditis, osteomyelitis, soft-tissue abscess
Penicillin-resistant streptococcal and enterococcal infections - endocarditis and necrotizing fascitis
meningitis due to penicillin resistant s. pneumoniae
C. diff infection - first line (before it was metronidazole)
Gram-positive infections in penicillin-allergic patients
Vancomycin Cautions - AEs and DIs
Adverse Effects - red man syndrome (thought to be caused by direct release of histamine and not immunologic), hypersensitivity, phlebitis, ototoxicity and nephrotoxcity
Ototoxicity and nephrotoxicity are especially common when given with aminoglycosides
NSAIDs may increase serum levels of vancomycin
Daptomycin
Cyclic lipopeptide with poor absorption, given IV only - forms a pore in the bacterial membrane causing loss of membrane pot. and cell death
Inactivated by pulmonary surfactant
half life - 8/9hrs
bacteriocidal, AUC/MIC – Efficacy correlates with total drug exposure to MIC ratio
Daptomycin spectrum and therapeutic uses
all gram-positive pathogens – aerobic, facultative, and anaerobic
Effective against MRSA, MRSE, VISA, VRSA, and VRE
treatment of complicated skin and soft tissue infections, bacteremia, and VRE right-sided endocarditis
What are the limitations of Daptomyicin
infections by gram-neg organism - ineffective
left-sided endocarditis and pneumonia - because inactivated by pulmonary surfactant
Daptomycin Cautions
myopathy - monitor CK levels
Eosinophilic pneumonia - important to monitor, happens 2 to 4 weeks post-therapy
peripheral neuropathy
pregnancy category b, excreted in breast milk
not known to be safe in pediatrics
interacts with statins (HMG-CoA reductase inhibitors)
