IID 04: Pharmacology of Beta Lactams Flashcards
What are exotoxins?
release or secreted predominantly by gram-positive bacteria
- causes botulism and tetanus
What are endotoxins?
not secreted by bacteria, but are components of gram-negative bacteria cell wall
- most injurious and fatal components of gram-negative bacteria
What are antibiotics?
chemical substance produced by microorganisms that have the capacity to inhibit the growth or destroy bacteria and other microorganisms in dilute solution
What are broad spectrum antibiotics?
antibiotics which kill or inhibit a wide range of gram-positive and gram-negative bacteria
What are narrow spectrum antibiotics?
antibiotics effective mainly against gram-positive or gram-negative bacteria
What are limited spectrum antibiotics?
antibiotics effective against a single organism or disease
What is the concentration-dependent effect of antibiotics on bacteria?
rate and extent of bacterial loss is directly related with the increasing concentration of drugs
What is the post-antibiotic effect?
persistent suppression of bacterial growth that persists after brief exposure of organisms to antimicrobials
What is the time-dependent effect of antibiotics on bacteria?
- if plasma concentration is greater than minimum bactericidal concentration
concentration of drugs should be maintained above the MIC
What are bactericidal antibiotics?
antibiotics that kill bacteria
- ie. penicillin
What are bacteriostatic antibiotics?
antibiotics that stop the growth of bacteria
Are sulfonamides and tetracyclines bactericidal or bacteriostatic?
‘static’ at low doses and ’cidal’ at higher doses
Penicillins
Are penicillins bactericidal or bacteriostatic?
bactericidal – inhibit cell wall synthesis
- except Enterococcus
Penicillins
What are the 4 classifications of penicillins?
- natural penicillins
- penicillinase-resistant penicillins (antistaphylococcal penicillins)
- aminopenicillins
- antipseudomonal penicillins
Penicillins
What are natural penicillins?
ie. penicillin G, penicillin V potassium
Penicillins
What are penicillinase-resistant penicillins (antistaphylococcal penicillins)?
ie. cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin
Penicillins
What are aminopenicillins?
ie. amoxicillin, ampicillin, bacampicillin
Penicillins
What are antipseudomonal penicillins?
ie. piperacillin, ticarcillin, carbenicillin, mezlocillin
Penicillin G
- acid-labile compound with variable bioavailability after oral administration
- most appropriate for IM or IV therapy
- mainly effective against gram-positive bacteria and some gram-negative bacteria (N. gonorrhea and N. meningitidis)
Penicillin G
What is benzathine penicillin?
- used for treatment of beta-hemolytic streptococcal pharyngitis (Scarlet Fever) and latent syphilis
- do not inject IV or mix with other IV solutions
Penicillin G
What is procaine penicillin G?
- used for treatment of syphilis
Penicillin V
oral form of penicillin
- used for streptococcal infections
- poor bioavailability
- multiple daily doses needed
- used for minor infections (replaced by ampicillin)
Compare Penicillin V to Penicillin G.
- more acid stable than penicillin G
- has the same spectrum of activity as penicillin G
What are some penicillinase-resistant penicillins (antistaphylococcal penicillins)?
- methicillin (no longer in use)
- nafcillin
- oxaclillin
- dicloxacillin
Penicillinase-Resistant Penicillin (Antistaphylococcal Penicillins)
- relatively acid stable and well absorbed
- absorption impaired by food
- beta-lactamase-resistant due to bulky residues on their R side chains that prevent binding by the staphylococcal beta-lactamase
- not as effectives as penicillin G or penicillin V
- semi-synthetic penicillins with a narrow spectrum – used to treat infections caused by penicillinase-resistant staphylococci
Penicillinase-Resistant Penicillin (Antistaphylococcal Penicillins)
Describe the bacteria that are resistant to these drugs.
methicillin resistant bacteria
- have altered penicillin binding proteins
- vancomycin is the drug of choice in such infections
Penicillinase-Resistant Penicillin (Antistaphylococcal Penicillins)
What are these antibiotics most useful against?
infections caused by staphylococci, with the exception of MRSA
Aminopenicillins
extended-spectrum penicillins – ampicillin and amoxicillin
- similar activity against organisms targeted by penicillin G
- greater activity against gram-negative bacteria
- beta-lactamase sensitive
Aminopenicillins
What are these drugs useful for treating?
urinary tract infections, respiratory infections
What is a key consult point of aminopenicillins?
should not be taken on an empty stomach – food impairs absorption of drug
Antipseudomonal Penicillins
- similar activity against organisms targeted by ampicillin
- side chains allow for greater penetration into gram-negative bacteria than aminopenicillins
- generally, more resistant to cleavage by gram-negative beta-lactamase than aminopenicillins
- show activity against Pseudomonas aeruginosa, Klebsiella
- effective against some Staph. Aureus
Antipseudomonal Penicillins
What are these drugs useful for treating?
urinary tract infections, respiratory infections
Are penicillins toxic?
no – generally non-toxic
What hypersensitivity reactions can occur with penicillin?
- GI upset (large oral doses) – nausea, vomiting, diarrhea, abdominal pain
- rash
- fever
- bronchospasm (abnormal smooth muscle contraction, respiratory obstruction)
- vasculitis (inflammation of blood vessel)
- exfoliative dermatitis (severe inflammation of entire skin)
- anaphylaxis – rare, about 0.5-1 of 10,000 patients
Do cross-allergic reactions occur among beta-lactam antibiotics?
yes
Penicillins
Hypersensitivity (3-10%)
- 5% ranging from maculopapular rash (common rash with ampicillin hypersensitivity) to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis
- patients with mononucleosis and treated with ampicillin – incidence of maculopapular rash approaches 100%
Penicillins
Neurotoxicity
- patients with renal failure: high doses → seizures
- penicillins are irritating to neuronal cells, provoke seizures if injected intrafecal or if very high blood levels are reached
- epileptic patients are particularly at risk
- high doses of penicillin causes seizures by inhibiting GABA
Penicillins
Diarrhea
- common problem
- disruption of the normal balance of intestinal microorganisms with drugs
- also pseudomembranous colitis with some other antibiotics
Penicillins
Nephritis
all penicillins, but particularly methicillin, are potential cause of acute interstitial nephritis
- note: methicillin is therefore no longer available
Penicillins
Cation Toxicity
- penicillins are generally sodium or potassium salt
- toxicities due to large quantities of Na or K
- Na excess may result in hypokalemia (rare)
-0 this can be avoided by using the most potent antibiotic, which permits lower doses of drug and accompanying cations - hyperkalemia (rare) – increased potassium load due to rapid IV doses of penicillin G potassium in patients with renal failure
Penicillin Metabolism
Major Determinant
benzyl penicilloyl (95%) formed when the beta-lactam ring is opened
Penicillin Metabolism
Minor Determinant
penilloate, penicilloate, and benzyl-n-propylamine formed by drug degradation in GI tract
What plays an important role in allergic reactions to penicillins?
major and minor determinants of metabolism
What is a type I penicillin allergy?
- minutes to hours
- offending drugs – IgE (histamine and other proinflammatory from mast cells and basophils)
- anaphylaxis, urticaria, angioedema, pruritus, hypotension, respiratory distress/bronchospasm
What is a type II penicillin allergy?
- 72 hours cytotoxic reaction
- IgG directed against haptenized proteins
- antibody bind to renal intestinal cells or RBC complement system
- hemolytic anemia, thrombocytopenia, cytopenia, proteinuria, and/or hematuria
What is a type III penicillin allergy?
- 10-21 days hypersensitivity to penicillin
- delayed immune complex reactions mediated by IgG and IgM
- circulating immune complexes complement deposited in blood vessels of kidneys, joints, or skin
- fever, serum sickness, vasculitis, erythema multiform, interstitial nephritis, lymphadenopathy, splenomegaly, arthralgias
What is a type IV penicillin allergy?
- 2-4 days or more
- induction of T cells interacting with an antigen
- proinflammatory cytokines, tissue inflammation, and clinical manifestations
- morbilliform eruptions or contact dermatitis
- Stevens-Johnson syndrome or toxic epidermal necrolysis
How are penicillin allergies managed?
- penicillin allergy testing – skin testing
- desensitization
- severe non-IgE-mediated reactions related to penicillin use requires strict avoidance of penicillin
Penicillins
What are the hematologic toxicities?
- decreased coagulation with the antipseudomonal penicillins and, to some extent, with penicillin G
- in patients who are predisposed to hemorrhage (ie. uremic) or those receiving anticoagulants
- additional toxicities include eosinophilia
Penicillins
What is the major concern with penicillin allergy?
associated with:
- longer hospital admissions, higher rates of readmission, treatment failure, and intensive care unit admission
- increased risk of exposure to significantly more antibiotics associated with Clostridium difficile, vancomycin-resistant Enterococcus, and methicillin-resistant S aureus (MRSA)
Penicillins
What are the mechanisms of resistance? (4)
- antibiotic is inactivated by beta-lactamase produced by the bacteria itself (very common)
- modification of target PBPs
- impaired penetration of drug to target PBPs
- efflux pump mechanism to remove drug
Penicillins – Mechanism of Resistance
Antibiotic is inactivated by beta-lactamase produced by the bacteria itself (very common).
- over 300 beta-lactamases (penicillinase) identified
- specificity can be variable
- large amounts often secreted by gram-positive bacteria
- gram-negative bacteria tend to secrete less penicillinase
- weak correlation between a given antibiotic’s bactericidal action and its susceptibility to beta-lactamase
- beta-lactamase may also hydrolyze cephalosporin
Penicillins – Mechanism of Resistance
Modification of target PBPs.
- PBPs may have low affinity for binding to beta-lactam antibiotics
- inhibition of bacterial growth occurs only with high drug concentrations – very rare but common with Staphylococci, Pneumococci, Enterococci, and Neisseria gonorrhoeae
- clinical usefulness of beta-lactam may be compromised
- MRSA expresses a new PBP
Penicillins – Mechanism of Resistance
Impaired penetration of drug to target PBPs.
- peptidoglycan layer in (G+) bacteria is near the cell surface
- small beta-lactam drugs easily penetrate the outer layer of cytoplasmic membrane and bind to PBP
- outer membrane in gram negative (G-) bacteria forms an impenetrable barrier to certain antibiotics
- aqueous channels (porins) in (G-) bacteria allow access to certain hydrophilic antibiotics
- pore size and density can vary among different (G-) bacteria
Penicillins – Mechanism of Resistance
Efflux pump mechanism to remove drug.
- certain gram negative bacteria possess protein components for efflux pumps
- efflux pumps transport beta-lactam antibiotics back across the outer membrane
- ie. nafcillin extrusion by Salmonella tyhinurium
Cephalosporins
- semi-synthetic derivatives from a fungus
- structurally and pharmacologically related to penicillins
- generally, beta-lactamase resistant (not totally)
- high therapeutic index
Are cephalosporins bactericidal or bacteriostatic?
bactericidal action – dose-related
- inhibit cell wall synthesis and bind to the same proteins as penicillin
Why are cephalosporins needed?
wider/broad spectrum that may work against penicillin-resistant bacteria
In what ways are cephalosporins generally the same as penicillin?
- mechanism of action
- mechanisms of resistance
- absorption and excretion
- toxicity
What are cephalosporins effective against?
- gram positive bacteria
- E. coli
- Klebsiella
- Proteus
What are cephalosporins inactive against?
- enterococci
- methicillin-resistant staphylococcus aureus (MRSA)
What are some 1st generation cephalosporins?
- cephalexin
- cefazolin
- cefadroxil
1st Generation Cephalosporins
- stronger antimicrobial action against G+ bacteria than G- bacteria
- nephrotoxic (to a certain degree)
- not effective against pseudomonas
- stable against beta-lactamase (penicillinase)
- cefazolin does not penetrate CNS and cannot be used to treat meningitis
What are some 2nd generation cephalosporins?
- cefoxitin
- cefotetan
- cefaclor
- cefuroxime
- cefprozil
2nd Generation Cephalosporins
- less effective against G+ bacteria than 1st generation with enhanced antimicrobial action against G- bacteria
- stable against beta lactamases and exert less nephrotoxicity than 1st generation
- cefuroxime has ability to cross the blood-brain barrier and suitable for the treatment of meningitis, especially H. influenzae meningitis, and sepsis
What are some 3rd generation cephalosporins?
- cefixime
- cefotaxime
- ceftriazone
- ceftazidime
3rd Generation Cephalosporins
broadest spectrums of all cephalosporins
- highest activities against G- bacteria
- lowest activities against G+ bacteria
- highest resistance to beta-lactamase
- best penetration into the CSF – almost no nephrotoxicity
3rd Generation Cephalosporins
What is unique about ceftriaxone?
has longest half-life (8 hr) of any cephalosporin
3rd Generation Cephalosporins
What is unique about cefixime?
oral preparation
3rd Generation Cephalosporins
What is unique about ceftazidime?
best anti-pseudomonal cephalosporin
3rd Generation Cephalosporins
What is unique about cefoperazone?
eliminated (70%) in the bile – therefore very useful in patients with renal failure
What are some 4th generation cephalosporins?
- cefepime
4th Generation Cephalosporins
- greater stability against beta-lactamases
- extended spectrum of activity against gram-positive organisms – similar to ceftriaxone
- effective against Pseudomonas aeruginosa
- very good activity against penicillin resistant strain of streptococci and it may be useful in the treatment of Enterobacter infections
- otherwise, clinical role is similar to third generation cephalosporins
Cephalosporins
Describe the kinetics of 1st and 2nd generation cephalosporins.
first and second generation cephalosporins are used with aminoglycosides to treat serious gm(-) infections
Cephalosporins
Describe the kinetics of 3rd generation cephalosporins.
third generation cephalosporins are effective against gm(-) meningitis and in multi-resistant gm(-) infections – pneumonias, UTI, osteomyelitis, pelvic and intra-abdominal infections
Cephalosporins
What are the side effects?
similar to penicillins
- hypersensitivity
- diarrhea
- nephritis
- neurotoxicity
- hematologic toxicities
- cation toxicity
third generation cephalosporins may decrease thrombin → increase bleeding
Cephalosporins
Hypersensitivity Reactions (1-7%)
- anaphylaxis (rare)
- rash (maculopapular, urticarial) (1-3%)
- serum sickness-like reaction (especially with cefaclor)
- some cross-sensitivity with penicillin (5-10% – perhaps as low as 1%)
- if a patient develops urticaria, anaphylaxis, or angioedema with penicillin or a cephalosporin, avoid using any of the other cephalosporin
Cephalosporins – Side Effects
Hypoprothrombinemia
- associated with methylthiotetrazole ring
- common with cefoperazone, cefamandole, and cefotetan – occurs in 20-60% of patients
- give Vitamin K (menadione) as preventative measure – less bleeding problems with cefotetan
- cephalosporins may also cause bleeding due to reduction of gut flora
Cephalosporins – Side Effects
Disulfiram-like Reaction
- flushing, sweating, headache, tachycardia associated with alcohol ingestion
- associated with methylthiotetrazole-containing cephalosporin only (cefoperazone, cefamandole, cefotetan)
Cephalosporins – Side Effects
GI Complaints
diarrhea more common with cefixime, cefdinir, and cefoperazon
Cephalosporins – Side Effects
Elevation of Liver Enzymes (5-10%)
–
Cephalosporins – Side Effects
Cholecystitis-like syndrome with ceftriaxone (~20% with chronic dosing).
- precipitation of ceftriaxone in bile leads to biliary sludge
- may require surgery
Cephalosporins – Side Effects
Displacement of bilirubin from albumin binding sites.
- major concern in neonates
- occurs with ceftriaxone and cefoperazone
Cephalosporins – Side Effects
Phlebitis, pain at IM injection site.
- most common with cephalothin and cephapirin
- may also occur with cefotaxime
Cephalosporins
Interactions
- some produce disulfiram-like reactions with alcohol (symptoms include flushing of the skin, accelerated heart rate, SOB, nausea, vomiting)
- H2 antagonists and antacids decrease absorption
- probenecid increases/prolongs cephalosporin’s effect
- false-positive glucosuria testing with a copper reduction test (clinitest) may occur with many cephalosporins
- depletion of gut flora resulting in decreased vitamin K synthesis (problem with 2nd and 3rd generation cephalosporins)
Cephalosporins
What drugs do cephalosporins interact with?
- aminoglycosides
- anticoagulant
Cephalosporins
Drug Interaction with Aminoglycosides
aminoglycoside nephrotoxicity may be potentiated with the use of certain cephalosporins – especially cephalothin
Cephalosporins
Cephalosporin (with Methylthiotetrazole Group) Drug Interaction with Anticoagulant
- hypoprothrombinemic effects of anticoagulants are increased
- bleeding complications may occur
What is responsible for the cross-reactivity between penicillins and cephalosporins?
structural similarities
- originally theorized that the common beta-lactam ring was the cause of cross sensitivity, but further research suggests the cause to be similar side-chains
- penicillins contain a single side-chain at the 6-position, while cephalosporins have two side-chains at the 7- and 3-position
- when the penicillin side-chain is similar to either of the cephalosporin side-chains, the likelihood of cross-sensitivity increases
- many first- and second-generation cephalosporins have similar side-chains to penicillin antibiotics, thus increasing the chance of cross-sensitivity
- the other generation agents have structurally different side-chains, and therefore patients have a lower likelihood of experiencing cross-sensitivity
What are some 5th generation cephalosporins?
- ceftaroline
- ceftobiprole
5th Generation (Advanced) Cephalosporins
- active against a wide range of both gram-positive and gram-negative organisms including methicillin resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, pseudomonas aeruginosa
5th Generation (Advanced) Cephalosporins
What is ceftaroline?
- prodrug form of a new semi-synthetic cephalosporin
- effective against MRSA and multidrug-resistant Streptococcus pneumonia, as well as some gram-negative organisms
5th Generation (Advanced) Cephalosporins
Why is ceftaroline special?
- binds to the penicillin-binding protein (PBP)2a, an MRSA-specific protein, which makes it unique among the cephalosporins
- efficacy against endocarditis, pneumonia, myositis, and osteomyelitis has been demonstrated in animal models
- efficacy in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia has been confirmed in humans
5th Generation (Advanced) Cephalosporins
Describe the antibacterial spectrum of ceftaroline.
broad spectrum with bactericidal activity
- effective against many resistant gram-positive bacteria as well as gram-negative bacteria
- retains activity against isolates with reduced susceptibility to vancomycin or linezolid
- inactive against ESBL-producing or AmpC-over-expressing Enterobacteriaceae
- limited activity against non-fermenting gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter baumannii
5th Generation (Advanced) Cephalosporins
What is the mechanism of action of ceftaroline?
- ability to bind to PBP2a, demonstrating superior affinity as compared with cefozopran and other beta-lactams
- high affinity for S. aureus PBPs correlates well with its low minimum inhibitory concentration (MIC) for MRSA or methicillin-susceptible S. aureus (MSSA) strains
5th Generation (Advanced) Cephalosporins
Describe the pharmacokinetics of ceftaroline.
- following IV infusion, ceftaroline prodrug is rapidly converted to its bioactive metabolite, ceftaroline, by plasma phosphatases
- no drug accumulation at therapeutic doses upon IV administration in healthy volunteer
- comparable bioavailability when administered IM or IV – IV more expensive
- upon conversion of ceftaroline fosamil in the plasma to the active metabolite, ceftaroline, a small fraction is converted to an inactive metabolite, ceftaroline-M-1
- half-life of active ceftaroline is 2.6 h and that of the ceftaroline-M-1 metabolite is 4.5 h in healthy volunteers
- ceftaroline and ceftaroline-M-1 are eliminated primarily through the kidney and half of the dose is excreted in the urine as an active drug, with a small amount excreted in the urine as ceftaroline-M-1
- dosage adjustment may be needed in patients with moderate but not mild renal impairment
5th Generation (Advanced) Cephalosporins
What are the adverse effects of ceftaroline?
- generally mild
- nausea, headache, pruritus, and rash (which infrequently require discontinuation of therapy)
- occurrence of Clostridium difficile-induced diarrhea is rare with this novel cephalosporin
- no evidence of hepatic, renal, or cardiac toxicity or any infection/fatalities
- ceftaroline should not be used in cephalosporin sensitive patients
5th Generation (Advanced) Cephalosporins
Ceftaroline Interactions
- no clinical drug-drug interaction studies have been conducted with ceftaroline fosamil
- neither ceftaroline fosamil nor ceftaroline inhibits the major cytochrome P450 isoenzymes
- neither ceftaroline fosamil nor ceftaroline inhibits or induces the clearance of drugs that are metabolized by the cytochrome P450 isoenzymes
5th Generation (Advanced) Cephalosporins
What are the warnings and precautions of ceftaroline?
- hypersensitivity reactions
- Clostridium difficile-associated diarrhea
- development of drug-resistant bacteria
5th Generation (Advanced) Cephalosporins
What are the contraindications of ceftaroline?
- known serious hypersensitivity to ceftaroline or other members of the cephalosporin class
- anaphylaxis and anaphylactoid reactions (resemble generalized anaphylaxis but not IgE-mediated)
5th Generation (Advanced) Cephalosporins
What is the mechanism of resistance of ceftaroline?
- production of beta-lactamase enzymes
- modification of target PBPs
- impaired penetration of drug to target PBPs
- shortage of autolytic enzyme
- presence of an efflux pump
- passage of the cephalosporins through Porin
What are the 4 carbapenems?
- imipenem
- meropenem
- doripenem
- ertapenem
Carbapenems
- meropenem, imipenem/cilastatin, doripenem, and ertapenem are parenteral synthetic beta-lactams
- derived from thienamycin, an antibiotic produced from Streptomyces cattleya
- have beta-lactam ring, like penicillins and cephalosporins, but also have a methylene moiety in the ring
Carbapenems
What are carbapenems the most reliable class of antibiotics against?
ESBL organisms and the SPICE A organisms (Serratia, Pseudomonas/Providencia, Indole-positive Proteus, Citrobacter, Enterobacter, and Acinetobacter)
- possess the broadest spectrum of activity of all antimicrobials
- active against gram-positive and gram negative organisms – broad spectrum
- resistant to most beta-lactamases
Carbapenems
What is the mechanism of action?
similar to other beta-lactams
Carbapenems
What are some common characteristics?
- all administered IV
- half life = 1 hr (except ertapenem = 4 hrs; once daily)
- bactericidal against: B. fragilis, Enterobacteriaceae, Pseudomonas, and gram-positive organisms
- bacteriostatic against: Listeria and E. faecalis
Carbapenems
Which carbapenems have CSF penetration?
- meropenem
- imipenem
Carbapenems
Describe metabolism.
only meropenem is rapidly metabolized by kidneys
Carbapenems
Describe excretion.
excreted by kidneys
Carbapenems
What are the common side effects?
- nausea, vomiting, diarrhea, seizures, eosinophilia, and neutropenia
- cause seizures in patients with renal dysfunction
Carbapenems
Describe the distribution of imipenem.
- distributes to most tissues including the CNS
- inactivated by the renal enzyme dehydropeptidase which lowers imipenem concentration and renders it ineffective
- co-administered with cilastatin – cilastatin inhibits dehydropeptidase → increases drug concentration
Carbapenems
What is meropenem?
- another thienamycin derivative
- has a 1-beta-methyl substitution in its side chain
- this accounts for its differences in pharmacologic properties from imipenem
- co-administration with a DHP-I inhibitor is NOT required
Carbapenems
What is doripenem?
- broad spectrum carbapenem antibiotic
- structural analog of imipenem
- unlike imipenem, doripenem is resistant to cleavage by renal dehydropeptidase I
- co-administration with cilastatin is NOT required
Carbapenems
Pharmacokinetics of (?)
- similar to imipenem
- IV administration – dose adjustment is required in patients with renal insufficiency, generally safe and well tolerated, lower adverse event rate than imipenem
- excretion – excreted unchanged into the urine by glomerular filtration and tubular secretion
Carbapenems
Safety of Meropenem
- even at higher doses, it still has a low risk of seizures and its gastrointestinal effects are not dose-dependent
= as a result, meropenem doses can be elevated to improve efficacy and potentially reduce the emergence of resistant organisms - its safety at higher doses and lower CNS toxicity permit it to be used to treat bacterial meningitis
Carbapenems
Describe the development of resistance to meropenem.
- mechanisms by which P. aeruginosa resistance to meropenem is acquired are similar to those for imipenem
- unlike imipenem, resistance to meropenem requires two independent mutations: mutation that reduces porin channels, and
mutation that up-regulates efflux mechanisms (one of these mutations alone only reduces sensitivity to meropenem and does not confer resistance)
Carbapenems
What is the mechanism of action of doripenem?
- doripenem derives its bactericidal action from inhibition of PBPs and blocking cell wall synthesis
- doripenem binds to several high MW PBPs including (PBPs 1, 2, 3 & 4)
- binding intensity of doripenem is species specific – ie. PBP3 in P.aeruginosa, PBPs 1, 2 and 4 in S.aureus, and PBP2 in E.coli
- results in defective cell walls, cell lysis and bacterial death
Carbapenems
What is ertapenem?
- unique member of the carbapenem group
- was and remains the least prescribed of the carbapenems
- pharmacologic properties and spectrum of activity are different from imipenem and meropenem
- belongs to its own separate class within the carbapenem group
Carbapenems
Describe the pharmacokinetics of ertapenem.
- safe and well tolerated
- intramuscular or intravenous administration
- high protein-binding percentage and long half-life
- once daily administration/low risk of seizure
- less susceptible to renal insufficiency
- IM administration is irritating → drug is formulated with 1% lidocaine
Carbapenems
Describe the efficacy of ertapenem.
- limited activity against gram-negative, non-fermenting bacteria such a P. aeruginosa, B. cepacia, and Acinetobacter spp
- clinically used to treat infections with ESBL-producing pathogens, but ertapenem activity is lower against these bacteria than other carbapenems
- use is limited to treating serious community-acquired infections
- should not be routinely used empirically to treat nosocomial infections
Carbapenems
What are the adverse effects of ertapenem?
- signs of an allergic reaction include: hives, difficulty breathing, swelling of face, tongue, or throat
- loss of balance or coordination, trouble walking
- tremors, twitching, or rigid (very stiff) muscles
- seizures (black-out or convulsions) or
- diarrhea that is watery or bloody
Carbapenems
How do carbapenems induce neurotoxicity (seizure)?
carbapenems bind to GABA receptors
- decreased valproic acid levels and absorption
- antibiotics inhibition of intestinal transporters
- decrease enterohepatic circulation of valproic acid
- decreased gut bacterial beta glucuronidase
- increased valproic acid in erythrocytes
Carbapenems
What are the contraindications to ertapenem?
- patients who have demonstrated anaphylactic reactions to beta-lactams
- probenecid increases the risk of ertapenem’s side effects
- effectiveness of divalproex sodium or valproic acid may be decreased by ertapenem
Carbapenems
What is the spectrum of activity of ertapenem?
- ertapenem has been designed to be effective against gram-negative and gram-positive bacteria – also effective against anaerobic bacteria
- not effective against MRSA, ampicillin-resistant enterococci, Pseudomonas aeruginosa, or Acinetobacter species
- does NOT cover Pseudomonas, but does still cover ESBL (main advantage is convenient once daily dosing – great outpatient IV drug)
Carbapenems
What is the mechanism of resistance for all 4 carbapenems?
- bacterial specific beta-lactamase
- mutation: loss of the outer membrane porin → transport of the drug into the cell is blocked
- cross-resistance may occur between the carbapenems
- efflux pump more active – not for imipenem, but for meropenem and doripenem
Monobactams
What is aztreonam?
- relatively resistant to beta-lactamases
- active against gram negative organisms
- inactive against gram positive organisms or anaerobic strains
- well tolerated, little or no allergic reactions in patients who are sensitive to penicillins or cephalosporins
- may be useful as a replacement for aminoglycoside antibiotic
Monobactams
Describe the spectrum.
narrow spectrum
- active only against aerobic gram-negative bacteria (Enterobacteriaceae, pseudomonas)
- no gram-positive or anaerobic activity
- aztreonam IV or IM (no oral admiration)
- therapeutic concentrations in CSF if meninges inflamed
Monobactams
What are the adverse effects?
- side effects include phlebitis, skin rash, inflammation abnormal liver function
- little cross reactivity with penicillin
Fosfomycin
What is fosfomycin?
- derivative of phosphonic acid
- isolated from a Streptomyces fradiae strain
- broad spectrum antibiotic – effective against both gram-positive and gram-negative bacteria, including ESBL-producer strains
- bactericidal
Fosfomycin
Describe the absorption.
- fosfomycin trometamol is more soluble and stable in the gastric acidic environment.
- oral administration – rapidly absorbed and converted to the free acid
- bioavailability (37-44%)
Fosfomycin
Describe the distribution.
- fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles
- fosfomycin is not protein bound
Fosfomycin
Describe the elimination.
- fosfomycin is excreted unchanged in urine via glomerular filtration (38%) and feces (18%)
- mean half-life elimination is 5.7 hours
- CrCl 7-54 mL/min is 50 hours
- urinary excretion decreases to 11% in patients with CrCl 7-54 mL/min
- urinary concentrations remain >100 mg/L for at least 30-40 h post-dose
Fosfomycin
Mechanism of Action
–
Fosfomycin
Describe resistance to fosfomycin.
mainly chromosomal:
- due to mutations that interfere with transport systems required for fosfomycin uptake resulting in reduced intracellular concentrations of the drug
- plasmid mediated resistance:
- however, these mutations are uncommon
Fosfomycin
What is fosfomycin effective against?
- all ESBL positive E. coli, P. mirabilis
- methicillin-resistant S. saprophyticus strains isolated from urine
- KPC-producing K. pneumoniae isolates (82%)
Fosfomycin
Describe fosfomycin and renal failure.
- half-life of fosfomycin is increased in patients with chronic severe renal failure, significantly (up to 50 h), with low recovery in urine
- in case of creatinine clearance is >10 mL/min: reduce the dose
Fosfomycin
What are the side effects of fosfomycin?
- well tolerated, very low incidence of side effects
- diarrhea and nausea are most common but mild
