Antimicrobials Flashcards
Define beta-lactams
Antibiotics that contain a beta-lactam ring in their molecular structure
Name the 4 types of penicillins
Natural
Anti-staphylococcal
Aminopenicillins
Antipseudomonal
Name 2 natural penicillins
Penicillin G
Penicillin V
Name 3 anti-staphylococcal penicillins
Oxacillin
Nafcillin
Dicloxacillin
Name 2 aminopenicillins
Amoxicillin
Ampicillin
Name 2 antipseudomonal penicillins
Piperacillin
Ticarcillin
Name the 4 carbapenems
Imipenem
Meropenem
Ertapenem
Doripenem
Name a monobactam
Aztreonam
Give examples of 1st generation cephalosporins
Cefadroxil
Cefalexin
Cefazolin
Cefazedone
Give examples of 2nd generation cephalosporins
2nd graders wear fake fox fur to tea parties
Cefaclor
Cefoxitin
Cefuroxime
Cefotetan
Give examples of 3rd generation cephalosporins
Cefixime
Ceftriaxone
Cefdinir
Cefodizine
Cefotaxime
Ceftazadime
Give examples of 4th generation cephalosporins
Cefepime
Cefquinome
Give examples of 5th generation cephalosporins
Ceftaroline
Ceftobiprole
Ceftolozane
Are beta-lactams bactericidal/bacteriostatic?
Bactericidal
Discuss the mechanism of action of beta-lactams
- Inhibit cell wall synthesis
- mimics D-ala-D-ala structure of bacterial peptidoglycan residue
- irreversibly binds to PBPs which act as transpeptidases -> stalled peptidoglycan cross linking -> inability to synthesize new cell wall -> bacterial death - Activate autolytic enzymes
Which beta lactams have good CNS penetration?
Ceftriaxone
Aztreonam
When could beta-lactams other than ceftriaxone and aztreonam have CNS penetration?
Inflammation of the meninges -> disruption of the blood-brain-barrier
How are beta-lactams excreted?
Name exceptions.
Primarily renal
Exceptions
- nafcillin (biliary)
- anti-staphylococcal penicillins (renal and biliary)
- ceftriaxone (renal and biliary)
Name potential adverse effects of beta-lactams
Hypersensitivity reactions
Jarisch-Herxheimer reaction (syphilis)
Which organisms usually produce beta-lactamases?
Gram negative
Anaerobic
Give examples of beta lactamase inhibitors
Clavulanate
Avibactam
Sulbactam
Tazobactam
What is the other name for penicillin G?
Benzylpenicillin
What are the forms of penicillin G?
IV - crystalline penicillin
IM - procaine penicillin, benzathine penicillin
What is the other name for penicillin V?
Phenoxymethylpenicillin
What is the spectrum of cover of natural penicillins?
Gram +ve aerobes
Gram -ve cocci
Spirochetes
Branching gram +ve anaerobes
Name adverse effects of natural penicillins
Hypersensitivity reactions
Hemolytic anemia
Drug-induced interstitial nephritis
Seizures
How can natural penicillins
Penicillins bind to the bacterial breakdown products that form haptens -> formation of antibodies (anti-IgG) that trigger hemolysis with a positive direct Coombs test
Name the mechanisms of penicillin resistance
Penicillinases
PBP mutations
Name penicillinase-resistant penicillins
Nafcillin
Dicloxacillin
Oxacillin
Floxacillin
Methicillin
Why is methicillin no longer adminstered?
High rate of side effects
What characteristics of penicillinase-resistant penicillins allow them to be intrinsically beta-lactamase resistant?
Addition of bulky side chains e.g. isoxazolyl which prevent the beta-lactam ring from being hydrolysed
The penicillinase-resistant penicillins are broad/narrow spectrum?
Narrow spectrum
Name the mechanisms of resistance to penicillinase-resistant penicillins
Alteration of PBP binding site
Which aminopenicillin has a greater oral bioavailability?
Amoxicillin > ampicillin
What is the spectrum of cover of aminopenicillins?
“Extended-spectrum penicillin”
Gram +ve aerobes
Gram -ve bacilli
Which gram -ve bacilli are aminopenicillins not effective against?
Enterobacter spp.
Name adverse effects of aminopenicillins
Diarrhea
Pseudomembranous colitis
Drug-induced rash (incorrectly diagnosed infectious mononucleosis)
Hypersensitivity reactions
Acute interstitial nephritis (rare)
What is the mechanism of resistance to aminopenicillins?
Penicillinases
What kind of antipseudomonal penicillin is piperacillin?
Ureidopenicillin (IV)
What kind of antipseudomonal penicillin is mezlocillin?
Ureidopenicillin (IV)
What is the spectrum of cover of antipseudomonal penicillins?
Gram -ve rods
Anaerobes
Gram +ve aerobes
Which gram +ve aerobe are antipseudomonal penicillins not effective against?
S. viridans
Which drug is usually added with imipenem and why?
Cilastatin
Inhibits dehydropeptidase, a renal tubular enzyme that metabolizes imipenem
What is the spectrum of cover of carbapenems
Gram +ve cocci
Gram -ve bacilli
Anaerobes
Which carbapenem has limited activity against pseudomonas?
Ertapenem
Which gram +ve cocci are intrinsically resistant to carbapenems?
MRSA
Enterococcus faecalis
Enterococcus faecium
Name adverse effects of carbapanems
Secondary fungal infections
CNS toxicity
GI upset
Rash
Thrombophlebitis
Which carbapenems carry the highest and lowest risk of CNS toxicity?
Highest risk - imipenem
Lowest risk - meropenem
Name bacteria that commonly produce carbapenemases
Keep Every Antibiotic, Protect Every Carbapenem!
Klepn
Ecoli
Aciba
Pseae
Enterobacter
Citfr
What are the special characteristics of aztreonam?
Bind to PBP3
Less susceptible to beta-lactamases
What is the spectrum of cover of monobactams?
Gram -ve bacteria
Can add vanco/clinda to create broad-spectrum coverage
Which beta-lactams are an alternative for penicillin allergic patients?
Monobactams (no cross sensitivity)
Name adverse effects of monobactams
GI upset
Injection reactions
Rash
Which generation of cephalosporins has the least activity against gram +ve bacteria?
3rd generation
Which gram -ve bacteria are covered by 1st generation cephalosporins?
Proteus mirabilis
E.coli
Klepn
1 PEcK
Which gram -ve bacteria are covered by 2nd generation cephalosporins?
Haem influenza
Enterobacter aerogenes
Neisseria
Serratia
Proteus mirabilis
E.coli
Klebs pneumo
2 HENS PEcK
Which generation of cephalosporins is active against MRSA?
5th generation
Which generation of cephalosporins is active against listeria?
5th generation
Which generation of cephalosporins is active against enterococcus?
5th generation
Which generation of cephalosporins is active against pseudomonas?
3rd and 4th generation
Name adverse effects of cephalosporins
- Penicillin allergy cross reactivity
- Autoimmune hemolytic anemia
- Vitamin K deficiency
- Disulfiram-like reaction
- Increases aminoglycoside nephrotoxic effect
- Neurotoxicity
- Hyperbilirubinemia (neonates)
What is the mechanism of hypoprothrombinemia secondary to cephalosporin use?
Not fully understood
Theories:
- inhibit growth of vitamin K producing intestinal bacteria
- inhibit enzymes of vitamin K metabolism
Explain drug-induced autoimmune hemolytic anemia
Drugs bind to RBC membrane proteins -> preformed anti-drug antibodies bind to drug-coated RBCs -> hemolysis in the spleen
What are the mechanisms of resistance to cephalosporins?
Cephalosporinase
PBP changes
Why are cephalosporins (1st-4th generation) LAME?
Ineffective against:
Listeria
Atypicals
MRSA
Enterococci
Are glycopeptides bactericidal/bacteriostatic?
Bactericidal
Which organism are glycopeptides bacteriostatic against?
C. diff
Give examples of glycopeptides
Vancomycin
Bacitracin
Teicoplanin
Telavancin
Dalbavancin
Oritavancin
What is the route of elimination of glycopeptides?
Renal via glomerular filtration
What is the spectrum of cover of glycopeptides?
Gram +ve bacteria
MRSA
S. epidermidis
Enterococci
C. diff
Name adverse effects of glycopeptides
Nephrotoxicity
Ototoxicity
Thrombophlebitis
Vancomycin flushing reaction
DRESS syndrome
Neutropenia
Dysgeusia
GIT upset
What is vancomycin flushing reaction?
Anaphylactoid reaction caused by rapid infusion of vancomycin -> nonspecific mast cell degranulation -> rapid histamine release
Which kind of vancomycin therapy is associated with neutropenia?
Prolonged (>7 days)
What does DRESS syndrome stand for?
Drug reaction with eosinophilia and systemic symptoms
Name contraindications for glycopeptides
Pregnancy
Name mechanisms of resistance to glycopeptides
Modification of D-ala-D-ala to D-ala-D-lac (mainly enterococcus)
What is the mechanism of action of epoxides?
Inhibits enolpyruvate transferase (MurA) -> no formation of N-acetylmuramic acid -> inhibition of cell wall synthesis
Epoxides are bactericidal/bacteriostatic?
Bactericidal
Name an epoxide
Fosfomycin
What is the route of elimination of fosfomycin?
Renal
Name adverse effects of fosfomycin
Mild electrolyte imbalances (hypernatremia, hyopkalemia)
Diarrhea
What is the mechanism of resistance to fosfomycin?
MurA mutations
Give an example of a lipopeptide
Daptomycin
What is the mechanism of action of daptomycin?
Incorporates K+ channels into the cell membrane of gram +ve bacteria -> rapid membrane depolarization -> loss of membrane potential -> inhibition of DNA, RNA and protein synthesis
Daptomycin is bactericidal/bacteriostatic?
Bactericidal
What is the route of elimination of daptomycin?
Renal
What is the spectrum of cover of daptomycin?
Gram +ve bacteria
MRSA
VRE
What are the main sites in the body that daptomycin is effective?
Skin
Blood
Heart
Why can daptomycin not be used for pneumonias?
It is bound and inactivated by surfactant
Name adverse effects of daptomycin
Reversible myopathy
Rhabdomyolysis
Allergic pneumonitis
What is the mechanism of resistance to daptomycin?
Repulsion of daptomycin molecules due to change in bacterial surface charge
Give examples of polymyxins
Polymyxin E = colistin
Polymyxin B
What kind of molecule are polymyxins?
A cationic detergent (polypeptide) molecule
What is the mechanism of action of colistin?
Binds to phospholipids (LPS endotoxin) of the cytoplasmic membrane of gram -ve bacteria -> increase membrane permeability -> leakage of cell contents
What is the route of elimination of colistin?
Renal
How can polymyxin B be used for superficial skin infections?
Triple antibiotic ointment
- bacitracin
- neomycin
- polymyxin B
How can polymyxin B be used to prevent ICU infections?
May be used to disinfect the bowel
Name adverse effects of colistin
Nephrotoxicity
Neurotoxicity
Anaphylactoid reactions
Respiratory failure
Give examples of aminoglycosides
Gentamycin
Amikacin
Tobramycin
Streptomycin
Neomycin
Capreomycin
Kanamycin
What is the mechanism of action of aminoglycosides?
Bind to 30S subunit of bacterial ribosome -> irreversible inhibition of initiation complex -> inhibition of bacterial protein synthesis
With which drug class are aminoglycosides synergistic?
Beta-lactams inhibit cell wall synthesis to facilitate entry of aminoglycoside drugs into the cytoplasm
What is the route of elimination of aminoglycosides?
Renal via glomerular filtration
What is the spectrum of cover of aminoglycosides?
Gram -ve bacilli
Why are aminoglycosides not effective against anaerobes?
Require oxygen to be absorbed by cells
Name adverse effects of aminoglycosides
Nephrotoxicity
Ototoxicity
Vestibulotoxicity
Neuromuscular blockade
Teratogenecity
Concurrent use with which drugs increase the risk of ototoxicity secondary to aminoglycoside use?
Loop diuretics
Name contraindications for aminoglycosides
Myasthenia gravis
Botulism
Pregnancy
What are the mechanisms of resistance to aminoglycosides?
Bacterial transferase enzyme inactivation via
- acetylation
- phosphorylation
- adenylation
Give examples of tetracyclines
Minocycline
Tetracycline
Doxycycline
Demeclocyline
What is the mechanism of action of tetracyclines?
Bind 30s subunit -> aminoacyl-tRNA is blocked from binding to ribosome acceptor site -> inhibition of bacterial protein synthesis
Are tetracyclines bactericidal/bacteriostatic?
Bacteriostatic
What is the route of elimination of tetracyclines?
Renal
Which tetracycline is not contraindicated in patients with renal failure and why?
Doxycycline - only gastrointestinal elimination
What is the spectrum of cover of tetracyclines?
Atypical bacteria
Community-acquired MRSA
Which substances should oral tetracyclines not be taken with and why?
Any substance containing large amounts of divalent cations which inhibit intestinal absorption of tetracyclines
Name adverse effects of tetracyclines
Hepatotoxicity
Teeth and bone changes
Mucous membrane damage (esophagitis)
Photosensitivity
Fanconi syndrome
Pseudotumor cerebri
Why do tetracyclines cause photosensitivity?
Tetracyclines absorb UV radiation -> photochemical reaction -> free radical formation -> damage to cellular components -> inflammation
Give contraindications to tetracyclines
Children <8yo
Pregnant/breastfeeding women
Renal failure
Hepatic dysfunction
What is the mechanism of resistance to tetracyclines?
Plasmid-encoded efflux pumps
Give an example of a glycylcycline
Tigecycline
What is the mechanism of action of tigecycline?
Binds to 30S subunit -> blockage of entry of amino-acyl tRNA into ribosomal A site -> inhibition of protein synthesis
What is the route of elimination of tigecycline?
Mostly biliary
What is the spectrum of cover of tigecycline?
Gram positive aerobes
Gram negative aerobes
MRSA
VRE
Anaerobes
Non-gram staining bacteria
Which gram positive aerobes is tigecycline not effective against?
S. viridans
Enterococci
MSSA
Which gram negative aerobes is tigecycline not effective against?
Proteus
Name adverse effects of tigecycline
GI upset
Hepatotoxicity
Teeth and bone deposition
Photosensitivity
What are the contraindications to tigecycline?
Children <8yo
Pregnant/breastfeeding women
Hepatic dysfunction
Give examples of macrolides
Erythromycin
Azithromycin
Clarithromycin
Roxithromycin
What is the mechanism of action of macrolides?
Bind to 23S ribosomal RNA molecule of 50S subunit -> blockage of translocation -> inhibition of bacterial protein synthesis
What is the route of elimination of macrolides?
Biliary
What is the spectrum of cover of macrolides?
Atypical pneumonias
Bordetella
Chlamydia
Gram +ve cocci
Neisseria
Mycobacterium avium (azithro)
H. pylori
Ureaplasma urealyticum
Babesia spp. (azithro + atovaquone)
Name adverse effects of macrolides
Increased intestinal motility
QT prolongation
Arrythmias
Acute cholestatic hepatitis
Eosinophilia
Rash
HPS risk in infant <6w
Which drugs does erythromycin interact with?
All affected by CYP450
Which macrolide does not have a short half life?
Azithromycin
What can erythromycin be used off label for?
Gastroparesis (increases intestinal motility)
Which macrolides are contraindicated in pregnant women?
Erythromycin estolate
Clarithromycin
What is erythromycin estolate use in pregnant women during the 1st trimester associated with?
Hepatic failure
Can erythromycin forms other than erythromycin estolate be used in pregnant women?
Yes (ethyl succinate, stearate)
Which macrolide must be used cautiously in patients with renal failure?
Clarithromycin
What is the mechanism of resistance to macrolides?
Methylation of the binding site of 23S rRNA -> macrolide cannot bind to rRNA
What bacterial class is clindamycin?
Lincosamides
What is the mechanism of action of clindamycin?
Binds to 50s subunit to block peptide translocation -> inhibition of peptide chain elongation -> inhibition of bacterial protein synthesis
What the route of elimination of clindamycin?
Renal and biliary
What is the spectrum of cover of clindamycin?
Anaerobes
Gram +ve aerobes
Babesia (with quinine)
What does clindamycin share cross resistance with?
Macrolides
Name adverse effects of clindamycin
GI upset
Pseudomembranous colitis
Fever
Teratogenicity
Give examples of streptogramins
Dalfopristin
Quinupristin
What is the mechanism of action of dalfopristin?
Binds to 23S portion of 50S subunit -> change conformation -> enhanced binding of quinupristin and inhibits peptidyl transferase
What is the mechanism of action of quinupristin?
Binds to 50S subunit -> prevents elongation of polypeptide -> incomplete chains released
What is the route of elimination of streptogramins?
Biliary and renal
What is the spectrum of cover of streptogramins?
Skin infections
- staph
- strep
- VRE
Which enterococcus are streptogramins NOT effective against?
Enterococcus faecalis
Which cytochrome is inhibited by streptogramins?
CYP3A4
Name adverse effects of streptogramins
GI upset
Headache
Arthralgia
Myalgia
Thrombophlebitis
Pseudomembranous colitis
Pruritis (rare)
Has safety been establish for streptogramins in pregnant/breastfeeding women or children <16yo?
No
Name mechanisms of resistance to streptogramins
Modification of ribosome binding site
Enzyme-mediated methylation
Efflux pumps
Which drug class does linezolid belong to?
Oxazolidinones
What is the mechanism of action of linezolid?
Binds to 23S RNA of 50S subunit -> inhibition of initiation complex formation -> inhibition of bacterial protein synthesis
Non-selective MAOI
Against which bacteria is linezolid bactericidal?
Streptococci
What is the CNS penetration of linezolid?
Good
What is the route of elimination of linezolid?
Hepatic metabolism
Biliary and renal elimination
Name adverse effects of linezolid
GI upset
Pancytopenia
Peripheral neuropathy
Serotonin syndrome
Give contraindications for linezolid
SSRIs
Selective MAOIs
Name mechanism of resistance to linezolid
Point mutation of 23S rRNA
What is the mechanism of action of chloramphenicol?
Binds to 50S subunit -> blockage of peptidyltransferase -> inhibition of bacterial protein synthesis
What is the CNS penetration of chloramphenicol?
Good
What is the route of elimination of chloramphenicol?
Hepatic metabolism
Renal elimination
What is the spectrum of cover of chloramphenicol?
Meningitis
Rickettsia
Which cytochromes does chloramphenicol inhibit?
CYP2C19
CYP3A4
Name adverse effects of chloramphenicol
Dose dependent BM suppression
Gray baby syndrome
What is the mechanism of resistance in chloramphenicol?
Drug inactivation via plasmid-encoded acetyltransferase
Give examples of 1st generation fluoroquinolones
Nalidixic acid
Give examples of 2nd generation fluoroquinolones
Ciprofloxacin
Norfloxacin
Ofloxacin
Enoxacin
Give examples of 3rd generation fluoroquinolones
Levofloxacin
Give examples of 4th generation fluoroquinolones
Moxifloxacin
Gemifloxacin
Gatifloxacin
Which is the only fluoroquinolone also available in IV form?
Levofloxacin
Enoxacin
What is the mechanism of action of fluoroquinolones?
Inhibition of prokaryotic topoisomerase II and IV -> DNA supercoiling -> formation of double-stranded breaks -> inhibition of DNA replication and transcription
What is the CNS penetration of fluoroquinolones?
Good
What is the route of elimination of fluoroquinolones?
Renal via glomerular filtration and tubular secretion
Which fluoroquinolone undergoes biliary excretion?
Moxifloxacin
Which substances reduce fluoroquinolone absorption?
Polyvalent cations
Name the “respiratory” fluoroquinolones
Levofloxacin
Moxifloxacin
Gemifloxacin
What is the spectrum of cover of the non-respiratory fluoroquinolones?
Gram -ve rods (urinary, GI)
Genitourinary infections (gonorrhoeae, chlamydia, ureaplasma)
Which flouroquinolone is effective against pseudomonas?
Ciprofloxacin
What is the spectrum of cover of the respiratory fluoroquinolones?
Atypical bacteria
Anaerobes
Which fluoroquinolone is highly potent against penicillin-resistant pneumococci?
Gemifloxacin
Name adverse effects of fluoroquinolones
GI upset
Neurological
Hypo/hyperglycemia
QT prolongation
Photosensitivity
Superinfection
Tendon rupture
Life threatening exacerbation of myasthenia gravis
What neurological adverse effects can be caused by fluoroquinolones?
Headache
Dizziness
Mood changes
Peripheral neuropathy
Lower seizure threshold
Which factors increase risk for lower seizure threshold with fluoroquinolones?
NSAID use
Prev epilepsy hx
Which cytochrome do fluoroquinolones inhibit?
CYP450
Name mechanisms of resistance to fluoroquinolones
Chromosome encoded mutations in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Give examples of nitroimidazoles
Metronidazole
Tinidazole
What is the mechanism of action of metronidazole?
Creates free radicals within bacterial cell -> DNA strand breakage -> cell death
What is the CNS penetration of metronidazole?
Good
What is the route of elimination of metronidazole?
Renal
What is the spectrum of cover of metronidazole?
Some protozoa (giardia, tricho, entamoeba)
Anaerobes
Facultative anaerobes
Name adverse effects of metronidazole
Headache
Metallic taste
Peripheral neuropathy
Vestibular dysfunction
Can nitroimidazoles cause disulfiram-like reactions?
Disproved despite case reports
Metronidazole does not inhibit acetaldehyde dehydrogenase
Possible explanations - change in gut flora, histamine reactions
Give examples of diaminopyrimidine derivatives
Trimethoprim
Pyrimethamine
Give examples of antibiotic sulfonamides
Sulfamethoxazole
Sulfadiazine
Sulfisoxazole
Give examples of non-antibiotic sulfonamides
Diuretics (thiazides, furosemide, acetazolamide)
Anti-inflammatory drugs (celecoxib)
Sulfonylureas
Probenecid
What is the mechanism of action of trimethoprim versus sulfamethoxazole?
Both inhibit bacterial folic acid synthesis
Trimethoprim - inhibits dihydrofolate reductase (DHFR)
Sulfamethoxazole - inhibits dihydropteroate synthase
What is the CNS penetration of TMP-SMX?
Good
What is the route of elimination of TMP-SMX?
Primarily renal via tubular secretion
What is the spectrum of cover of TMP-SMX?
Shigella
Salmonella
Empiric UTI treatment
Prophylaxis (P. jirovecii, toxoplasmosis)
What is the spectrum of cover of sulfisoxazole?
Broad spectrum gram +ve and -ve
N. meningitidis
Chlamydia trachomatis
Nocardia asteroides
Toxoplasma gondii
Plasmodia
Name adverse effects of sulfonamides
CYP450 drug interactions
Kernicterus (infants)
Nephrotoxicity
GI upset
Hyperkalemia
Agranulocytosis
Pancytopenia
Hemolytic anemia
Steven Johnson’s
Photosensitivity
Fever
What is the most common form of nephrotoxicity secondary to sulfonamide use?
Acute tubulointerstitial nephritis
In which patients can sulfonamides trigger hemolytic anemia?
G6PD-deficiency
Name adverse effects of trimethoprim
Megaloblastic anemia
Leukopenia
Granulocytopenia
Hyperkalemia
Increased creatinine
How does trimethoprim cause hyperkalemia?
Competitive inhibition of ENaC channels in the distal convoluted tubule -> decreased NA reabsorption -> decreased K secretion
What are the mechanisms of resistance to sulfonamides?
Mutation in bacterial dihydropteroate synthase
Increased PABA synthesis
Decreased sulfonamide uptake
Which drug class does nitrofurantoin belong to?
Nitrofurans
What is the mechanism of action of nitrofurantoin?
Reduced by bacterial nitroreductases to reactive metabolites -> bind to ribosome -> impaired metabolism + synthesis of protein, DNA, RNA -> cell death
What is the route of elimination of nitrofurantoin?
Primarily renal
Minimal in the feces
What is the spectrum of cover of nitrofurantoin?
UTI pathogens (gram +ve and -ve)
Which UTI pathogens is nitrofurantoin NOT effective against?
Pseudomonas
Proteus
Can nitrofurantoin be used in pyelonephritis?
No! It does not achieve adequate concentrations in renal tissue.
Name adverse effects of nitrofurantoin
Nitrofurantoin-induced lung disease (NILD)
Pulmonary fibrosis
Hemolytic anemia in G6PD deficiency
GI upset
Reversible peripheral neuropathy
Distinguish between acute vs chronic NILD
Acute = hypersensitivity reaction usually 9 days after exposure
Chronic = cell-mediated or toxic reaction usually 6 months after exposure
Name contraindications for nitrofurantoin
Children <1mo
Breastfeeding women
Women GA 38-42w
Hepatic dysfunction
eGFR <60