Pharmacology of Renal Infections Flashcards
What are some characteristics associated with cases of complicated UTI?
Urinary obstruction
Urinary retention caused by neurologic disease
Immunosuppression
Renal failure
Renal transplant
Pregnancy
Foreign bodies (calculi, indwelling catheters)
—Indwelling catheters may be most common cause of complicated UTI
MCC of uncomplicated vs. complicated UTI
Uropathogenic E.coli causes majority of uncomplicated AND complicated UTI cases (but slightly less prevalent in complicated cases)
Other possibilities: K.pneumoniae S.saprophyticus Enterococcus spp. GBS P.mirabilis P.aeruginosa S.aureus Candida spp.
Components of biofilm formed by UPEC
Type 1 pili (essential!)
Antigen 43
Curli
What urea-producing organism forms crystalline biofilms associated with calcium and magnesium ammonium phosphate precipitates?
P.mirabilis
P.aeruginosa exhibits microcolony formation by changing hydrophobicity of its surface. What are the 2 main components of its biofilm?
Lectins
Rhamnolipids
What must be present for E.faecalis to cause catheter-associated UTI?
Fibrinogen — so UTI cannot be formed in vitro — need inflammatory response because fibrinogen acts as scaffold for bacteria to colonize
Tx for asymptomatic bacteriuria
Usually none is warrented
3 tx options for simple cystitis (first, second, and third line)
- Nitrofurantoin, TMP-SMX, fosfomycin
- Oral beta lactams (amoxicillin, cefpodoxime, cefdinir, cefadroxil)
- Fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin)
Nitrofurantoin is bactericidal for what bacterial species? What 2 are known to be resistant?
Nitrofurantoin is bactericidal for gram positive AND gram negative bacteria
P.aeruginosa and strains of Proteus are resistant
MOA of nitrofurantoin
Not fully understood
Conversion of nitrofurantoin into highly reactive intermediates by bacterial reductases — toxic intermediates react nonspecifically with many ribosomal proteins and disrupt synthesis of proteins, RNA, DNA, and metabolic processes
Nitrofurantoin is metabolized and excreted so quickly that no systemic antibacterial action is achieved, which is good because then it concentrates in the bladder. What are some AE’s, drug interactions, and contraindications associated with this drug?
AEs: anorexia, N/V
Interactions: antagonizes nalidixic acid (synthetic quinolone antibiotic)
Contraindicated in pts with G6PD deficiency (—> hemolysis)
What bacterial species is fosfomycin active against?
Gram positives AND gram negatives
MOA of fosfomycin
What causes resistance to this drug?
Cell wall synthesis inhibitor
Inhibits cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue fo the active site and blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine
Resistance is d/t inadequate transport of drug into cell
Fosfomycin is only available in oral form in the US. Its oral bioavailability is 40%, which is good because we don’t need systemic effects when treating cystitis. What are some adverse effects? Is it safe to use in pregnancy?
Limited AEs — HA and diarrhea
It is safe to use in pregnancy
T/F: nitrofurantoin and fosfomycin may be used in cases of suspicion for early pyelonephritis, as long as it is early case
False — if there is suspicion of early pyelonephritis must use something else because these drugs do not achieve adequate renal tissue levels
TMP-SMX is considered a first-line option for simple cystitis, however what is a situation in which you would avoid using it?
Avoid if prevalence if resistance is known to exceed 20%
Oral beta lactams are considered second line for simple cystitis. What drugs are used and what families do they fall into?
Amoxicillin — aminopenicillin
Cefpodoxime — 3rd gen cephalosporin
Cefdinir — 3rd gen cephalosporin
Cefadroxil — 1st gen cephalosporin
Oral beta lactams are ____ effective than fluoroquinolones and TMP-SMX
Less
[they are used before fluoroquinolones anyway because of the AEs associated with fluoroquinolones]
Fluoroquinolones utilized for cystitis include ciprofloxacin, levofloxacin, and ofloxacin. Which fluoroquinolone is NOT recommended, and why?
Moxifloxacin — attains lower urinary levels than the other fluoroquinolones
The FDA states that disabling and potentially irreversible AEs of systemic fluoroquinolones outweigh their benefits in treating uncomplicated cystitis. What are these AEs?
Tendonitis and tendon rupture
Peripheral neuropathy
CNS effects
Which drugs should NOT be used to empirically treat uncomplicated cystitis d/t possibility of drug resistance?
Ampicillin
Amoxicillin
If drug resistance is identified while treating uncomplicated cystitis, what drug is used, and what organisms is it effective/not effective against?
Ertapenem (a carbapenem)
As a class, the carbapenems have wide spectrum with good activity against gram negatives, gram positives, and anaerobes
However, ERTAPENEM specifically is NOT effective against P.aeruginosa
First and second line tx for pyelonephritis
- Fluoroquinolones (ciprofloxacin, levofloxacin)
2. TMP-SMX, oral beta lactam, aztreonam
First line defense for pyelonephritis is fluoroquinolones. If the case of pyelonephritis is severe, or if there are risk factors for drug resistance, they are administered with parenteral broad spectrum antibiotics like _____ or an aminoglycoside until susceptibility data is available
What 2 aminoglycosides are typically used?
Ceftriaxone
Aminoglycosides used are gentamycin and tobramycin
What bacteria are the aminoglycosides: gentamycin and tobramycin active against?
Aerobic gram-negatives (depend on O2 to get into cell)
P.aeruginosa
MOA of gentamycin and tobramycin
Irreversible protein synthesis inhibitor, binds to 30S ribosomal subunit
Interference with the initiation complex of peptide formation
Misreading of mRNA leads to production of non-functional proteins
Gentamycin and tobramycin are cleared by the kidneys — good because we are treating the kidneys! What are some AEs?
CN VIII toxicity — vertigo, hearing loss
Renal toxicity
Neuromuscular blockade
When is aztreonam chosen for treating pyelonephritis?
Used in cases of fluoroquinolone hypersensitivity, or bacterial resistance; as well as inability to tolerate other second-line agents like TMP-SMX or oral beta-lactams (amoxicillin, cefpodoxime, cefdinir, cefadroxil)
It can also be used in penicillin hypersensitive pts because there is little cross-reactivity with bicyclic beta-lactams
What bacteria is aztreonam active against?
Aerobic gram-negatives (p.aeruginosa)
[NO activity against gram positives or anaerobes]
MOA of aztreonam
Cell wall synthesis inhibitor, transpeptidase inhibitor
Aztreonam is available in IV formulation with 1-2 hr half-life (prolonged in renal failure); what are some AEs associated?
Limited; neutropenia (children 3-11%), pain at injection (children 12%)
Organisms causing complicated UTIs are more likely to be resistant to commonly used oral agents recommended for empiric treatment of uncomplicated cystitis.
What are the agents of choice for complicated cystitis?
Ciprofloxacin
Levofloxacin
Organisms causing complicated UTIs are more likely to be resistant to commonly used oral agents recommended for empiric treatment of uncomplicated cystitis.
What are the agents of choice for mild, complicated pyelonephritis?
Ceftriaxone
Ciprofloxacin
Levofloxacin
Aztreonam
Organisms causing complicated UTIs are more likely to be resistant to commonly used oral agents recommended for empiric treatment of uncomplicated cystitis.
What are the agents of choice for severe, complicated pyelonephritis?
Cefepime
Piperacillin + tazobactam (use higher dose if P.aeruginosa expected)
Ceftolozane + tazobactam
Ceftazidime + avibactam
Meropenem (use higher dose if P.aeruginosa suspected)
Imipenem
Doripenem
What drugs are used to tx complicated cystitis with presence of gram-positive cocci on gram stain?
This is suggestive of enterococcal UTI (E.faecalis or E.faecium)
Use ampicillin or amoxicillin
What are poor empiric choices to tx complicated cystitis d/t high prevalence of resistance?
Nitrofurantoin
TMP-SMX
Fosfomycin
Oral beta-lactams
USE OF THESE DRUGS IS ONLY ACCEPTABLE IF THE UROPATHOGEN IS KNOWN TO BE SUSCEPTIBLE
Urinary analgesic with unknown mechanism, known to cause significant nausea and orange/red colored urine
Phenazopyridine
What drug offers an alternative tx to mild, complicated pyelonephritis in the setting of beta lactam allergy and is active against gram negative aerobics?
Aztreonam
MOA of beta-lactamase inhibitors
Resemble beta-lactam molecules, very weak antibacterial action
Protect hydrolysable beta-lactams from inactivation by these enzymes
Good inhibitors of Ambler class A beta-lactamases (produced by E.coli, K.pneumoniae, etc.)
POOR inhibitors of class C beta-lactamases (produced by Enterobacter spp., P.aeruginosa, etc.)
Adverse effects of beta lactamase inhibitors
Limited (<10%) — diarrhea, constipation, vomiting, skin rash
Resistant cystitis may be tx by carbapenems like imipenem, doripenem, meropenem, and ertapenem. These have wide spectrum and good activity against what types of bacteria?
Gram negatives (including P.aeruginosa —except ertapenem), gram-positives, and anaerobes
Note that doripenem and meropenem have slightly greater activity against gram-negatives and slightly less activity against gram positives
MOA of carbapenems
Inhibit transpeptidase, similar to penicillins and cephalosporins
[resistant to beta-lactamases]
In terms of pharmacokinetics of the carbapenems:
______ is metabolized by dihydropeptidase in the kidney, while doripenem, meropenem, and ertapenem are not
______ has the longest half life (4 hrs), administered with lidocaine to reduce irritation after IM injection
Imipenem
Ertapenem
Which of the carbapenems is most likely to exhibit AEs? What are they?
Imipenem most commonly exhibits N/V, diarrhea, skin rashes, infusion site reaction, seizures
Doripenem, meropenem, and ertapenem are LESS likely to cause seizures
Name and family of beta-lactams used as first-line defenses for severe complicated pyelonephritis
Piperacillin — anti-pseudomonal penicillin
Ceftazidime — 3rd gen cephalosporin
Cefepime — 4th gen cephalosporin
Ceftolazone — 5th gen cephalosporin
MOA and AEs associated with beta-lactams used to tx severe complicated pyelonephritis
Cell wall synthesis inhibitors, bind and inhibit transpeptidase
AEs: beta-lactam hypersensitivity
Most likely pathogens associated with prostatitis
E.coli (58-88%)
Proteus spp (3-6%)
P.aeruginosa (3-7%)
Enterobacteriaceae including Klebsiella, Enterobacter, and Serratia spp. (3-11%)
Symptoms and clinical presentation of prostatitis
Symptoms: fever, chills, malaise, myalgia, dysuria, LUTS, pelvic or perianal pain, cloudy urine
Clinical presentation: pt is acutely ill with spiking fever, possible complaint of pain; DRE reveals warm, firm, edematous, and tender prostate
Tx for prostatitis
TMP-SMX
Ciprofloxacin
Levofloxacin
Etiology and clinical presentation of post-streptococcal glomerulonephritis (PSGN)
Etiology: prior infection with group A beta-hemolytic streptococcus (gram-positive)
Usually presents in children as asymptomatic microscopic hematuria OR acute nephritic syndrome (red/brown urine, proteinuria, edema, HTN, elevated SCr)
Tx of PSGN
Management: loop diuretics, anti-hypertensive agents, dialysis
Recurrent group A beta-hemolytic strep infection — repeat tx should be with an agent with greater beta-lactamase stability:
Penicillin G
Cephalexin or cefadroxil (1st gen)
Cefpodoxime or cefdinir (3rd gen)
Amoxicillin (aminopenicillin) or clindamycin
What organisms is clindamycin effective against? What organisms are resistant?
VERY effective against anaerobes; Streptococci, staphylococci, and pneumococci
Resistant organisms: enterococci and gram negative aerobes
MOA and pharmacokinetics of clindamycin
MOA: protein synthesis inhibitor, binds to 50S ribosomal subunit
Pharmacokinetics: penetrates most tissues (not brain and CSF); metabolized in liver and excreted in urine
Adverse effects with clindamycin
Diarrhea, nausea, skin rash
Risk factor for C.diff induced diarrhea and colitis
A 22 y/o female presents to the ED with 3 days of increased urinary frequency and suprapubic pain after urinating. She has no fevers, chills, flank pain, nausea, vomiting, or urethral discharge. There have been no similar complaints in the past. She has recently become sexually active and uses barrier mode of contraception. She has no hx of STDs. No allergies to meds or food. PE is unremarkable. Spot urine pregnancy test is negative. Urinalysis reveals gram positive cocci.
Which of the following is most likely?
A. Cystis B. Pyelonephritis C. Complicated cystitis D. Complicated pyelonephritis E. Cystitis and pyelonephritis
A. Cystitis
A 22 y/o female presents to the ED with 3 days of increased urinary frequency and suprapubic pain after urinating. She has no fevers, chills, flank pain, nausea, vomiting, or urethral discharge. There have been no similar complaints in the past. She has recently become sexually active and uses barrier mode of contraception. She has no hx of STDs. No allergies to meds or food. PE is unremarkable. Spot urine pregnancy test is negative. Urinalysis reveals gram positive cocci.
What is the likely pathogen?
A. Uropathogenic E.coli (UPEC) B. Enterococcus spp. C. K.pneumoniae D. P.mirabilis E. P.aeruginosa
B. Enterococcus spp.
[only gram positive organism listed!]
A 22 y/o female presents to the ED with 3 days of increased urinary frequency and suprapubic pain after urinating. She has no fevers, chills, flank pain, nausea, vomiting, or urethral discharge. There have been no similar complaints in the past. She has recently become sexually active and uses barrier mode of contraception. She has no hx of STDs. No allergies to meds or food. PE is unremarkable. Spot urine pregnancy test is negative. Urinalysis reveals gram positive cocci.
Patient is prescribed moxifloxacin, what is the likely result?
A. Anaphylaxis B. Eight CN toxicity C. Seizure D. C.diff induced diarrhea E. Infection persists
E. Infection persists
A 55 y/o female presents with suprapubic pain, dysuria, and CVA tenderness. Hx reveals sensitivity to penicillin. She has no hx of STDs. Spot urinary pregnancy test is negative.
What is the diagnosis?
A. Cystitis B. Pyelonephritis C. Complicated cystitis D. Complicated pyelonephritis E. Cystitis and pyelonephritis
E. Cystitis and pyelonephritis
A 55 y/o female presents with suprapubic pain, dysuria, and CVA tenderness. Hx reveals sensitivity to penicillin. She has no hx of STDs. Spot urinary pregnancy test is negative.
Which antibiotic would be contraindicated for this patient?
A. Ciprofloxacin B. Cefpodoxime C. Aztreonam D. Gentamicin E. TMP-SMX
B. Cefpodoxime
A 55 y/o female presents with suprapubic pain, dysuria, and CVA tenderness. Hx reveals sensitivity to penicillin. She has no hx of STDs. Spot urinary pregnancy test is negative.
The antibiotic of choice for this pt works by inhibiting which of the following bacterial proteins?
A. Dihydrofolate reductase
B. Dihydropteroate synthase
C. DNA gyrase
C. DNA gyrase
A 53 y/o woman suffering from uncomplicated cystitis started tx with TMP-SMX. 1 week later, burning upon urination was still pronounced, and the physician suspected that resistance to sulfamethoxazole had occurred.
The resistance was most likely d/t which of the following mechanisms?
A. Increased permeability of bacterial cell membrane
B. Decreased sulfonamide binding to bacterial ribosomes
C. Increased production of para-aminobenzoic acid (PABA)
D. Decreased sulfonamides binding dihydrofolate reductase
E. Decreased activity of the multidrug efflux pump
C. Increased production of para-aminobenzoic acid (PABA)
A 53 y/o woman suffering from uncomplicated cystitis started tx with TMP-SMX. 1 week later, burning upon urination was still pronounced, and the physician suspected that resistance to sulfamethoxazole had occurred.
Which of the following follow-up treatments would be best to empirically tx this pts cystitis?
A. Phenazopytidine B. Ampicillin C. Amoxicillin D. Nitrofurantoin E. Moxifloxacin
D. Nitrofurantoin
