Editing Infections: Antibiotics


===Antibiotics===
*Factors to consider when selecting
**Empirical therapy include whether the infection is complicated or uncomplicated, spectrum of activity of the drug against the probable pathogen, history of hypersensitivity, potential side effects, and cost
**Duration of therapy include the extent and duration of tissue invasion, bacterial concentration in urine, achievable urine concentration of the antimicrobial agent, and risk factors that impair the host and natural defense mechanisms
'''Principles of antibiotic therapy'''
*'''<span style="color:#ff0000">Antimicrobials are excreted in a concentrated form compared to their serum concentrations'''
**Resolution of infection is associated with the susceptibility of the bacteria to the concentration of the antimicrobial agent in the urine.
**'''Susceptibility testing is based on concentrations obtained in the serum'''
***'''Some antibiotics do not achieve adequate serum concentration levels to be considered effective for bacteriemia, but could be effective at its achievable urinary concentration.'''
****For example, E. Coli susceptible testing may show resistance to amoxicillin, even though amoxicillin may actually be effective for urinary E. Coli because of the high concentrations achieved.
***'''The concentration of the antimicrobial agent achieved in blood is not important in treatment of uncomplicated UTIs. However, blood levels are critical in patients with bacteremia and febrile urinary infections consistent with parenchymal involvement of the kidney and prostate'''
**'''<span style="color:#ff0000">In patients with renal insufficiency, dosage modifications are necessary for antibiotics that are renally cleared, including:'''
**#'''<span style="color:#ff0000">Ciprofloxacin'''
**#'''<span style="color:#ff0000">Nitrofurantoin'''
**#'''<span style="color:#ff0000">Trimethoprim/sulfamethoxazole'''
**#'''<span style="color:#ff0000">Trimethoprim'''
**#'''<span style="color:#ff0000">Amoxicillin'''
**#'''<span style="color:#ff0000">Piperacillin/tazobactam'''
**#'''<span style="color:#ff0000">Cephalexin'''
**#'''<span style="color:#ff0000">Cefuroxime'''
**#'''<span style="color:#ff0000">Levofloxacin'''
**#'''<span style="color:#ff0000">Clarithromycin'''
**#'''<span style="color:#ff0000">Tetracyclin'''
***'''In renal failure, the kidneys may not be able to concentrate an antimicrobial agent in the urine; hence, difficulty in eradicating bacteria may occur.'''
**Urinary tract obstruction may reduce concentration of antimicrobial agents within the urine.
*'''Bacterial resistance'''
**'''Mechanisms (3)'''
**#'''Inherited chromosomal-mediated'''
**#'''Acquired chromosomal'''
**#'''Extrachromosomal (plasmid)-mediated'''
***'''Inherited chromosomal resistance'''
****Exists in a bacterial species because of the absence of the proper mechanism on which the antimicrobial agent can act. For example, '''Proteus and Pseudomonas species are always resistant to nitrofurantoin'''
***'''Acquired chromosomal resistance'''
****'''Caused by exposure of an organism to antimicrobial agents'''
***'''Extrachromosomal-mediated resistance'''
****'''May be acquired and transferable via plasmids, which contain the genetic material for the resistance'''
*****'''This so-called R-factor resistance occurs in the bowel flora and is much more common than selection of pre-existing mutants in the urinary tract.'''
*****'''All antibiotic classes are capable of causing plasmid-mediated resistance. However, for the fluoroquinolones, resistance is rarely transmitted by plasmids, and nitrofurantoin plasmid-mediated resistance has not been reported.'''
******'''Clinical implication: because the bowel flora is the major reservoir for bacteria that ultimately colonize the urinary tract, infections that occur after antibiotic therapy and that can cause plasmid-mediated resistance are commonly caused by organisms with multidrug resistance. However, resistant E. coli in the bowel flora that infect the urinary tract almost always show susceptibility to nitrofurantoin or to the quinolones.'''
**'''Antibiotic resistance is also influenced by the duration and amount of antibiotic agent used.'''
====Mechanism of action of common antimicrobials used in the treatment of urinary tract infections====
{| class="wikitable"
|'''<span style="color:#ff0000">Drug or drug class'''
|'''<span style="color:#ff0000">Mechanism of action'''
|'''Mechanisms of drug resistance'''
|-
|'''<span style="color:#ff0000">β-Lactams (penicillins, cephalosporins, carbapenems, aztreonam)'''
|'''<span style="color:#ff0000">Inhibits bacterial cell wall synthesis'''
|Production of β-lactamase
Alteration in binding site of penicillin-binding protein

Changes in cell wall porin size (decreased penetration)
|-
|'''<span style="color:#ff0000">Vancomycin'''
|'''<span style="color:#ff0000">Inhibits bacterial cell wall synthesis'''
|Enzymatic alteration of peptidoglycan at different point
than target
|-
|'''<span style="color:#ff0000">Fosfomycin'''
|'''<span style="color:#ff0000">Inhibits bacterial cell wall synthesis'''
|Novel amino acid substitutions or the loss of function of transporters
|-
|'''<span style="color:#ff0000">Aminoglycosides (gentamicin, tobramycin, etc.)'''
|'''<span style="color:#ff0000">Inhibits ribosomal protein synthesis'''
|Downregulation of drug uptake into bacteria
Bacterial production of aminoglycoside-modifying enzymes
|-
|'''<span style="color:#ff0000">Clindamycin, macrolides (erythromycin, clarithromycin, azithromycin)'''
|'''<span style="color:#ff0000">Inhibits ribosomal protein synthesis'''
|
|-
|'''<span style="color:#ff0000">Quinolones (ciprofloxacin, levofloxacin, etc.)'''
|'''<span style="color:#ff0000">Inhibits bacterial DNA gyrase'''
|Mutation in DNA gyrase-binding site
Changes in cell wall porin size (decreased penetration)

Active efflux
|-
|'''<span style="color:#ff0000">Trimethoprim-sulfamethoxazole'''
|'''<span style="color:#ff0000">Competitive inhibition of dihydrofolate reductase'''
|Draws folate from environment (enterococci)
|-
|'''<span style="color:#ff0000">Nitrofurantoin'''
|'''<span style="color:#ff0000">Inhibits several bacterial enzyme systems'''
|Not fully elucidated—develops slowly with prolonged exposure
|}
====Reliable coverage of antibiotics used in the treatment of UTIs from commonly encountered pathogens====
{| class="wikitable"
|'''Antibiotic agent or class'''
|'''Gram-positive pathogens'''
|'''Gram-negative pathogens'''
|-
|'''Penicillins'''
|
|
|-
|'''Broad-spectrum penicillins'''
|
|
|-
|'''    Amoxicillin or ampicillin'''
|'''''Streptococcus'''''
'''Enterococci'''
|'''''Proteus mirabilis'''''
|-
|'''    Amoxicillin with clavulanate'''
|'''''Streptococcus'''''
'''Enterococci'''
|'''''Proteus, Klebsiella'''''
|-
|'''    Ampicillin with sublactam'''
|'''''Staphylococcus'' (not MRSA)'''
'''Enterococci'''
|'''''Proteus, Klebsiella'''''
'''''H. influenzae'''''
|-
|'''Anti-staphylococcal penicillins (methicillin, nafcillin, oxacillin, cloxacillin and dicloxacillin)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''

'''Not enterococci'''
|'''None'''
|-
|'''Anti-pseudomonal penicillins (piperacillin, ticaracillin)'''
|'''''Streptococcus'''''
'''Enterococci'''
|'''Most, including ''Pseudomonas'''''
|-
|'''Cephalosporins'''
|'''Not enterococci'''
|
|-
|'''First-generation cephalosporins (e.g. cefazolin, cephalexin)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''

'''Enterococci''' (CW12 p442)
|'''''E. coli, Proteus, Klebsiella'''''
|-
|'''Second-generation cephalosporins (cefamandole, cefuroxime, cefaclor)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''
|'''''E. coli, Proteus, Klebsiella'''''
'''''H. influenzae'''''
|-
|'''Second-generation cephalosporins (cefoxitin, cefotetan)'''
|'''''Streptococcus'''''
|'''''E. coli, Proteus''''' (including indole-positive), '''''Klebsiella'''''
'''''H. influenzae'''''
|-
|'''3rd-generation cephalosporins (ceftriaxone)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''
|'''Most, excluding ''P. aeruginosa'''''
|-
|'''3rd-generation cephalosporins (ceftazidime)'''
|'''''Streptococcus'''''
|'''Most, including ''P. aeruginosa'''''
|-
|Aztreonam
|None
|Most, including ''P. aeruginosa''
|-
|'''Aminoglycosides (gentamicin, tobramycin)'''
|'''''Staphylococcus'' (urine)'''
|'''Most, including ''P. aeruginosa'''''
|-
|'''Fluoroquinolones (e.g. ciprofloxacin)'''
|'''''Streptococcus''''' ''(depending which fluoroquinolone)''
'''Not enterococci'''
|'''Most, including ''P. aeruginosa'''''
|-
|'''Nitrofurantoin'''
|'''''Staphylococcus'' (not MRSA)'''
'''Enterococci'''
|'''Many Enterobacteriaceae (not ''Klebsiella, Proteus)'''''
'''''Does not cover P. aeruginosa, Providencia, Serratia, Acinetobacter'''''
|-
|'''Fosfomycin'''
|'''Enterococci'''
Variable activity against s. saprophyticus
|'''Most Enterobacteriaceae''' (variable activity against Klebsiella and Enterobacter)
'''Does not cover ''P. aeruginosa'')'''
|-
|Pivmecillinam
|None
|Most, excluding ''P. aeruginosa''
|-
|'''Trimethoprim-sulfamethoxazole'''
|'''''Streptococcus'''''
'''''Staphylococcus'''''

'''Not enterococci'''
|'''Most Enterobacteriaceae'''
'''Does not cover ''P. aeruginosa'''''
|-
|'''Vancomycin''' (can be used in penicillin allergy for gram-positive coverage)
|'''All, including MRSA'''
|'''None'''
|-
|'''Clindamycin''' (can be used in penicillin allergy for gram-positive coverage)
|'''''Streptococcus'''''
'''''Staphylococcus'''''

'''''NOT Enterococci'''''
|'''Anaerobes'''
'''NOT Enterobacteriaceae'''
|-
|'''Macrolides (clarithromycin, erythromycin, azithromycin)'''
|
|
|-
|'''Carbapenams (ertapenem, imipenem, meropenem)'''
|
|'''Ertapenam has weak pseudomonas coverage compared to meropenam'''
|}
====Common adverse reactions, precautions, and contraindications for antibiotics used in treatment of UTIs====
{| class="wikitable"
|'''Drug or drug class'''
|'''Common adverse reactions'''
|'''Precautions and contraindications'''
|-
|'''Amoxicillin or ampicillin'''
'''Ampicillin with sulbactam'''
|
**'''Hypersensitivity (immediate or delayed)'''
**'''Diarrhea (especially with ampicillin), GI upset'''
**'''Antimicrobial-associated pseudomembranous colitis'''
**'''Maculopapular rash (not hypersensitivity)'''
**'''Decreased platelet aggregation'''
|
**'''Increased risk of rash with concomitant viral disease,allopurinol therapy'''
|-
|'''Amoxicillin with clavulanic acid'''
|
**'''Increased diarrhea, GI upset'''
|
|-
|'''Anti-staphylococcal penicillins'''
|
**'''Same as with amoxicillin/ampicillin'''
**'''GI upset (with oral agents)'''
**'''Acute interstitial nephritis (especially withmethicillin)'''
|
|-
|'''Anti-pseudomonal penicillins'''
|
**'''Same as with amoxicillin/ampicillin'''
**'''Hypernatremia (these drugs are given as sodium salt; especially carbenicillin, ticarcillin)'''
**'''Local injection site reactions'''
|
**'''Use with caution in patients very sensitive to sodiumloading'''
|-
|'''Cephalosporins'''
|
**'''Hypersensitivity (less than with penicillins)'''
**'''GI upset (with oral agents)'''
**'''Antimicrobial-associated pseudomembranous colitis'''
**'''Local injection site reactions'''
**'''Positive Coombs test'''
**'''Decreased platelet aggregation (especially''' '''with cefotetan, cefamandole, cefoperazone)'''
|
**'''Avoid in patients with immediate hypersensitivity to penicillins; may use with caution in patients with delayed hypersensitivity reactions'''
**'''Ceftriaxone is contraindicated in neonates'''
|-
|Aztreonam
|
**Hypersensitivity (less than with penicillins)
|
**<1% incidence of cross-reactivity in penicillin- or cephalosporin-allergic patients; may be used with caution in these patients
|-
|'''Aminoglycosides'''
'''(gentamicin, tobramycin)'''
|
**'''Ototoxicity: vestibular and auditorycomponents'''
**'''Nephrotoxicity: nonoliguric azotemia'''
**'''Neurotoxicity: neuromuscular blockade with high levels'''
|
**'''Avoid in pregnant patients, except in pyelonephritis.'''
**'''Avoid, if possible, in patients with severely impaired renal function, diabetes, or hepatic failure'''
**'''Use with caution in myasthenia gravis patients (owing to potential for neuromuscular blockade)'''
**'''Use with caution with other potentially ototoxic andnephrotoxic drugs.'''
|-
|'''Fluoroquinolones'''
|
**'''<span style="color:#ff0000">Tendon rupture</span>''' (incidence 20 cases/100,000), should be discontinued at the first sign of tendon pain
**'''<span style="color:#ff0000">Aortic rupture</span>''' (incidence 20 cases/100,000), should be discontinued at the first sign of tendon pain
**'''<span style="color:#ff0000">QT interval prolongation;'''should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia or hypomagnesemia, and patients receiving some antiarrhythmic agents
**'''Photosensitivity'''
**'''Mild GI effects'''
**'''Central nervous system effects, including''' '''dizziness, tremors, confusion, mood disorder, hallucinations, light-headedness'''
**'''Hypoglycemia and hyperglycemia''' have been reported in patients treated concurrently with fluoroquinolones and anti-diabetic agents; '''avoid or monitor glucose levels closely in patients on anti-diabetic drugs'''
|
**'''Avoid in children or pregnant patients due to arthropathic effects.'''
**'''Concomitant antacid, iron, zinc, or sucralfate usedramatically decreases oral absorption'''; use another antimicrobial agent or discontinue sucralfate use while on quinolones. Space administration of quinolones from antacids, iron, or zinc products by at least 2 hr to ensure adequate absorption.
**'''Can significantly increase theophylline plasma levels; avoid quinolones or monitor theophylline levels closely.'''
**'''Can lower seizure threshold'''; avoid in patients with epilepsy and in patients with other risk factors (medications or illness) that may lower the seizure threshold.
**'''Avoid in patients receiving warfarin; can enhance warfarin effects'''; closely monitor coagulation tests.
**'''Avoid with other drugs that prolong QT interval, such as amiodarone'''
|-
|'''Fosfomycin'''
|
**'''Headache'''
**'''GI upset'''
**'''Vaginitis'''
|
|-
|Pivmecillinam
|
**Rash GI upset
|
**Use with caution in patients with penicillin hypersensitivity
|-
|'''Nitrofurantoin'''
|
**'''<span style="color:#ff0000">Pulmonary</span> hypersensitivity reactions can range from acute to chronic and include cough, dyspnea, fever, and interstitial changes [e.g. fibrosis].'''
**'''<span style="color:#ff0000">Hepatoxicity'''
**'''<span style="color:#ff0000">Peripheral neuropathy''' (especially in patients with impaired renal function, anemia, diabetes, electrolyte imbalance, vitamin B deficiency, and debilitated)
**'''<span style="color:#ff0000">GI upset'''
**'''<span style="color:#ff0000">Hemolysis in patients with G6PD deficiency'''
|
**'''Avoid in patients with decreased renal function(<50 mL/min) because adequate urine concentrations will not be achieved.'''
**'''Avoid concomitant probenecid use, which blocks renal excretion of nitrofurantoin.'''
**'''Monitor long-term patients closely.'''
**'''Avoid concomitant magnesium or quinolones, which are antagonistic to nitrofurantoin'''
**'''Can be given safely to patients receiving warfarin'''
**'''See below regarding use in pregnancy'''
|-
|'''Trimethoprim-sulfamethoxazole'''
|
**'''Hypersensitivity, rash'''
**'''GI upset'''
**'''Photosensitivity'''
**'''Hematologic toxicity (AIDS patients)'''
|
**'''Higher incidence of all adverse reactions occurs in AIDS patients and the elderly.'''
**'''Avoid TMP-SMX in pregnancy because of early potential for teratogenicity and late potential for kernicterus'''
**'''Avoid TMP-SMX in neonates due to risk of kernicterus from hyperbilirubinemia'''
**'''Trimethoprim alone should be avoided in pregnancy due to risk of megaloblastic anemia'''
**'''Trimethoprim alone can be used in neonates'''
**'''Avoid in patients receiving warfarin; can enhance warfarin effects'''; closely monitor coagulation tests.
**'''Avoid with other anti-arrhythmics, such as amiodarone'''
|-
|'''Vancomycin'''
|
**'''“Red-man syndrome”: flushing, fever, chills,''' '''rash, hypotension (histaminic effect)'''
**'''Nephrotoxicity and/or ototoxicity when combined with other nephrotoxic and/or ototoxic drugs'''
**'''Local injection site reactions'''
|
**'''Use with caution with other potentially ototoxic andnephrotoxic drugs.'''
|}
===Characteristics of Antibiotics by Class===
====Aminopenicillins====
*Ampicillin and amoxicillin have been used often in the past for the treatment of UTIs, but the '''emergence of resistance''' in 40-60% of common urinary '''isolates has lessened the usefulness of these drugs (See Toronto antibiograms''')
*'''The effects of ampicillin and amoxocillin on the normal bowel and vaginal flora can''' predispose patients to reinfection with resistant strains and '''often lead to candida vaginitis'''
*'''The addition of the β-lactamase inhibitor clavulanate to amoxicillin greatly improves activity against β-lactamase–producing bacteria resistant to amoxicillin alone. However, its high cost and frequent gastrointestinal side effects limit its usefulness.'''
*'''The extended-spectrum penicillin derivatives (e.g., pivmecillinam, piperacillin, mezlocillin, azlocillin) retain ampicillin’s activity against enterococci and offer activity against many ampicillin-resistant gram-negative bacilli'''
*'''Safe for use in pregnancy'''
====Cephalosporins====
*'''In general, as a group, activity is high against Enterobacteriaceae and poor against enterococci'''
*First-generation cephalosporins have greater activity against gram-positive organisms, as well as common uropathogens such as E. coli and Klebsiella pneumoniae, whereas second-generation cephalosporins have activity against anaerobes. Third-generation cephalosporins are more reliably active against community-acquired and nosocomial gram-negative organisms than other β-lactam antimicrobials.
*Use of these broad-spectrum agents should be limited complicated infections and situations in which parenteral therapy is required and resistance to standard antimicrobial agents is likely.
*'''Safe for use during pregnancy'''
*'''Ceftriaxone is contraindicated in neonates'''
====Nitrofurantoin====
*'''Effective against common uropathogens'''; '''not effective against Pseudomonas and Proteus'''
*Rapidly excreted in the urine but '''does not obtain therapeutic levels in most body tissues. Therefore, not useful for upper tract and complicated infections.'''
*'''Minimal effects on the resident bowel and vaginal flora''' and has been used effectively in prophylactic regimens
*Acquired bacterial resistance is exceedingly low
*'''Pregnancy'''
**'''2017 American College of Obstetricians and Gynecologists recommendations'''§''':'''
***'''First trimester'''
****Consider and discuss with patients the benefits as well as the potential unknown risks of teratogenesis and fetal and maternal adverse reactions.
****'''Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available.'''
***'''Second and third trimesters'''
****'''Can be used as first-line agents''' for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms.
***Contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency, or in pregnant women identified to be at risk of this condition.
**'''CW12 page 1186-1187'''
***'''First and second trimester'''
****'''May be used safely in patients without glucose-6-phosphate dehydrogenase deficiency'''
***'''Third trimester'''
****'''Should be discontinued at 35 weeks''' because of an increased risk of hemolytic anemia in the neonate.
====Trimethoprim (TMP)-sulfamethoxazole (SMX)====
*'''TMP alone or in combination with SMX is effective against most common uropathogens; not effective against Enterococcus and Pseudomonas.'''
**TMP alone is as effective as the combination for most uncomplicated infections and may be associated with fewer side effects; however, the addition of SMX contributes to efficacy in the treatment of upper tract infection via a synergistic bactericidal effect and may diminish the emergence of resistance and attains therapeutic levels in most tissues.
*Advantages are inexpensive and have '''minimal adverse effects on the bowel flora'''
*Disadvantages are relatively common adverse effects, consisting primarily of rashes and gastrointestinal complaints.
*'''Trimethoprim blocks the tubular secretion of creatinine.'''
**Since creatinine is produced at a steady state, the serum creatinine will rise, but the GFR does not change
*'''<span style="color:#ff0000">TMP-SMX should be avoided during pregnancy because of early potential for teratogenicity and late potential for kernicterus'''
*'''<span style="color:#ff0000">Trimethoprim alone should be avoided in pregnancy due to risk of megaloblastic anemia; trimethoprim alone can be used in neonates'''
====Fosfomycin====
*Effective against most uropathogens; '''not effective against Pseudomonas'''
*Effective against the majority of gram-negative organisms and vancomycin-resistant Enterococcus (VRE)
*Limited cross-resistance between most other common antibacterial agents
*Shown to be effective as a single-dose agent when used as an empirical treatment for uncomplicated cystitis
*Generally well tolerated with low incidences of GI upset and headache and very rare adverse events
====Fluoroquinolones====
*'''Broad spectrum of activity'''
**'''Highly effective against Enterobacteriaceae and P. aeruginosa'''
**'''Activity is also high against S. aureus and S. saprophyticus, but, in general, anti-streptococcal coverage is marginal'''
**'''Modest activity against enterococcus'''
*'''Most anaerobic bacteria are resistant to these drugs; therefore, the normal vaginal and bowel flora are not altered'''
*'''Increasing rates of resistance due to indiscriminate use of these agents'''
*Not nephrotoxic, but renal insufficiency prolongs the serum half-life, '''requires dose adjustment in patients with creatinine clearances of <30 mL/min.'''
*'''<span style="color:#ff0000">Contraindicated in children, adolescents, and pregnant or nursing women due to concerns of damage to developing cartilage'''
*'''Drug interactions''':
**'''Rare increases in the anticoagulant effects of warfarin when taken with fluoroquinolones'''.
**'''Concomitant antacid''' (containing magnesium or aluminum)''', iron, zinc, or sucralfate use dramatically decreases oral absorption'''
**Antacids containing magnesium or aluminum interfere with absorption of fluoroquinolones.
**Certain fluoroquinolones (enoxacin and ciprofloxacin) elevate plasma levels of theophylline and prolong its half-life
**'''Avoid with other drugs that prolong QT interval, such as amiodarone'''