Does penicillin achieve therapeutic concentrations in urine?

Does Penicillin Achieve Therapeutic Concentrations in Urine?

Yes, penicillin achieves extremely high urinary concentrations—often 10 to 100 times higher than serum levels—making it highly effective for treating susceptible urinary tract infections despite poor tissue penetration elsewhere in the body. 1

Pharmacokinetic Evidence for Urinary Concentration

Renal Excretion and Urinary Levels

• Penicillin G is rapidly excreted in urine primarily as unchanged drug, with 58-85% of the administered dose recovered in urine through both glomerular filtration and active tubular secretion 1

• Approximately 60% of a 300,000-unit dose is excreted within 5 hours, resulting in very high urinary concentrations that far exceed serum levels 1

• Oral penicillin G (500 mg potassium penicillin G) produces mean urine levels of 597 mcg/mL in the first two hours, 324 mcg/mL in hours 2-4, and 40 mcg/mL in hours 4-6, with 13.4% of the dose excreted in 24 hours 2

• Penicillin G is actively secreted into bile at levels at least 10 times those in serum, demonstrating the drug's capacity for concentration in excretory pathways 1

Contrast with Poor Tissue Penetration

• Penicillin G penetrates poorly into cerebrospinal fluid, eyes, and prostate in the absence of inflammation, with CSF/serum ratios of only 2-6% even with inflamed meninges 1

• Penetration into human polymorphonuclear leukocytes is poor, limiting efficacy in tissue infections 1

• This poor tissue distribution contrasts sharply with the excellent urinary concentrations, making penicillin particularly suited for urinary tract infections 1

Clinical Application for Urinary Tract Infections

Susceptibility Thresholds

• Most Gram-negative urinary pathogens are sensitive to 5-50 mcg/mL of penicillin G, well below the urinary concentrations achieved with standard oral dosing 2

• There is a rational basis for using oral penicillin G to treat urinary infections due to Gram-negative bacilli, given the high urinary levels relative to pathogen susceptibility 2

Aminopenicillin Use in Resistant Infections

• Aminopenicillin concentrations in urine may be high enough to achieve bacterial eradication and clinical cure for lower genitourinary tract infections, even when in vitro testing shows resistance based on serum susceptibility breakpoints 3

• Three retrospective cohort studies reported that aminopenicillins had similar clinical cure rates as other antibiotic classes for enterococcal urinary tract infections, even with ampicillin-resistant isolates 3

• Both pharmacokinetic/pharmacodynamic principles and clinical data support using aminopenicillins for lower urinary tract infections caused by Enterococcus species when the MIC exceeds the susceptibility breakpoint, because urinary concentrations far exceed serum-based breakpoints 3

Amoxicillin-Clavulanate for Resistant Organisms

• In a randomized double-blind trial of 22 patients with urinary tract infections caused by penicillin-resistant bacteria, amoxicillin plus clavulanic acid achieved absence of bacteriuria in 85% within 7 days, compared with only 25% for amoxicillin alone 4

• The combination is useful for uncomplicated urinary tract infections caused by penicillin-resistant bacteria, leveraging both high urinary concentrations and beta-lactamase inhibition 4

Dosing Considerations

Normal Renal Function

• High and frequent doses are required to maintain elevated serum levels for severe systemic infections in individuals with normal kidney function, because renal clearance is extremely rapid 1

• For urinary tract infections, however, standard doses produce therapeutic urinary concentrations without requiring the massive doses needed for systemic infections 2

Renal Impairment

• In patients with impaired renal function, penicillin excretion is considerably delayed, with beta-phase serum half-lives of 1-2 hours in azotemic patients (creatinine clearance <3 mg/100 mL) and up to 20 hours in anuric patients 1

• A linear relationship exists between the serum elimination rate constant and creatinine clearance, allowing dose adjustment based on renal function 1, 5

• The daily maintenance dose of penicillin G (units) can be calculated as: Cpen (mL/min) × desired mean serum concentration (mcg/mL) × 2300, where Cpen is total plasma clearance 5

• Hemodialysis reduces penicillin G serum levels, requiring post-dialysis supplementation 1

Common Pitfalls to Avoid

• Do not assume that serum-based susceptibility breakpoints apply to urinary tract infections—urinary concentrations are 10-100 times higher than serum, allowing treatment of organisms that appear "resistant" by standard testing 3, 2

• Do not use penicillin for upper urinary tract infections (pyelonephritis) when tissue penetration is required—the poor tissue distribution limits efficacy outside the urinary collecting system 1

• Do not overlook the need for dose reduction in renal impairment for systemic infections, though urinary concentrations remain high even with reduced dosing 1, 5

• Do not use penicillin V or erythromycin (which are not excreted in urine) for urinary tract infections—a retrospective study of 66 Swedish schoolgirls showed that penicillin V eradicated bacteriuria in only 5 girls, while 6 developed acute pyelonephritis and 1 developed cystitis within 5 months, whereas erythromycin (not excreted in urine) failed to clear bacteriuria in any patient 6