Antibacterial activity of phosphanilic acid, alone and in combination with trimethoprim

Abstract

We explored the antibacterial activity ef phosphanilic acid (P), an analog of sulfanilic acid, alone and in combination with trimethoprim (T; TP, 1:5) with sulfamethoxazole (S),and co-trimoxazole; the combingtion of this sulfonaniide with trimethoprim (TS, 1:5) as the reference. P resembled S in spectrum but, in addition, had significant activity against Pseudfomnnas aeruginos'a. The overall frequency and, degree bf synergism with TP were lower than with co-triinoxazole. P; like 8, was strongly affected by changes in inoculumnsize and was ntdt bactericidal: P was well absorbed parenterally but not orally in inice. Despite low (but prolonged) blood levels, P, given orally to iice, was effective in treating infections -ausied by P. aeruginosiz. However, Aggainst' mnost experimental infections the therapeutic effectiveness of P, as well as that ot TP, administered either intramnuscularly or orally was unimpressive. Based on in vivo data, the therapeutic applicatioin of P or TP would appear to be limited.Phosphanilic acid -(P) resembles sulfamethoxazdle (S)' in chemical structure and mode of action since its activity, like that of the sulfonamides, is inhibited by p7aminobenzoic acid (PABA) (6, 7). Published reports (5-7, 10, 11; 13, 16) on the antibacterial. activity of P'have been limited to a few speciated organisms, excluding Pseudomonas aeruginosa, and a number of unspeciated strains. There is no published comparison of the antibacterial spectrum, therapeutic efficacy, and pharmactskinetics of P and S in mice. Also, the potential of P as a combinant with trimethoprim (T) has not been explored. Data are presented in this study on the in vitrb antibacterial a'ctivity and efficacy of P, S, T, T in.combination with P (TP against experimental infections in mice; 1:5), and co-trimoxazole, a combination of T and S (TS; 1:5), against various experimental infections mice. Also presented are comparative data on biood levels ard urinary recovery for P and S in mice. Effect of inoculum'size. The influence of inoculum size on the inhibitory activity of P and S against strains of members bf the family Enterobacteriaceae and P. aetuginosa was determined inMH broth with 1.3% Noble agar. Final inocula of 10', 103, and 105 CFU were used.Bactericidal activity. The effect of P and 'S on the viability of strains of members of the Enterobacteriaceae and P. aeruginosa was determined in MH broth. An inoculum.of i04 to 105 CFU was incubated, for '21. h at 37°C with various cOncentrations of antimicrobi4l agents in 1 ml of broth. The number of cells remaining viable was determined by plating 0.1 ml of culture on MH'medium except for strains bf Proteus spp., Wvbich were plated on nutrient agar (Difco) to minitnize spreading. The-MBC was defined as the lowest concentration of drug that reduced the viability of the initial cell populationi by 99%.Antagonistic effect of PABA. The growth-inhibitory activity of P for eight strains of P. aeruginosa was assayed alone 761 on April 27, 2019 by guest http://aac.asm.org/ Downloaded from

A quantitative systems pharmacology (QSP) model for Pneumocystis treatment in mice

“…. [ 35 ] Andes et al [ 40 ] Andes et al [ 40 ] Misiek et al [ 41 ] Validation data Andes et al [ 42 ] Andes et al [ 40 ]; Hajdu et al [ 43 ] Andes et al [ 40 ]; Misiek et al [ 41 ] Goodness of fit (SSE) 459.26 2602.56 202.14 131.15 …”

Phosphanilic acid inhibits dihydropteroate synthase

“…The antimicrobial activity of PA, as that of the sulfonamides, has been reported to be antagonized by pABA in intact cells (4)(5)(6). The antimicrobial spectrum of PA resembled that of the sulfonamide sulfamethoxazole, but PA had significantly greater activity against Pseudomonas aeruginosa (6).…”

“…The antimicrobial spectrum of PA resembled that of the sulfonamide sulfamethoxazole, but PA had significantly greater activity against Pseudomonas aeruginosa (6). Thus, while PA was effective in treating P. aeruginosa in intraperitoneally inoculated mice, the therapeutic effectiveness of PA against other organisms when given by this parenteral route was unimpressive (6).…”