Duodeno-pancreatic secretions enhance bactericidal activity of antimicrobial drugs

Mett, Helmut; Gyr, K.; Zak, O.; Vosbeck, K

doi:10.1128/aac.26.1.35

Cited by 24 publications

(8 citation statements)

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“…This pH effect was demonstrable in canine prostatic secretion and human urine ( Table 3) and suggests that it might be worthwhile to adjust pH to around 7.0 when treating urinary tract infections with fleroxacin. Interaction between body fluids and antimicrobial agents has been previously described (16,21). In our study, however, the investigated body fluids had no significant effect on MIC, indicating that the antibacterial activity of fleroxacin would be unaffected by prostatic secretion and urine.…”

Section: Discussioncontrasting

confidence: 50%

Fleroxacin (Ro 23-6240) distribution in canine prostatic tissue and fluids

Gasser

Graversen

Madsen

1987

Antimicrob Agents Chemother

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The distribution of fleroxacin (Ro 23-6240) in canine prostatic tissue and fluids was investigated under steady-state conditions during intravenous infusion. Mean ratios of fleroxacin concentration in tissue and fluids over concentration in plasma were 1.57 0.25 for prostatic tissue, 1.12 ± 0.28 for prostatic secretion, and 0.93 ± 0.14 for prostatic interstitial fluid. These levels and concentrations in urine were several times higher than the MIC for most pathogens that cause chronic bacterial prostatitis and urinary tract infection. The MICs for several isolates of Escherichia coli were only slightly affected by canine prostatic secretion, human prostatic tissue extract, and human urine. Clinical trials with fleroxacin appear justified for chronic bacterial prostatitis and urinary tract infection.Chronic bacterial prostatitis may be the most common cause of recurrent urinary tract infection in men (20). Despite the availability of antimicrobial agents with suitable antibacterial spectra, results of treating chronic bacterial prostatitis have been rather disappointing. The best cure rates reported, using trimethoprim-sulfamethoxazole for 4 to 16 weeks, vary from 32 to 71% (19).Fleroxacin (Ro 23-6240 or AM-833) is a newly developed quinolone derivative structurally related to the latest generation of 6-fluoro-7-piperazine-4-quinolones. It has a broad antibacterial spectrum against both gram-positive and gramnegative bacteria, including Pseudomonas aeruginosa and the Enterobacteriaceae (4, 8, 10). Fleroxacin is well absorbed after oral administration in experimental animals (13), and its long half-life of 9 to 11 h may allow once-per-day dosing (data on file, Hoffmann-La Roche, Inc.). Its antibacterial and pharmacokinetic properties make fleroxacin a potential drug for the treatment of urologic infections, possibly including chronic bacterial prostatitis.The purpose of this study was to evaluate the distribution of fleroxacin in plasma, prostatic secretion, prostatic interstitial fluid, prostatic tissue, and urine of dogs. We investigated in vitro the influence of dog prostatic secretion, human prostatic tissue extract, and human urine on the antibacterial activity of fleroxacin. MATERIALS AND METHODSAnimal studies. Fleroxacin was obtained from HoffmannLa Roche, Inc., Nutley, N.J. The dog model used for drug infusion studies has been previously described (15). Five adult male mongrel dogs weighing 23 to 33 kg were anesthetized intravenously with sodium thiopental. The prostrate was exposed through a low midline abdominal incision, and a multiperforated polyethylene tissue chamber (10 by 6 mm) with two connecting tubes (Engineering Industries, Verona, Wis.) was implanted in each lateral lobe (Fig. 1). The tubes were irrigated with heparin and placed subcutaneously. Approximately 4 weeks later, the dogs were anesthetized again. The bladder neck was ligated, and a vasectomy was * Corresponding author. t Present address: Urology Section, University Hospital, 4031 Basel, Switzerland.performed to prevent contaminati...

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Section: Discussioncontrasting

confidence: 50%

Fleroxacin (Ro 23-6240) distribution in canine prostatic tissue and fluids

Gasser

Graversen

Madsen

1987

Antimicrob Agents Chemother

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“…1B) is an interesting 8-hydroxyquinoline-based hit that might serve as a potential starting point for medicinal chemistry. Other hits that may be of interest as tool compounds, though not chemically attractive for drug discovery, include SAHH-2, a quinazosin, a known vasodilator with alpha-1 adrenergic receptor as its target [40] and SAHH-3, known as phanquinone, an antimicrobial agent [41]. …”

Section: Resultsmentioning

confidence: 99%

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Crowther

Napuli

Gilligan

et al. 2011

Molecular and Biochemical Parasitology

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The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for P. falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5,655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC50 values below 1.25 μM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5′-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.

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“…Anomalous enhancement activity of serum has been reported (13,18,19,28,33). Serum enhancement of antibiotic activity can be attributed to various factors, including the influence of serum on growth of the bacteria (2), serum alpha-2-globulin (22), changes in the pH of the test media (8), antibacterial peptides (4), or as yet unidentified synergistic host factors (18,19,21). Leggett and Craig (19) have shown that the increases in the MICs of ceftriaxone and other highly protein bound cephalosporins observed in the presence of albumin were significantly less than those predicted when they were determined in serum-containing medium and were not predicted from the protein-binding properties of the antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of antibacterial activity of azithromycin and other macrolides by normal human serum

Pruul

McDonald

1992

Antimicrob Agents Chemother

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The interaction of azithromycin with normal human serum was examined in relation to serum protein binding, MIC, and kinetics of killing of bacteria. While the binding of azithromycin to serum proteins is low (8.5% at a concentration of 0.01 mM in 95% serum), the presence of 40% serum during the MIC test decreased MICs by 26-fold for serum-resistant Escherichia coli and 15-fold for Staphylococcus aureus. Erythromycin had a similar but lesser effect, while roxithromycin was less active against S. aureus in the presence of serum. The rate of killing of E. coli and S. aureus by azithromycin was increased in the presence of serum. The enhancement of antibiotic activity by serum was pH independent, and heat inactivation and preabsorption with homologous bacteria failed to inhibit enhancement by serum. The macromolecular incorporation of [3H]thymidine by E. coli continuously exposed to 2 ,ug of azithromycin per ml (0.25x the MIC) and 40% serum was decreased by 80% at pH 7.8 and by 48% at pH 7.2, while azithromycin alone failed to inhibit incorporation. Inhibition of nucleic acid biosynthesis at pH 7.2 in the presence of serum was also detected with sub-MICs of erythromycin, norfloxacin, and gentamicin but not roxithromycin. A diffusible serum factor was shown to interact with azithromycin to inhibit the growth of E. coli in an agar diffusion assay to detect antibiotic-serum synergy.

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Duodeno-pancreatic secretions enhance bactericidal activity of antimicrobial drugs

Cited by 24 publications

References 5 publications

Fleroxacin (Ro 23-6240) distribution in canine prostatic tissue and fluids

Fleroxacin (Ro 23-6240) distribution in canine prostatic tissue and fluids

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Potentiation of antibacterial activity of azithromycin and other macrolides by normal human serum

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