Transcript Cycloserine as an alternative urinary tract infection

Cycloserine as an alternative urinary tract infection therapy; susceptibilities of 500 urinary pathogens to standard
and alternative therapy antimicrobials
R. Kugathasan1, M. Wootton1, R. Howe1
1Specialist
Antimicrobial Chemotherapy Unit, Public Health Wales Microbiology Cardiff, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW.
Email: [email protected]
Results
Introduction
Cycloserine is an alanine analogue with activity against a wide variety of urinary
coliforms and has been used previously in some areas of the world for the treatment
of urinary tract infections. Trimethoprim is still commonly used as a first line
empirical treatment for urinary tract infections despite resistance rates of 35% in the
United Kingdom. The emergence of multi-resistant strains of Enterobacteriaceae and
the lack of new agents in the development pipeline has prompted a need to review
the activity of older agents.
Susceptibility testing of cycloserine has historically been problematic since standard
media contains competitive alanine, leading to falsely elevated minimum inhibitory
concentrations (MICs). This study tests urinary coliforms, including resistant
phenotypes, against cycloserine in both standard and minimal media.
Materials and Methods
Susceptibilities were performed on 500 “wild type” UTI coliforms against cycloserine,
trimethoprim, nitrofurantoin, cefotaxime and ceftazidime using Muller-Hinton broth in
the range 0.008-128 mg/l in accordance with ISO guidelines. Cycloserine was also tested
in Minimal-Salts media + 2% 1M glucose + 0.2% 1M magnesium sulphate. MICs were
recorded after 18 hours incubation at 35⁰C and interpreted with EUCAST breakpoints
(where available).
To exclude differences in growth potential, growth of a 1x105 inoculum of Escherichia coli
ACTC 25922 in Mueller-Hinton broth and Minimal-Salts medium following incubation at
35⁰C for 20 hours was estimated by spiral plating onto blood agar and counting resulting
colonies.
Table 1: Cycloserine susceptibilities and antimicrobial comparators against all Enterobacteriaceae
Number
and type
of isolate
MIC50
(µl/ml)
MIC90
(µl/ml)
Range
%Susc.
%Res.
All isolates
Cycloserine (MS)
Cycloserine (MHB)
451a
500b
2
32
64
128
0.12->128
8->128
N/A
N/A
N/A
N/A
Cefotaxime
500b
0.06
0.25
<0.008->128
93.8
5.2
Ceftazidime
500b
0.25
1
0.03->128
94.0
4.8
Nitrofurantoin
500b
16
64
0.5->128
93.0
7.0
Trimethoprim
500b
1
>128
0.06->128
60.6
36.4
Fosfomycin
500b
0.25
4
0.12-1024
98.2
2.0
TRM resistant strains
Cycloserine (MS)
164c
2
16
0.12 - >128
N/A
N/A
Cycloserine (MHB)
182d
32
128
16->128
N/A
N/A
Cefotaxime
182d
0.06
4
0.016->128
89.6
9.0
Ceftazidime
182d
0.25
2
0.03-128
90.0
9.0
Nitrofurantoin
182d
16
64
4 - >128
91.0
8.8
Fosfomycin
182d
0.25
2
0.12-128
99.5
0.5
3rd generation cephalosporin resistant strains
Cycloserine (MS)
21e
4
64
1->128
N/A
N/A
Cycloserine (MHB)
24f
64
>128
16->128
N/A
N/A
Nitrofurantoin
24f
16
128
4->128
91.3
8.7
Trimethoprim
24f
>128
>128
0.5->128
21.7
69.6
Fosfomycin
24f
0.25
32
0.12-64
95.7
4.3
Cycloserine MIC50 for the “wild type” coliforms was 32 µg/ml in Mueller-Hinton broth compared to 2 µg/ml in
Minimal-Salts. 87% of “wild type” UTI coliforms show cycloserine MICs <=8 µg/ml in Minimal-Salts. Growth in
Minimal-Salts medium and Mueller-Hinton was similar after 20 hours incubation. Susceptibilities and % resistance to
other antimicrobials are shown in Table 1.
Conclusions
The epidemiological cut-off values of cycloserine for E. coli in this study were 64 µg/ml using Mueller-Hinton broth and 8 µg/ml using Minimal-Salts medium. 94% of trimethoprim resistant and 82% of 3rd
generation cephalosporin resistant E.coli had MICs in Minimal-Salts <=8 µg/ml. Escherichia coli accounts for 75-95% of all uncomplicated urinary tract infections and pyelonephritis. Urinary cycloserine
concentrations of 50 µg/ml at 8hrs and 30 µg/ml at 24hrs can be achieved following standard dosing of 250mg [1]. Cycloserine toxicity typically occurs at plasma levels above 30 µg/ml [2]. Our data suggests
cycloserine could be used at a lower dose and still effectively treat urinary tract infections, while lowering the chance of toxicity. Cycloserine is still licensed in some countries for the treatment of urinary
infections and the data presented here suggests that it may have a role in the management of infections resistant to trimethoprim and 3rd generation cephalosporins.
References
1. P. Kaltenis (1986). Cycloserine as a urinary tract antiseptic. Institute of urology and nephrology. 1986, Volume 18, Issue 2, pp 125-130.
2. Maclean, R. L (1956). Transactions of the 15th conference on the chemotherapy for tuberculosis. Veterans Administration, St. Louis, Missouri.
Kugathasan R1, Wootton M, Howe R. (2014). Cycloserine as an alternative urinary tract infection therapy: susceptibilities of 500 urinary pathogens to standard and alternative therapy antimicrobials. Eur J Clin Microbiology Infectious
Disease 2014 Jan 29. [Epub ahead of print]. The final publication is available at http://link.springer.com/article/10.1007/s10096-014-2051-9