Clinical Report Chemotherapy 21: 99-107 (1975)
Fosfomycin in Treatment of Chronic Urinary Tract Infection M. G obernado , J. O leza , M. Santos , J. R oman , M. P az , E. M ascaros and J. A lmela Services of Microbiology and Urology, Ciudad Sanitaria La Fe, Valencia
Abstract. A study was made of fosfomycin in the Key Words treatment of chronic urinary infection in 51 patients. Fosfomycin 72°/o of the 67 bacteria isolated and tested in the labo- Urinary Tract infection ratory with discs containing 50 /ug of fosfomycin Renal insufficiency were found to be sensitive to the antibiotic. The ma- Disc test jority of E. coli, Klebsiella, P. mirabilis and Ps. aeru ginosa strains were sensitive to the antibiotic. Generally, 60 mg of fosfomycin/kg body weight was administered intramuscular ly, 6-hourly for 7-15 days. A clinical and bacteriological cure was obtained in 39 patients (76°/o), and after 4-6 weeks in 31 patients (61°/o). Blood and urine fosfomy cin levels were determined in seven patients, three with normal renal function, three with moderate renal insufficiency, and one with severe renal insufficiency. The anti biotic levels and elimination time maintained a clear relation with the degree of ren al insufficiency.
In 1969, H e n d l in et al. [7] reported the discovery of the antibiotic MK 955, now known as fosfomycin. The pharmacological properties, mechanism of action, toxicity, in vitro action and the first clinical trials were published in the same year [2, 5, 6, 9, 11, 14, 15]. The antibacterial spectrum of the antibiotic and its concentrations in urine and the tissues suggested that it could be useful in the treatment of infections of the uri nary tract. The limited number of publications in this aspect up to now [3, 8] have dealt fundamentally with its application in the treatment of acute infections. This paper reports our experience of the treatment with fosfomycin of 51 patients with chronic urinary infections.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Introduction
100
G obernado/O leza/S antos/R oman/P az/M ascaros/A lmela
Material and Methods Clinical Studies 51 urological patients admitted to the Department of Urology of ‘La Fe’ Hospi tal, Valencia, were treated with fosfomycin. Their ages ranged from 8 to 82 years, the average age being 55. 44 were males and 7 were females. All exhibited clinical and bacteriological signs of urinary infection which, in the majority of cases, affect ed the urinary tract and kidneys. The urological diagnoses of these patients are pre sented in table I, in their order of frequency of occurrence. 26 of the 51 patients were catheterized at some time during their treatment. The general state of the pa tients on admission was considered as serious in 12 cases, fair in 24, and good in 15. Fosfomycin was administered intramuscularly in the form of its sodium salt, generally in doses of 1 g every 6 h for 10 days. The individual doses varied between 30 and 180 mg/kg body weight/day, with a mean of 60 mg/kg/day. The total dura tion of the treatment varied between 4 and 24 days; however, 76% of the patients were only treated for between 7 and 15 days. Laboratory Studies The urine samples were obtained using the ‘clean catch’ rules of Spencer et al. [13], except in the cases where the urine was obtained by catheter because of com plete retention. Counting and identification of the germs was carried out in the usual manner. Bacteriological counts equal or greater than 105 organisms/ml of ur ine were taken as criterion of infection. Qualitative tests of sensitivity were carried out by the disc plate method follow ing the WHO criteria [12] and those of E ricsson and Serris [4], with discs of 50 «g of fosfomycin with a considered limiting diameter of 13 mm. The MICs of the strains isolated in the 51 patients was determined by means of series of dilutions in Mueller-Hinton agar from 0.5 to 256 ,«g/ml starting with inoculums of between 106 and 107 living bacteria.
Diagnosis
Number of patients
Prostatism Bladder tumor Urinary lithiasis Chronic pyelonephritis Urethral stricture Others
18 12 10 4 4 3
Total
51 Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Table I. Clinical diagnoses of patients treated with fosfomycin
Fosfomycin in Treatment of Chronic Urinary Tract Infection
101
All the isolated strains of bacteria were also tested for sensitivity against a fur ther 9 antibiotics and 3 chemotherapeutic agents using the disc method. Determinations of the levels of fosfomycin in the blood and urine of seven pa tients, three with normal renal function and four with renal insufficiency, were car ried out after the administration of 1 g of the sodium salt of fosfomycin intramus cularly. The samples of blood were taken sequentially, depending on the cases, be tween 1 and 24 h after the administration of the antibiotic. For this determination the standard biological method of plate diffusion was employed using Proteus vul garis ATCC 2210, cultivated in NAYE (Difco Nutrient Broth, Difco Yeast Extract and Agar), as a test microorganism. The germ, after incubation at 37 °C for 1618 h, was suspended in saline until a transmission of 40% in Spectronic 20 with a wavelength of 660 nm was obtained. This was subsequently diluted to 3.3% in NAYE at 47 °C, and 100 ml was distributed on 100X300 mm plates with ten cylin ders of 8X15 mm on each plate. The concentration of the antibiotic for the stand ard curve was 0.5, 1.0, 2.0, 3.0, and 4.0 fig/m\ in pH 8 Tris buffer (0.05 M). Human serum was used as a diluent in the determination of antibiotic levels in blood serum and Tris solution as the diluent for the determination in urine. Urine cultures were carried out every one or two days and in some cases every 12 h, with the aim of studying the dynamics of the bacteria under the influence of the antibiotic. The infection was considered to be cured when the clinical picture was controlled and the causative germ had disappeared 1 week after the end of a course of treatment and, in patients found to be clear at this time, again 4-6 weeks later. Toxicity Control analyses of urine and blood were taken from all patients before, during, and after the administration of fosfomycin. The blood analyses included hematocrit, hemoglobin, platelet count, leucocyte count and differential, alkaline phosphatase, transaminases (GOT and GPT), bilirubin, urea, creatinin, creatinin clearance, cholesterine and coagulation tests and the urine analyses, urine pH, albumin, glucose and sediment.
Results
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Laboratory Studies 67 strains of bacteria were identified from 51 urine samples. In 44 samples a single germ was isolated, while in the other 7, several germs were found. Their distribution, sensitivity to fosfomycin and eradication by the treatment is presented in table II. The majority of the strains have an MIC of between 32 and 128 /tg/ml. E. coli was quite sensitive, one of the strains having an MIC of only 1 /¿g/ml, the majority of the remainder varying between 8 and 128 /¿g/ml. P. mirabilis with an MIC between 4 and 64 «g/ml was also quite sensitive. The most resistant were the Pro teus indoligenous and the Providence strains with MIC generally higher than 128 /¿g/ml.
102
G obernado/O leza/S antos/R oman/P az/M ascaros/A lmela
Table II. MIC of fosfomycin of the isolated microorganisms before treatment. Number of strains eradicated after treatment, and MIC of resistant microorganisms Organism
MIC of fosfomycin before treatment, flg/ml____________________________ 1 2 4 8 16 32 64 128 256 >256
I
g3
23
»o
*M
«
S 3 'S a
z E. coli
II O
1
4 4
7
3
3 1
I
1
3 1 1
Klebsiella sp. Enterobacter P. mirabilis P. rettgeri
6 2 8 6
P. vulgaris P. morganii Providence
1 1 4
1
Ps. aeruginosa Strep, faecalis
13 3
1
Total
67
1 1 1 1
2 1
1 2
1 1
1
1 5 6 13
1 2 2
I
E 3
Z Ö
z
21
2
6 1 6 3 1 1
-
1 2 3 4
3
-
3 2
10 3
3 -
9 15 4 13
52
15
3 1
6
en a. o U
§ 32 256 -
>256 >256 256 >256 (2) -
128 >256 (3) >256 -
The comparison between the sensitivity to fosfomycin and to the other antibiotics and chemotherapeutic agents is presented in table III. 72% of the strains isolated were found to be sensitive to fosfomycin. The culture controls carried out immediately following the treatment showed a good result in 39 cases, the initial flora disappearing between 12 and 48 h after the initiation of treatment with fosfomycin in 70% of these cases. In two patients with mixed flora only one of the germs was eradicated. In the remaining ten cases no modification of the flora was observed during the treatment with fosfomycin. The levels of fosfomycin in the blood of the seven patients studied are presented in figure 1. With a single dose of 1 g of the sodium salt of fosfo mycin administered intramuscularly to adults with normal renal function, as shown by a urea in blood of 30-42 mg% and creatinin clearance of 85120 ml/min, levels of 30-35 «g/ml were reached after 1 h and levels of Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
1 Number of strains.
103
Fosfomycin in Treatment of Chronic Urinary Tract Infection
67
23 5 2 7 5 1 1 1 11 -
20 1 1 5 5 1 I 9 2
nitrofurantoin
20 5 2 6 4 1 1 I -
19 3 2 6 3 1 1 3
fosfomycin
13 -
20 5 2 5 5 I 1 -
nalidixic acid
-
23 6 2 8 5 1 4 3
nitroxoline
1 2
rifampicin
-
gentamicin
23 6 2
aminosidine
8 5 2
kanamycin
colimycin
11 4 I 7 2 1 1 1 12 . 3
cephalosporin
tetracycline
8 4 1 2 1 3
23 5 2 7 6 1 4 11 3
23 4 2 7 5 1 I -
22 3 1 7 3 1 10 1
28% 64% 27% 66% 78% 58% 60% 84% 67% 57% 92% 66% 72%
8-16 ng/ml after 6 h. A further gram of fosfomycin was administered to two patients 6 h after the first injection; in these cases the levels of fosfo mycin reached 39-44 ¿tg/ml 1 h after this second injection. The half-life of the antibiotic in the patients with normal renal function was 172-2 h. In the two patients with moderate renal insufficiency, expressed by creatinin clearance between 40 and 60ml/min, the levels of fosfomycin reached 28-64 pg/m[ in the first hour and maintained levels of 2432 /rg/inl after 6 h and 8-14 //g/ml after 24 h. In one of the patients with serious renal insufficiency, creatinin clearance of only 3 ml/min, creatinin in blood of 7 mg% and 230 mg#/o of urea, the levels of fosfomycin reached 92 ng/ml after 2 h, 20 ¿¿g/ml after 16 h, and 8 f i g / ml after 24 h. The half-life of the antibiotic was extended to 6 h in the cases of moder ate renal insufficiency and 12 h in the case of severe renal insufficiency. The concentration of fosfomycin in urine oscillated between 480 and 3,200 jUg/ml in the patients with normal renal function or moderate renal insufficiency. In the patient with severe renal insufficiency the level in ur ine remained constant during the first 16 h at less than 100 ,ttg/ml. Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Total
carbenicillin
E. coli 23 Klebsiella sp. 6 Enterobacterae 2 P. mirabilis 8 P. rettgeri 6 1 P. vulgaris 1 P. morganii 4 Providence Ps. aeruginosa 13 Strep.faecalis 3
Antimicrobial agents
ampicillin
Organisms
Number of strains
Table III. In vitro sensitivity of the different strains isolated from 51 cases of urinary tract infections to fosfomycin and other antimicrobial agents
104
G obernado/O leza/S antos/R oman/P az/M ascaros/A lmela
Time, h
Fig. 1. Fosfomycin blood levels in seven patients, at different times after the intra muscular administration of 1 g of fosfomycin.----- = Normal renal function; ........= moderate renal insufficiency;-------- severe renal insufficiency.
Clinical Studies Of the 51 patients treated with fosfomycin (table IV), 39 (76%) were free of infection one week immediately after the treatment, a further 8 (16%) showed an improvement in their condition, and in 4 patients (8%) no change of their condition was apparent. Of the 39 patients initially cured, 7 (14%) were reinfected during the course of the next 4-6 weeks, and one could not be followed up. Thus a definite cure was obtained in 31 patients (61%) of the initial 51.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Toxicity and Side Effects The drug in general was well tolerated. Seven patients complained of local pain after the intramuscular injection of the antibiotic. No alteration in hepatic or renal function was observed, nor was blood clotting affected. 21 of the patients treated exhibited an eosinophilia of 2-10% which is dif ficult to attribute to the antibiotic as this often appears during the normal evolution of the disease. One of the patients who was allergic to penicillin did not exhibit any alteration during the course of treatment with fosfo-
Fosfomycin in Treatment of Chronic Urinary Tract Infection
105
Table IV. Response of urinary tract infections to fosfomycin administration (51 cases) Response
Good Fair No response No control
Bacteriological initial 39 (76%) 2 (4%) 10 (20%)
delayed 31 (61%) 1
Clinical initial 39 (76%) 8 (16%) 4 (8%)
delayed 31 (61%) 1
mycin. In another patient, after one intramuscular injection of the antibiot ic, a gluteal abscess was formed but this responded favorably to local heat treatment without interrupting the administration of fosfomycin.
According to these results, it is apparent that fosfomycin is a useful antibiotic for the treatment of chronic urinary infections. The favorable response of 61% of the patients with a subsequent control of the infection is high for this type of urological condition caused by germs quite resist ant to antibiotics. However, for an exact evaluation, one must take into account the surgical solution of the urological problems with which the majority of the patients presented; this also favors the disappearance of the infection. A good correlation existed between the in vitro sensitivities of the germs and the subsequent clinical response, given that the MICs of the 15 strains that were not eradicated by the treatment (2 E. coli, 1 Enterobacter, 2 P. mirabilis, 3 P. rettgeri, 4 Providence and 3 Ps. aeruginosa) were of 256 /
Fosfomycin in Treatment of Chronic Urinary Tract Infection M. G obernado , J. O leza , M. Santos , J. R oman , M. P az , E. M ascaros and J. A lmela Services of Microbiology and Urology, Ciudad Sanitaria La Fe, Valencia
Abstract. A study was made of fosfomycin in the Key Words treatment of chronic urinary infection in 51 patients. Fosfomycin 72°/o of the 67 bacteria isolated and tested in the labo- Urinary Tract infection ratory with discs containing 50 /ug of fosfomycin Renal insufficiency were found to be sensitive to the antibiotic. The ma- Disc test jority of E. coli, Klebsiella, P. mirabilis and Ps. aeru ginosa strains were sensitive to the antibiotic. Generally, 60 mg of fosfomycin/kg body weight was administered intramuscular ly, 6-hourly for 7-15 days. A clinical and bacteriological cure was obtained in 39 patients (76°/o), and after 4-6 weeks in 31 patients (61°/o). Blood and urine fosfomy cin levels were determined in seven patients, three with normal renal function, three with moderate renal insufficiency, and one with severe renal insufficiency. The anti biotic levels and elimination time maintained a clear relation with the degree of ren al insufficiency.
In 1969, H e n d l in et al. [7] reported the discovery of the antibiotic MK 955, now known as fosfomycin. The pharmacological properties, mechanism of action, toxicity, in vitro action and the first clinical trials were published in the same year [2, 5, 6, 9, 11, 14, 15]. The antibacterial spectrum of the antibiotic and its concentrations in urine and the tissues suggested that it could be useful in the treatment of infections of the uri nary tract. The limited number of publications in this aspect up to now [3, 8] have dealt fundamentally with its application in the treatment of acute infections. This paper reports our experience of the treatment with fosfomycin of 51 patients with chronic urinary infections.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Introduction
100
G obernado/O leza/S antos/R oman/P az/M ascaros/A lmela
Material and Methods Clinical Studies 51 urological patients admitted to the Department of Urology of ‘La Fe’ Hospi tal, Valencia, were treated with fosfomycin. Their ages ranged from 8 to 82 years, the average age being 55. 44 were males and 7 were females. All exhibited clinical and bacteriological signs of urinary infection which, in the majority of cases, affect ed the urinary tract and kidneys. The urological diagnoses of these patients are pre sented in table I, in their order of frequency of occurrence. 26 of the 51 patients were catheterized at some time during their treatment. The general state of the pa tients on admission was considered as serious in 12 cases, fair in 24, and good in 15. Fosfomycin was administered intramuscularly in the form of its sodium salt, generally in doses of 1 g every 6 h for 10 days. The individual doses varied between 30 and 180 mg/kg body weight/day, with a mean of 60 mg/kg/day. The total dura tion of the treatment varied between 4 and 24 days; however, 76% of the patients were only treated for between 7 and 15 days. Laboratory Studies The urine samples were obtained using the ‘clean catch’ rules of Spencer et al. [13], except in the cases where the urine was obtained by catheter because of com plete retention. Counting and identification of the germs was carried out in the usual manner. Bacteriological counts equal or greater than 105 organisms/ml of ur ine were taken as criterion of infection. Qualitative tests of sensitivity were carried out by the disc plate method follow ing the WHO criteria [12] and those of E ricsson and Serris [4], with discs of 50 «g of fosfomycin with a considered limiting diameter of 13 mm. The MICs of the strains isolated in the 51 patients was determined by means of series of dilutions in Mueller-Hinton agar from 0.5 to 256 ,«g/ml starting with inoculums of between 106 and 107 living bacteria.
Diagnosis
Number of patients
Prostatism Bladder tumor Urinary lithiasis Chronic pyelonephritis Urethral stricture Others
18 12 10 4 4 3
Total
51 Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Table I. Clinical diagnoses of patients treated with fosfomycin
Fosfomycin in Treatment of Chronic Urinary Tract Infection
101
All the isolated strains of bacteria were also tested for sensitivity against a fur ther 9 antibiotics and 3 chemotherapeutic agents using the disc method. Determinations of the levels of fosfomycin in the blood and urine of seven pa tients, three with normal renal function and four with renal insufficiency, were car ried out after the administration of 1 g of the sodium salt of fosfomycin intramus cularly. The samples of blood were taken sequentially, depending on the cases, be tween 1 and 24 h after the administration of the antibiotic. For this determination the standard biological method of plate diffusion was employed using Proteus vul garis ATCC 2210, cultivated in NAYE (Difco Nutrient Broth, Difco Yeast Extract and Agar), as a test microorganism. The germ, after incubation at 37 °C for 1618 h, was suspended in saline until a transmission of 40% in Spectronic 20 with a wavelength of 660 nm was obtained. This was subsequently diluted to 3.3% in NAYE at 47 °C, and 100 ml was distributed on 100X300 mm plates with ten cylin ders of 8X15 mm on each plate. The concentration of the antibiotic for the stand ard curve was 0.5, 1.0, 2.0, 3.0, and 4.0 fig/m\ in pH 8 Tris buffer (0.05 M). Human serum was used as a diluent in the determination of antibiotic levels in blood serum and Tris solution as the diluent for the determination in urine. Urine cultures were carried out every one or two days and in some cases every 12 h, with the aim of studying the dynamics of the bacteria under the influence of the antibiotic. The infection was considered to be cured when the clinical picture was controlled and the causative germ had disappeared 1 week after the end of a course of treatment and, in patients found to be clear at this time, again 4-6 weeks later. Toxicity Control analyses of urine and blood were taken from all patients before, during, and after the administration of fosfomycin. The blood analyses included hematocrit, hemoglobin, platelet count, leucocyte count and differential, alkaline phosphatase, transaminases (GOT and GPT), bilirubin, urea, creatinin, creatinin clearance, cholesterine and coagulation tests and the urine analyses, urine pH, albumin, glucose and sediment.
Results
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Laboratory Studies 67 strains of bacteria were identified from 51 urine samples. In 44 samples a single germ was isolated, while in the other 7, several germs were found. Their distribution, sensitivity to fosfomycin and eradication by the treatment is presented in table II. The majority of the strains have an MIC of between 32 and 128 /tg/ml. E. coli was quite sensitive, one of the strains having an MIC of only 1 /¿g/ml, the majority of the remainder varying between 8 and 128 /¿g/ml. P. mirabilis with an MIC between 4 and 64 «g/ml was also quite sensitive. The most resistant were the Pro teus indoligenous and the Providence strains with MIC generally higher than 128 /¿g/ml.
102
G obernado/O leza/S antos/R oman/P az/M ascaros/A lmela
Table II. MIC of fosfomycin of the isolated microorganisms before treatment. Number of strains eradicated after treatment, and MIC of resistant microorganisms Organism
MIC of fosfomycin before treatment, flg/ml____________________________ 1 2 4 8 16 32 64 128 256 >256
I
g3
23
»o
*M
«
S 3 'S a
z E. coli
II O
1
4 4
7
3
3 1
I
1
3 1 1
Klebsiella sp. Enterobacter P. mirabilis P. rettgeri
6 2 8 6
P. vulgaris P. morganii Providence
1 1 4
1
Ps. aeruginosa Strep, faecalis
13 3
1
Total
67
1 1 1 1
2 1
1 2
1 1
1
1 5 6 13
1 2 2
I
E 3
Z Ö
z
21
2
6 1 6 3 1 1
-
1 2 3 4
3
-
3 2
10 3
3 -
9 15 4 13
52
15
3 1
6
en a. o U
§ 32 256 -
>256 >256 256 >256 (2) -
128 >256 (3) >256 -
The comparison between the sensitivity to fosfomycin and to the other antibiotics and chemotherapeutic agents is presented in table III. 72% of the strains isolated were found to be sensitive to fosfomycin. The culture controls carried out immediately following the treatment showed a good result in 39 cases, the initial flora disappearing between 12 and 48 h after the initiation of treatment with fosfomycin in 70% of these cases. In two patients with mixed flora only one of the germs was eradicated. In the remaining ten cases no modification of the flora was observed during the treatment with fosfomycin. The levels of fosfomycin in the blood of the seven patients studied are presented in figure 1. With a single dose of 1 g of the sodium salt of fosfo mycin administered intramuscularly to adults with normal renal function, as shown by a urea in blood of 30-42 mg% and creatinin clearance of 85120 ml/min, levels of 30-35 «g/ml were reached after 1 h and levels of Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
1 Number of strains.
103
Fosfomycin in Treatment of Chronic Urinary Tract Infection
67
23 5 2 7 5 1 1 1 11 -
20 1 1 5 5 1 I 9 2
nitrofurantoin
20 5 2 6 4 1 1 I -
19 3 2 6 3 1 1 3
fosfomycin
13 -
20 5 2 5 5 I 1 -
nalidixic acid
-
23 6 2 8 5 1 4 3
nitroxoline
1 2
rifampicin
-
gentamicin
23 6 2
aminosidine
8 5 2
kanamycin
colimycin
11 4 I 7 2 1 1 1 12 . 3
cephalosporin
tetracycline
8 4 1 2 1 3
23 5 2 7 6 1 4 11 3
23 4 2 7 5 1 I -
22 3 1 7 3 1 10 1
28% 64% 27% 66% 78% 58% 60% 84% 67% 57% 92% 66% 72%
8-16 ng/ml after 6 h. A further gram of fosfomycin was administered to two patients 6 h after the first injection; in these cases the levels of fosfo mycin reached 39-44 ¿tg/ml 1 h after this second injection. The half-life of the antibiotic in the patients with normal renal function was 172-2 h. In the two patients with moderate renal insufficiency, expressed by creatinin clearance between 40 and 60ml/min, the levels of fosfomycin reached 28-64 pg/m[ in the first hour and maintained levels of 2432 /rg/inl after 6 h and 8-14 //g/ml after 24 h. In one of the patients with serious renal insufficiency, creatinin clearance of only 3 ml/min, creatinin in blood of 7 mg% and 230 mg#/o of urea, the levels of fosfomycin reached 92 ng/ml after 2 h, 20 ¿¿g/ml after 16 h, and 8 f i g / ml after 24 h. The half-life of the antibiotic was extended to 6 h in the cases of moder ate renal insufficiency and 12 h in the case of severe renal insufficiency. The concentration of fosfomycin in urine oscillated between 480 and 3,200 jUg/ml in the patients with normal renal function or moderate renal insufficiency. In the patient with severe renal insufficiency the level in ur ine remained constant during the first 16 h at less than 100 ,ttg/ml. Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Total
carbenicillin
E. coli 23 Klebsiella sp. 6 Enterobacterae 2 P. mirabilis 8 P. rettgeri 6 1 P. vulgaris 1 P. morganii 4 Providence Ps. aeruginosa 13 Strep.faecalis 3
Antimicrobial agents
ampicillin
Organisms
Number of strains
Table III. In vitro sensitivity of the different strains isolated from 51 cases of urinary tract infections to fosfomycin and other antimicrobial agents
104
G obernado/O leza/S antos/R oman/P az/M ascaros/A lmela
Time, h
Fig. 1. Fosfomycin blood levels in seven patients, at different times after the intra muscular administration of 1 g of fosfomycin.----- = Normal renal function; ........= moderate renal insufficiency;-------- severe renal insufficiency.
Clinical Studies Of the 51 patients treated with fosfomycin (table IV), 39 (76%) were free of infection one week immediately after the treatment, a further 8 (16%) showed an improvement in their condition, and in 4 patients (8%) no change of their condition was apparent. Of the 39 patients initially cured, 7 (14%) were reinfected during the course of the next 4-6 weeks, and one could not be followed up. Thus a definite cure was obtained in 31 patients (61%) of the initial 51.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/14/2018 9:06:52 AM
Toxicity and Side Effects The drug in general was well tolerated. Seven patients complained of local pain after the intramuscular injection of the antibiotic. No alteration in hepatic or renal function was observed, nor was blood clotting affected. 21 of the patients treated exhibited an eosinophilia of 2-10% which is dif ficult to attribute to the antibiotic as this often appears during the normal evolution of the disease. One of the patients who was allergic to penicillin did not exhibit any alteration during the course of treatment with fosfo-
Fosfomycin in Treatment of Chronic Urinary Tract Infection
105
Table IV. Response of urinary tract infections to fosfomycin administration (51 cases) Response
Good Fair No response No control
Bacteriological initial 39 (76%) 2 (4%) 10 (20%)
delayed 31 (61%) 1
Clinical initial 39 (76%) 8 (16%) 4 (8%)
delayed 31 (61%) 1
mycin. In another patient, after one intramuscular injection of the antibiot ic, a gluteal abscess was formed but this responded favorably to local heat treatment without interrupting the administration of fosfomycin.
According to these results, it is apparent that fosfomycin is a useful antibiotic for the treatment of chronic urinary infections. The favorable response of 61% of the patients with a subsequent control of the infection is high for this type of urological condition caused by germs quite resist ant to antibiotics. However, for an exact evaluation, one must take into account the surgical solution of the urological problems with which the majority of the patients presented; this also favors the disappearance of the infection. A good correlation existed between the in vitro sensitivities of the germs and the subsequent clinical response, given that the MICs of the 15 strains that were not eradicated by the treatment (2 E. coli, 1 Enterobacter, 2 P. mirabilis, 3 P. rettgeri, 4 Providence and 3 Ps. aeruginosa) were of 256 /
