Journal of Antimicrobial Chemotherapy (1977) 3, 579-584
Studies on cinoxain 3. Concentrations of cinoxacin in serum, urine and tissues of urological patients
S. Colleen Department of Urology, University Hospital, S-221 85 Lund, Sweden K.-E. Andersson Department of Clinical Pharmacology, Institute of Pharmacology, University of Arhus, Dk-8000 Arhus C, Denmark and P.-A. Mardh Institute of Medical Microbiology, University of Lund, S-223 62 Lund, Sweden
The concentrations of cinoxacin in body fluids and tissues of the urinary tract were studied during a dose interval in 13 patients given 500 mg of the drug twice daily. There was a wide variation in the peak serum concentrations (2-8 to 28 ng/ml, mean 16-9 ug/ml); the highest concentrations were generally reached within 3 h of administration. A mean peak concentration of 766 ng/ml was found in urine, and the mean cumulative urinary excretion during a 12-h interval was 65%. In bladder and prostatic tissue, the concentrations of cinoxacin were lower than in serum. The concentrations in renal tissue showed a considerable variation, but were generally higher than those in serum. No clear relation was found between the concentrations in serum and renal tissue. Introduction Cinoxacin (compound 64716, Eli Lilly & Co) is a synthetic organic compound, chemically related to nalidixic acid. It has been shown to possess an antibacterial activity against the majority of Gram-negative bacterial species encounted in urinary tract infections (Wick, Preston, White & Gordee, 1973; Lumish & Norden, 1975; Kurtz & Turck, 1975; Giamarellou & Jackson, 1975; Jones & Fuchs, 1976; Mardh, Colleen & Andersson, 1977) and to be more active, when tested in vitro, than nalidixic acid. Data on the tissue distribution of cinoxacin in man are lacking. In the present study, the concentrations of cinoxacin in serum and urine of urological patients were determined during treatment. In addition, the concentrations were measured in homogenates of renal cortex and medulla, prostate, and bladder of patients subjected to renal resection, nephrectomy, transvesical prostatectomy, or total cystourethrectomy. 579
580
S. Colleen, K.-E. Andersson and P.-A. Mardh Materials and methods
Patients Nine male and four female patients, 32 to 75 years of age (mean 60 years), were studied. Five of the patients were admitted because of benign hyperplasia of the prostate, 4 with carcinoma of the kidney and one each with carcinomas of the renal pelvis, the ureter, and the bladder and one with nephrolithiasis. Informed consent was obtained. On the day of admission, red and white blood cell counts were performed, and the blood concentrations of haemoglobin, sodium, potassium, calcium, phosphate, creatinine, bilirubin, alkaline phosphatase, glutamine-transferase, aspartate-amino-transferase and alanine-amino-transferase were determined. These analyses were repeated every second day during the stay in the hospital. Treatment Treatment with 500 mg of cinoxacin was given twice daily to all 13 patients from 2 days before the elective surgery. In the 5 patients who underwent transversical prostatectomy (expected weight of prostatic adenomas exceeding 60 g), the treatment was continued until 2 days after the urethral catheter was removed. The removal was made 6 to 10 days after the surgery. In 2 patients, the antibiotic susceptibility pattern of the bacterial strains isolated from the catheter urine called for change in the chemotherapy. In the 8 patients who were subjected to renal surgery or cystourethrectomy, the treatment was continued after the post-operative ileus had subsided, i.e. within 2 to 7 days. Sampling schedule On the day before the opeiation, a blood specimen was taken immediately before the morning dose of cinoxacin was given. The patient was then also asked to empty the bladder and the urine was collected. After the intake of the drug, a blood specimen was drawn hourly during the first 3 h, and thereafter every second hour up to 12 h. The patients were asked to empty their bladders every third hour up to 12 h and the voided specimens were collected. Sera and urine were stored at —20°C until analysed. On the day of the operation, the patients received 500 mg of cinoxacin 4 h before the anaesthesia was given. A blood specimen was collected when the circulation to the tissue specimens was interrupted. At the prostatectomy, a tissue specimen from the bladder wall was excised in connection with the enucleation of the adenomas. Tissue specimens In 5 patients, about 1 g of the adenomatous prostatic tissue and of the urinary bladder was excised. The specimens were blotted with a dry towel, placed in sterile test tubes, which were stored at —20°C until used. In the remaining 7 patients, tissue specimens of about 1 g of macroscopically normal renal cortex as well as an entire pyramide were removed and handled in the same way. Determination of cinoxacin The concentrations of cinoxacin in body fluids and tissues were determined by a spectrophotofluorometric technique and by a bioassay using Escherichia coli as test organism.
Cinoxacin in body fluids and tissues
581
Results
Serum and urine concentrations of cinoxacin Although there was a considerable variation in the serum peak concentrations of cinoxacin (mean 16-9 ug/ml, range 2-4 to 28 ug/ml), the highest concentrations were generally reached within 3 h (mean 2-9 h, range 1 to 10 h) of administration (Figure 1). Except in a few cases, the highest concentrations of cinoxacin were found in the second urine specimen collected, i.e. collected 0 to 3 h after the intake of the drug. The mean peak concentration in these specimens was 763 ug/ml (range 235 to 1650 ug/ml). The cumulative urinary excretion of cinoxacin during the 12-h sampling period increased successively to a mean of 65%, ranging from 31 to 94%.
12
Figure 1. The concentrations (mean ±S.E.M., n=13) of cinoxacin in serum on the second day of treatment. At zero h, 500 mg cinoxacin was given orally.
Figure 2. The concentrations of cinoxacin in the bladder wall of 6 patients subjected to transvesical enucleation of prostatic adenomas. The values ( A) are paired with the simultaneous serum concentration (•) and related to the time of administration of the last dose (500 mg). The stippled area denotes the concentrations of cinoxacin in serum on the day before the operation.
Concentrations of cinoxacin in tissue specimens from the urinary tract Bladder. The concentrations of cinoxacin in the bladder of 6 patients (Figure 2) ranged from 0-79 to 4-10 ug/g tissue (mean 2-47 ug/g). This was 45 to 81 % (mean 71 %) of the concentration simultaneously found in serum.
582 S. Colleen, K.-E. Andersson and P.-A. Mardh Prostate. The cinoxacin concentrations in prostatic tissue (Figure 3) varied between 0-72 and 2-8 ug/g (mean 1-97 ug/g). In all cases, except one, this was below the concentration in the simultaneously obtained blood sample. The concentrations in prostatic tissue amounted to 32 ~ 107 % (mean 63 %) of the serum concentrations. Similar amounts of cinoxacin were found in the non-adenomatous tissue recovered from the specimen obtained at cystourethrectomy.
Figure 3. The concentrations of cinoxacin in adenomatous tissue of the prostate of 6 patients subjected to transvesical prostatectomy. The values (A) are paired with the simultaneous serum concentration (•) and related to the time of administration of the last dose (500 mg). The stippled area denotes the concentrations of cinoxacin in serum on the day before the operation.
12
Figure 4. The concentration of cinoxacin in renal cortex (A) and medulla (•) of 7 patients subjected to nephrectomy or renal resection. The values are paired with the simultaneous serum concentration (•) and related to the time of administration of the last dose (500 mg) of cinoxacin. The stippled area denotes the concentration of cinoxacin in serum on the day before the operation.
Renal tissue. The concentration of cinoxacin in renal tissue was found to vary considerably (Figure 4). The amounts in the renal cortex (0-95 to 21-26 ug/g, mean 815 ug/g) often differed from those obtained in the medulla (0-98 to 20-47 ug/g, mean 6-81 ug/g). The concentrations in serum, renal cortex and medulla for each patient are given in Figure 4. As can be seen, there was no clear relation between the concentrations in renal tissues and the simultaneously measured blood concentration.
Cinoxacin in body fluids and tissues
583
Side effects during cinoxacin treatment No side effects of the drug were recorded, nor were any drug-related abnormalities observed in any of the laboratory determinations.
Discussion The present study showed that cinoxacin was relatively rapidly absorbed from the gastrointestinal tract, the mean serum peak occurring 2-9 h after the administration. A low protein binding, 10% (Wick et al., 1973), will allow a high glomerular filtration rate, indicating cinoxacin's potential as a urinary tract chemotherapeutic. Although a low serum protein binding should give cinoxacin a high availability bactericidal effect in blood was rarely observed. The peak serum concentrations found in the present patients did not exceed the MIC for urinary tract pathogens, except for the most susceptible strains of genera belonging to the family Enterobacteriaceae (Mardh et al., 1946). Rapid penetration of biological barriers, i.e. tissue penetration, is facilitated by a high lipid solubility. In the patients of the present study, the concentrations of cinoxacin were found to be lower in specimens from the bladder, prostatic adenomas, and non-adenomatous prostatic tissue than in simultaneously obtained blood samples. Cinoxacin is a weak acid (pKa 4-7), and it is even in the non-dissociated state (at the physiological pH of blood) poorly water- and lipid-soluble. This may contribute to the low tissue concentrations of the drug. Although there is general agreement that bactericidal concentrations of an antibiotic in tissues as well as in urine are essential in the treatment of complicated urinary tract infections, i.e. in connection with obstructive uropathy, considerable disagreement exists as to the treatment of pyelonephritis without obstruction. Many authors (cf. Brumfitt & Reeves, 1969) strongly advocate high serum concentrations and presumably high tissue concentrations of antibiotics in non-obstructive pyelonephritis, a statement challenged by others (Stamey, Gowan & Pakmer, 1965; Turck, Ronald & Petersdorf, 1966; Stamey, Fair, Timothy, Miller & Minkara, 1974; Turck, 1975). Numerous studies prove that in the great majority of cases of non-obstructive acute pyelonephritis, the infection, although being located to the parenchyma, is eradicated by antibiotics or chemotherapeutics not giving bactericidal serum concentrations but extremely high concentrations in urine. The antimicrobial compounds considered in this connection are all efficiently excreted by the kidneys giving high urine concentrations compared with those obtained in serum. A passive diffusion from the tubuli or collecting system into the medulla, the main locus of the infection, has been suggested as an explanation of the therapeutic effect. However, many chemotherapeutics are weak acids, cinoxacin being no exception, and as such also supposed to be actively reabsorbed in the distal tubuli. This might account for tissue concentrations in the renal medulla exceeding those in serum. The presence of higher concentrations of such drugs in renal lymph, particularly when obtained from the renal medulla (Cockett, Roberts & Moore, 1966) than in serum seems to support such an assumption. It is difficult to achieve information of the tissue content of drugs in kidneys unless analysing renal lymph which is rarely possible in man. The variable content of urine and blood in renal tissue specimens will obscure the results when analysing tissue homogenates and probably accounts for the wide range in the observations in the present study.
584
S. Colleen, K.-E. Andersson and P.-A. Mardh
Very high concentrations of cinoxacin are achieved in the urine within few hours after oral administration of the drug, and the MICs for most urinary tract pathogens are exceeded (Mardh et ah, 1976). From a pharmacokinetic point of view cinoxacin fulfills several criteria favourable for urinary tract chemotherapeutics, i.e. rapid absorption, low toxicity, low protein binding, rapid renal excretion, and high urine concentrations. These findings together with an appropriate antibacterial spectrum seems to justify further clinical studies of cinoxacin. Acknowledgements This study was supported by grant no. B76-16X-4503 from the Swedish Medical Research Council. We wish to acknowledge the supply of cinoxacin from Eli Lilly and Company and also their support. References Brumfitt, W. & Reeves, D. S. Recent developments in the treatment of urinary tract infections. Journal of Infectious Diseases 120: 61-81 (1969). Cockett, A. T. K., Roberts, A. P. & Moore, R. Significance of antibacterial levels in the renal lymph during treatment for pyelonephritis. Journal of Urology 95: 164-8 (1966). Giamarellou, H. & Jackson, G. G. Antibacterial activity of cinoxacin in vitro. Antimicrobial Agents and Chemotherapy 7: 370-3 (1975). Jones, R. N. & Fuchs, P. C. In vitro antimicrobial activity of cinoxacin against 2968 clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 10: 146-9 (1976). Kurtz, S. & Turck, M. In vitro activity of cinoxacin, an organic acid antibacterial. Antimicrobial Agents and Chemotherapy 7: 370-3 (1975). Lumish, R. M. & Norden, C. W. Cinoxacin: in vitro antibacterial studies of a new synthetic organic acid. Antimicrobial Agents and Chemotherapy 7: 159-63 (1975). Mardh, P. A., Colleen, S. & Andersson, K.-E. Studies on cinoxacin. 1. In vitro activity of cinoxacin, as compared to nalidixic acid, against urinary tract pathogens. Journal of Antimicrobial Chemotherapy. 3 : 411-6 (1977). Stanley, T., Fair, W. R., Timothy, M. M., Miller, M. A. & Minkara, G. Serum versus urinary antimicrobial concentration and urinary tract infections. New England Journal of Medicine 291: 1159-63(1974). Stamey, T., Govan, D. E. & Pakmer, J. M. The localization and treatment of urinary tract infections. The role of bactericidal urine levels as opposed to serum levels. Medicine 44: 1-36 (1965). Turck, M. Therapeutic guidelines in the management of urinary tract infections and pyelonephritis. Urological Clinics of North America 2: 443-50 (1975). Turck, M., Ronald, A. R. & R. G. Petersdorf. Susceptibility of Enterobacteriaceae to nitrofurantoin correlated with eradication of bacteriuria. Antimicrobial Agents and Chemotherapy 6: 446-52 (1966). Wick, W. E., Preston, D. A., White, W. A. & Gordee, R. S. Compound 64716, a new synthetic antibacterial agent. Antimicrobial Agents and Chemotherapy 4: 415-20 (1973). (Manuscript accepted 5 April 1977)
Studies on cinoxain 3. Concentrations of cinoxacin in serum, urine and tissues of urological patients
S. Colleen Department of Urology, University Hospital, S-221 85 Lund, Sweden K.-E. Andersson Department of Clinical Pharmacology, Institute of Pharmacology, University of Arhus, Dk-8000 Arhus C, Denmark and P.-A. Mardh Institute of Medical Microbiology, University of Lund, S-223 62 Lund, Sweden
The concentrations of cinoxacin in body fluids and tissues of the urinary tract were studied during a dose interval in 13 patients given 500 mg of the drug twice daily. There was a wide variation in the peak serum concentrations (2-8 to 28 ng/ml, mean 16-9 ug/ml); the highest concentrations were generally reached within 3 h of administration. A mean peak concentration of 766 ng/ml was found in urine, and the mean cumulative urinary excretion during a 12-h interval was 65%. In bladder and prostatic tissue, the concentrations of cinoxacin were lower than in serum. The concentrations in renal tissue showed a considerable variation, but were generally higher than those in serum. No clear relation was found between the concentrations in serum and renal tissue. Introduction Cinoxacin (compound 64716, Eli Lilly & Co) is a synthetic organic compound, chemically related to nalidixic acid. It has been shown to possess an antibacterial activity against the majority of Gram-negative bacterial species encounted in urinary tract infections (Wick, Preston, White & Gordee, 1973; Lumish & Norden, 1975; Kurtz & Turck, 1975; Giamarellou & Jackson, 1975; Jones & Fuchs, 1976; Mardh, Colleen & Andersson, 1977) and to be more active, when tested in vitro, than nalidixic acid. Data on the tissue distribution of cinoxacin in man are lacking. In the present study, the concentrations of cinoxacin in serum and urine of urological patients were determined during treatment. In addition, the concentrations were measured in homogenates of renal cortex and medulla, prostate, and bladder of patients subjected to renal resection, nephrectomy, transvesical prostatectomy, or total cystourethrectomy. 579
580
S. Colleen, K.-E. Andersson and P.-A. Mardh Materials and methods
Patients Nine male and four female patients, 32 to 75 years of age (mean 60 years), were studied. Five of the patients were admitted because of benign hyperplasia of the prostate, 4 with carcinoma of the kidney and one each with carcinomas of the renal pelvis, the ureter, and the bladder and one with nephrolithiasis. Informed consent was obtained. On the day of admission, red and white blood cell counts were performed, and the blood concentrations of haemoglobin, sodium, potassium, calcium, phosphate, creatinine, bilirubin, alkaline phosphatase, glutamine-transferase, aspartate-amino-transferase and alanine-amino-transferase were determined. These analyses were repeated every second day during the stay in the hospital. Treatment Treatment with 500 mg of cinoxacin was given twice daily to all 13 patients from 2 days before the elective surgery. In the 5 patients who underwent transversical prostatectomy (expected weight of prostatic adenomas exceeding 60 g), the treatment was continued until 2 days after the urethral catheter was removed. The removal was made 6 to 10 days after the surgery. In 2 patients, the antibiotic susceptibility pattern of the bacterial strains isolated from the catheter urine called for change in the chemotherapy. In the 8 patients who were subjected to renal surgery or cystourethrectomy, the treatment was continued after the post-operative ileus had subsided, i.e. within 2 to 7 days. Sampling schedule On the day before the opeiation, a blood specimen was taken immediately before the morning dose of cinoxacin was given. The patient was then also asked to empty the bladder and the urine was collected. After the intake of the drug, a blood specimen was drawn hourly during the first 3 h, and thereafter every second hour up to 12 h. The patients were asked to empty their bladders every third hour up to 12 h and the voided specimens were collected. Sera and urine were stored at —20°C until analysed. On the day of the operation, the patients received 500 mg of cinoxacin 4 h before the anaesthesia was given. A blood specimen was collected when the circulation to the tissue specimens was interrupted. At the prostatectomy, a tissue specimen from the bladder wall was excised in connection with the enucleation of the adenomas. Tissue specimens In 5 patients, about 1 g of the adenomatous prostatic tissue and of the urinary bladder was excised. The specimens were blotted with a dry towel, placed in sterile test tubes, which were stored at —20°C until used. In the remaining 7 patients, tissue specimens of about 1 g of macroscopically normal renal cortex as well as an entire pyramide were removed and handled in the same way. Determination of cinoxacin The concentrations of cinoxacin in body fluids and tissues were determined by a spectrophotofluorometric technique and by a bioassay using Escherichia coli as test organism.
Cinoxacin in body fluids and tissues
581
Results
Serum and urine concentrations of cinoxacin Although there was a considerable variation in the serum peak concentrations of cinoxacin (mean 16-9 ug/ml, range 2-4 to 28 ug/ml), the highest concentrations were generally reached within 3 h (mean 2-9 h, range 1 to 10 h) of administration (Figure 1). Except in a few cases, the highest concentrations of cinoxacin were found in the second urine specimen collected, i.e. collected 0 to 3 h after the intake of the drug. The mean peak concentration in these specimens was 763 ug/ml (range 235 to 1650 ug/ml). The cumulative urinary excretion of cinoxacin during the 12-h sampling period increased successively to a mean of 65%, ranging from 31 to 94%.
12
Figure 1. The concentrations (mean ±S.E.M., n=13) of cinoxacin in serum on the second day of treatment. At zero h, 500 mg cinoxacin was given orally.
Figure 2. The concentrations of cinoxacin in the bladder wall of 6 patients subjected to transvesical enucleation of prostatic adenomas. The values ( A) are paired with the simultaneous serum concentration (•) and related to the time of administration of the last dose (500 mg). The stippled area denotes the concentrations of cinoxacin in serum on the day before the operation.
Concentrations of cinoxacin in tissue specimens from the urinary tract Bladder. The concentrations of cinoxacin in the bladder of 6 patients (Figure 2) ranged from 0-79 to 4-10 ug/g tissue (mean 2-47 ug/g). This was 45 to 81 % (mean 71 %) of the concentration simultaneously found in serum.
582 S. Colleen, K.-E. Andersson and P.-A. Mardh Prostate. The cinoxacin concentrations in prostatic tissue (Figure 3) varied between 0-72 and 2-8 ug/g (mean 1-97 ug/g). In all cases, except one, this was below the concentration in the simultaneously obtained blood sample. The concentrations in prostatic tissue amounted to 32 ~ 107 % (mean 63 %) of the serum concentrations. Similar amounts of cinoxacin were found in the non-adenomatous tissue recovered from the specimen obtained at cystourethrectomy.
Figure 3. The concentrations of cinoxacin in adenomatous tissue of the prostate of 6 patients subjected to transvesical prostatectomy. The values (A) are paired with the simultaneous serum concentration (•) and related to the time of administration of the last dose (500 mg). The stippled area denotes the concentrations of cinoxacin in serum on the day before the operation.
12
Figure 4. The concentration of cinoxacin in renal cortex (A) and medulla (•) of 7 patients subjected to nephrectomy or renal resection. The values are paired with the simultaneous serum concentration (•) and related to the time of administration of the last dose (500 mg) of cinoxacin. The stippled area denotes the concentration of cinoxacin in serum on the day before the operation.
Renal tissue. The concentration of cinoxacin in renal tissue was found to vary considerably (Figure 4). The amounts in the renal cortex (0-95 to 21-26 ug/g, mean 815 ug/g) often differed from those obtained in the medulla (0-98 to 20-47 ug/g, mean 6-81 ug/g). The concentrations in serum, renal cortex and medulla for each patient are given in Figure 4. As can be seen, there was no clear relation between the concentrations in renal tissues and the simultaneously measured blood concentration.
Cinoxacin in body fluids and tissues
583
Side effects during cinoxacin treatment No side effects of the drug were recorded, nor were any drug-related abnormalities observed in any of the laboratory determinations.
Discussion The present study showed that cinoxacin was relatively rapidly absorbed from the gastrointestinal tract, the mean serum peak occurring 2-9 h after the administration. A low protein binding, 10% (Wick et al., 1973), will allow a high glomerular filtration rate, indicating cinoxacin's potential as a urinary tract chemotherapeutic. Although a low serum protein binding should give cinoxacin a high availability bactericidal effect in blood was rarely observed. The peak serum concentrations found in the present patients did not exceed the MIC for urinary tract pathogens, except for the most susceptible strains of genera belonging to the family Enterobacteriaceae (Mardh et al., 1946). Rapid penetration of biological barriers, i.e. tissue penetration, is facilitated by a high lipid solubility. In the patients of the present study, the concentrations of cinoxacin were found to be lower in specimens from the bladder, prostatic adenomas, and non-adenomatous prostatic tissue than in simultaneously obtained blood samples. Cinoxacin is a weak acid (pKa 4-7), and it is even in the non-dissociated state (at the physiological pH of blood) poorly water- and lipid-soluble. This may contribute to the low tissue concentrations of the drug. Although there is general agreement that bactericidal concentrations of an antibiotic in tissues as well as in urine are essential in the treatment of complicated urinary tract infections, i.e. in connection with obstructive uropathy, considerable disagreement exists as to the treatment of pyelonephritis without obstruction. Many authors (cf. Brumfitt & Reeves, 1969) strongly advocate high serum concentrations and presumably high tissue concentrations of antibiotics in non-obstructive pyelonephritis, a statement challenged by others (Stamey, Gowan & Pakmer, 1965; Turck, Ronald & Petersdorf, 1966; Stamey, Fair, Timothy, Miller & Minkara, 1974; Turck, 1975). Numerous studies prove that in the great majority of cases of non-obstructive acute pyelonephritis, the infection, although being located to the parenchyma, is eradicated by antibiotics or chemotherapeutics not giving bactericidal serum concentrations but extremely high concentrations in urine. The antimicrobial compounds considered in this connection are all efficiently excreted by the kidneys giving high urine concentrations compared with those obtained in serum. A passive diffusion from the tubuli or collecting system into the medulla, the main locus of the infection, has been suggested as an explanation of the therapeutic effect. However, many chemotherapeutics are weak acids, cinoxacin being no exception, and as such also supposed to be actively reabsorbed in the distal tubuli. This might account for tissue concentrations in the renal medulla exceeding those in serum. The presence of higher concentrations of such drugs in renal lymph, particularly when obtained from the renal medulla (Cockett, Roberts & Moore, 1966) than in serum seems to support such an assumption. It is difficult to achieve information of the tissue content of drugs in kidneys unless analysing renal lymph which is rarely possible in man. The variable content of urine and blood in renal tissue specimens will obscure the results when analysing tissue homogenates and probably accounts for the wide range in the observations in the present study.
584
S. Colleen, K.-E. Andersson and P.-A. Mardh
Very high concentrations of cinoxacin are achieved in the urine within few hours after oral administration of the drug, and the MICs for most urinary tract pathogens are exceeded (Mardh et ah, 1976). From a pharmacokinetic point of view cinoxacin fulfills several criteria favourable for urinary tract chemotherapeutics, i.e. rapid absorption, low toxicity, low protein binding, rapid renal excretion, and high urine concentrations. These findings together with an appropriate antibacterial spectrum seems to justify further clinical studies of cinoxacin. Acknowledgements This study was supported by grant no. B76-16X-4503 from the Swedish Medical Research Council. We wish to acknowledge the supply of cinoxacin from Eli Lilly and Company and also their support. References Brumfitt, W. & Reeves, D. S. Recent developments in the treatment of urinary tract infections. Journal of Infectious Diseases 120: 61-81 (1969). Cockett, A. T. K., Roberts, A. P. & Moore, R. Significance of antibacterial levels in the renal lymph during treatment for pyelonephritis. Journal of Urology 95: 164-8 (1966). Giamarellou, H. & Jackson, G. G. Antibacterial activity of cinoxacin in vitro. Antimicrobial Agents and Chemotherapy 7: 370-3 (1975). Jones, R. N. & Fuchs, P. C. In vitro antimicrobial activity of cinoxacin against 2968 clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 10: 146-9 (1976). Kurtz, S. & Turck, M. In vitro activity of cinoxacin, an organic acid antibacterial. Antimicrobial Agents and Chemotherapy 7: 370-3 (1975). Lumish, R. M. & Norden, C. W. Cinoxacin: in vitro antibacterial studies of a new synthetic organic acid. Antimicrobial Agents and Chemotherapy 7: 159-63 (1975). Mardh, P. A., Colleen, S. & Andersson, K.-E. Studies on cinoxacin. 1. In vitro activity of cinoxacin, as compared to nalidixic acid, against urinary tract pathogens. Journal of Antimicrobial Chemotherapy. 3 : 411-6 (1977). Stanley, T., Fair, W. R., Timothy, M. M., Miller, M. A. & Minkara, G. Serum versus urinary antimicrobial concentration and urinary tract infections. New England Journal of Medicine 291: 1159-63(1974). Stamey, T., Govan, D. E. & Pakmer, J. M. The localization and treatment of urinary tract infections. The role of bactericidal urine levels as opposed to serum levels. Medicine 44: 1-36 (1965). Turck, M. Therapeutic guidelines in the management of urinary tract infections and pyelonephritis. Urological Clinics of North America 2: 443-50 (1975). Turck, M., Ronald, A. R. & R. G. Petersdorf. Susceptibility of Enterobacteriaceae to nitrofurantoin correlated with eradication of bacteriuria. Antimicrobial Agents and Chemotherapy 6: 446-52 (1966). Wick, W. E., Preston, D. A., White, W. A. & Gordee, R. S. Compound 64716, a new synthetic antibacterial agent. Antimicrobial Agents and Chemotherapy 4: 415-20 (1973). (Manuscript accepted 5 April 1977)
