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Neggram (Nalidixic Acid) in the Treatment of Urinary Infections
THE JOURNAL OF UROLOGY
Vol. 92, No. 5 November 1964 Copyright © 1964 by The Williams & Wilkins Co. Printed in U.S.A.
NEGGRAl\/I (NALIDIXIC ACID) IN THE TREATMENT OF URINARY INFECTIONS AHMAD AKBARI, JOSEPH N. WARD, MORRIS M. HILF, RUSSELL W. LAVENGOOD AND JOHN w. DRAPER From the Department of Surgery (Urology), Cornell University Division, Bellevue Hospital, New York, New York
In recent years a host of antibiotics and chemotherapeutic agents have been introduced for the treatment of urinary tract infections. In the managern.ent of acute infections, great success has been achieved. However, in eradicating or controlling the chronic infections, the clinicians frequently face a difficult and frustrating task. The untoward effects of some antibacterial agents and the rapidly increasing numbers of drug-resistant organisms stimulate the search for more effective and safer means of combating these infections.
as a monoglucuronide, and a considerable fraction is excreted as the 7-hydromethyl metabolite (both free and conjugated). Of single or repeated oral doses of negGram, about 80 per cent is recovered from the urine as definitely characterized products; fecal excretion is obviously of minor importance, although the drug does appear in the bile." "When studied in dogs and monkeys following long-term (more than 1 year) administration at high dose level, negGram has been found to have little tendency to accumulate in the tissues, with practically all tissues having lower concentration than those existing concomitantly in the plasma. The highest tissue concentration for both species was found in kidney, and the lowest in brain and fat." "The drug is well absorbed from the gastrointestinal tract. N onnal human volunteer subjects4 have shown excellent tolerance to daily oral medication with nalidixic acid for up to 180 successive days. The maximum sustained close level was 8 gm. a day. Rhesus monkeys showed good tolerance to daily oral medication with 25, 75, or 225 mg./kg. a day administered 316 times during 375 days. Single oral closes as high as 900 rn.g./kg. produced no evidence of toxicity in monkeys."
]V[ATERIAL
Nalidixic acid, negGram*, (1 ethyl-7-methyl1,8-naphthyridin-4-one-3 carbo)s.-ylic acid) is a newly developed naphthyridine derivative with the following structural formula :1 0
~COOH CH,~ N
N
I
CH,CH,
It is a pale yellow, crystalline substance with low solubility in water and ready solubility in dilute alkali. The drug is mostly effective against gram-negative organisms. 2 According to McChesney and associates: 3 "It is rapidly excreted in the urine by man, partly in a free (extractable, biologically detectable) form, but a much larger fraction is apparently excreted
CASE ]V[ATERIAL
Accepted for publication March 17, 1964. * Winthrop Laboratories, New York 18, New York. 1 Lesher, G. Y., Froelich, E. J., Gruett, M. D., Bailey, J. H. and Brundage, R. P.: 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J.Med. Pharm. Chem., 5: 1063-1065, 1962.
2 Deitz, W. H., Froelich, E. J. and Bailey, J. H.: The in-vitro antibacterial activity of nalidixic acid, a new drug active against gram-negative organisms. Sterling Winthrop Research Institute,
One hundred patients were treated with nalidixic acid. There were 27 women and 73 men, varying in age from 16 to 89 years, the majority between the fifth and sixth decades of life. Fortyeight of them were in-patients and 52 were outpatients. Nine patients were suffering from acute infections and the remainder had clffonic urinary infections. The latter cases had received som.e kind of antibacterial agent (or agents) in the past. Those with B. proteus, in particular, had all 4 A revised summary of laboratory and clinical tolerance data on Win 18,320, a new urinary antiseptic and chemotherapeutic agent for treatment of gram-negative infections. Department of Medical Research, Winthrop Laboratories, New York, N. Y., February 7, 1962.
N. Y., 1962.
3 McChesney, E. W. and others: Biochemical studies of nalidixic acid, a systemic antibacterial compound. To be published.
552
553
NEGGRAM IN TREATMENT OF URINARY INFECTIONS
failed to respond to the previous treatments and their organisms were resistant to the ordinary anti-infectious agents. More than two-thirds of the cases had some impairment of renal function. Fifteen patients had blood urea nitrogen (BUN) of 25 to 30 mg. per cent, and 12 patients had 40 to 45 mg. per cent. Eight patients had indwelling catheters: urethral, suprapubic or nephrostomy. Eighteen patients were suffering fron, prostatitis. There were 45 cases with chronic lower urinary tract infections, which included cystitis, urethritis or a combination of both. Twenty-five cases had chronic pyelonephritis, plus five with calculi.
Gram-negative organisms: Bacteriological results in 100 patients treated with negGram
TA:3LE 1.
Result Total
Organism
] 8
'8
"'
l'" P.
~
~
V1
] ~ ~
I
Newly Emerged
~
- - - - --- ~-
Proteus species ... Escherichia coli. Aerobacter aerogenes. Pseudomonas aeruginosa .
44 33
35 20
1 1
5
3
8
4
21
5
2
12
2
15
5
1
6
;3
METHOD OF CLINICAL STUDY
Each patient had a weekly blood cell count, blood urea nitrogen determination, urinalysis, urine culture and sensitivity test, and the majority had a bacterial colony count. Forty-three patients had cephalin cholesterol flocculation test, 21 an alkaline phosphatase, and 13 a prothrombin time determination. All of the patients had excretory urogram and panendoscopic examination prior to negGram therapy. In 54 cases, 2 gm. negGram was given as the initial dose and 1 gm., 4 times daily thereafter for 2 weeks; in 19 patients the same amount of the drug was given for 1 week. Twenty-seven patients were given only 0.5 gm. 4 times daily, for a period of 3 weeks or more. Among the latter patients there were three who were treated for a period of 3, 5, and 6 months respectively before their urine cultures became negative. They had Proteus species in their urine which were resistant to all the common antibacterial agents and sensitive to negGram. METHOD OF LABORATORY STUDY
In the men, midstream urinary specimens were obtained. In the women and those men who were unable to void, specimens were collected by catheterization. The presence of five or more white blood cells per high power field of uncentrifuged urine was considered as evidence of pyuria. For bacterial colony count, 0.1 cc urine was seeded onto blood agar plates. 5 If, on microscopic examination, the urine showed too many bacteria, it was then appropriately diluted for culturing. Part of the urine was centrifuged, de5 Sierp, M. and Draper, J. W.: The bacteriological evaluation of 2, 4-dimethoxy-6-sulfanilamido-l, 3-diazine (madribon®J in various urological disorders associated with urinary tract infection. Ann. N. Y. Acad. Sci., 82: 92-104, 1959.
* Organism considered suppressed when at least tenfold reducti0n in final colony count as compared with initial count.
canted, and inoculated into the various broth media for identification of the organisms. On the following day, disk-sensitivity tests for negGram and the common antibacterial agents were performed. The organism was considered eradicated if it did not grow in the final culture, suppressed if there was at least 10-fold reduction in the colony count, and persistent when the last colony count did not show such a reduction. 5 • 6 COMPLICATIONS
There were 6 cases of skin rashes, two severe enough to warrant discontinuing the treatment. One of these patients was sensitive to many other drugs. Six patients suffered mild nausea during their complete course of therapy. In 1 case there was a moderate, temporary fall in the white blood cell count which we are of the opinion probably was related to cobalt therapy given prior to and during administration of negGram. One case with a colostomy had diarrhea after 3 of therapy. This patient had a previous hi,tory of several episodes of diarrhea. No significant changes in blood urea nitrogen, liver function tests, or prothrombin time (when performed) were noted. RESUUIB
Bacteriological results. There were 53 infections with single organisms, 31 with two, and 16 with three. 6 Kass, E. H.: Chemotherapeutic and antibiotic drugs in the management of infections of the urinary tract. Amer. J. Med., 18: 764, 1955.
554
AKBARI AND ASSOCIATES TABLE
2. Gram-positive organisms: Bacteriological results Result Total
Organism
Staphylococcus aureus (coagulase negative) Staphylococcus aureus (coagulase positive) Staphylococcus albus Streptococci (beta & gamma)
13 2 3 15
Eradicated
Suppressed*
Persisted
Newly Emerged
2
0 0
8 0 2 8
3 2 0 5
0
1 2
0 0
* Organism considered suppressed when at least tenfold reduction in final colony count as compared with initial count. TABLE
3. Clinical results-100 patients Total Cured
Improved
Unimproved
-- -- --- ---
Pyelonephritis Acute ..... ........ Chronic. ... Chronic with stones. Lower tract infections Acute. .... . . . . . . . . . Chronic. ..... . . . . . . Prostatitis ... . . . . . Acute. Chronic-. . . . . .......
1 24 5 7 45
I
1 12 1
0 0 8 (2)* 4 (2)* 2 (1) * 2 (1 )*
7 29
0 9
1 I 1
17
9
0 7 (2)*
0
0
4
4
-------100
60
23
17
* Cases with indwelling catheter.
Among 44 cases with Proteus infections, 35 (79.5 per cent) were eradicated, 1 suppressed, 5 persisted, and 3 newly emerged. Twenty of 33 infections (60.6 per cent) of Escherichia coli were eradicated, 1 suppressed, 8 persisted, and 4 newly emerged. Pseudomonas aeruginosa was eradicated in 5 instances (33.3 per cent), 1 suppressed, 6 persisted, and 3 newly emerged. In 21 cases of Aerobacter aerogenes, 5 (23.8 per cent) were eradicated, 2 suppressed, 12 persisted, and 2 newly emerged (table 1). Among the gTam-positive organisms, we found none to be sensitive to the drug in vitro. However, in vivo, 2 cases of streptococci, 2 cases of Staphylococcus aureus (coagulase negative), and 1 Staphylococcus albus were eradicated by negGram (table 2). The emergence occurred with streptococci (5 cases), E. coli (4 cases), Ps. aeruginosa (3 cases) and Staph. aureus (coagulase negative) (3 cases) (tables 1 and 2). In this study we considered an organism with a colony count above 100,000 as a pathogen.
Clinical results. Clinically, the results of treatment were considered excellent when there was complete disappearance of the symptoms, improved when the symptoms were markedly decreased, and unimproved if the symptoms persisted. Table 3 shows the details of the clinical results. Sixty cases, including all acute infections, had excellent results. Among 17 unimproved cases, five had indwelling catheters. DISCUSSION
Except in 9 cases of acute infections, all patients in this study had been previously exposed to various antibacterial agents. The majority of their organisms were found resistant to the usual drugs and, therefore, the bacteriological results obtained by negGram therapy were encouraging. Minimal side effects are also worthy of consideration. However, a more definitive and fair evaluation of the drug must include long-range followup study of the patients whose organisms were eradicated, in order to detect the incidence of recurrence and possible late complications. It should also be tried in patients with ordinary infections and not solely in the resistant and complicated types. As with other antimicrobial agents, the presence of an indwelling catheter or calculi makes sterilization of urine with negGram difficult. SUMMARY
The results of the treatment with negGram, a new antibacterial agent, in 9 cases of acute urinary infections and 91 cases of chronic and complicated patients are reported. The best bacterial results were obtained against Proteus species. In this group, 35 (79.5 per cent) of the cases had excellent results. Side effects were minimal.
Vol. 92, No. 5 November 1964 Copyright © 1964 by The Williams & Wilkins Co. Printed in U.S.A.
NEGGRAl\/I (NALIDIXIC ACID) IN THE TREATMENT OF URINARY INFECTIONS AHMAD AKBARI, JOSEPH N. WARD, MORRIS M. HILF, RUSSELL W. LAVENGOOD AND JOHN w. DRAPER From the Department of Surgery (Urology), Cornell University Division, Bellevue Hospital, New York, New York
In recent years a host of antibiotics and chemotherapeutic agents have been introduced for the treatment of urinary tract infections. In the managern.ent of acute infections, great success has been achieved. However, in eradicating or controlling the chronic infections, the clinicians frequently face a difficult and frustrating task. The untoward effects of some antibacterial agents and the rapidly increasing numbers of drug-resistant organisms stimulate the search for more effective and safer means of combating these infections.
as a monoglucuronide, and a considerable fraction is excreted as the 7-hydromethyl metabolite (both free and conjugated). Of single or repeated oral doses of negGram, about 80 per cent is recovered from the urine as definitely characterized products; fecal excretion is obviously of minor importance, although the drug does appear in the bile." "When studied in dogs and monkeys following long-term (more than 1 year) administration at high dose level, negGram has been found to have little tendency to accumulate in the tissues, with practically all tissues having lower concentration than those existing concomitantly in the plasma. The highest tissue concentration for both species was found in kidney, and the lowest in brain and fat." "The drug is well absorbed from the gastrointestinal tract. N onnal human volunteer subjects4 have shown excellent tolerance to daily oral medication with nalidixic acid for up to 180 successive days. The maximum sustained close level was 8 gm. a day. Rhesus monkeys showed good tolerance to daily oral medication with 25, 75, or 225 mg./kg. a day administered 316 times during 375 days. Single oral closes as high as 900 rn.g./kg. produced no evidence of toxicity in monkeys."
]V[ATERIAL
Nalidixic acid, negGram*, (1 ethyl-7-methyl1,8-naphthyridin-4-one-3 carbo)s.-ylic acid) is a newly developed naphthyridine derivative with the following structural formula :1 0
~COOH CH,~ N
N
I
CH,CH,
It is a pale yellow, crystalline substance with low solubility in water and ready solubility in dilute alkali. The drug is mostly effective against gram-negative organisms. 2 According to McChesney and associates: 3 "It is rapidly excreted in the urine by man, partly in a free (extractable, biologically detectable) form, but a much larger fraction is apparently excreted
CASE ]V[ATERIAL
Accepted for publication March 17, 1964. * Winthrop Laboratories, New York 18, New York. 1 Lesher, G. Y., Froelich, E. J., Gruett, M. D., Bailey, J. H. and Brundage, R. P.: 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J.Med. Pharm. Chem., 5: 1063-1065, 1962.
2 Deitz, W. H., Froelich, E. J. and Bailey, J. H.: The in-vitro antibacterial activity of nalidixic acid, a new drug active against gram-negative organisms. Sterling Winthrop Research Institute,
One hundred patients were treated with nalidixic acid. There were 27 women and 73 men, varying in age from 16 to 89 years, the majority between the fifth and sixth decades of life. Fortyeight of them were in-patients and 52 were outpatients. Nine patients were suffering from acute infections and the remainder had clffonic urinary infections. The latter cases had received som.e kind of antibacterial agent (or agents) in the past. Those with B. proteus, in particular, had all 4 A revised summary of laboratory and clinical tolerance data on Win 18,320, a new urinary antiseptic and chemotherapeutic agent for treatment of gram-negative infections. Department of Medical Research, Winthrop Laboratories, New York, N. Y., February 7, 1962.
N. Y., 1962.
3 McChesney, E. W. and others: Biochemical studies of nalidixic acid, a systemic antibacterial compound. To be published.
552
553
NEGGRAM IN TREATMENT OF URINARY INFECTIONS
failed to respond to the previous treatments and their organisms were resistant to the ordinary anti-infectious agents. More than two-thirds of the cases had some impairment of renal function. Fifteen patients had blood urea nitrogen (BUN) of 25 to 30 mg. per cent, and 12 patients had 40 to 45 mg. per cent. Eight patients had indwelling catheters: urethral, suprapubic or nephrostomy. Eighteen patients were suffering fron, prostatitis. There were 45 cases with chronic lower urinary tract infections, which included cystitis, urethritis or a combination of both. Twenty-five cases had chronic pyelonephritis, plus five with calculi.
Gram-negative organisms: Bacteriological results in 100 patients treated with negGram
TA:3LE 1.
Result Total
Organism
] 8
'8
"'
l'" P.
~
~
V1
] ~ ~
I
Newly Emerged
~
- - - - --- ~-
Proteus species ... Escherichia coli. Aerobacter aerogenes. Pseudomonas aeruginosa .
44 33
35 20
1 1
5
3
8
4
21
5
2
12
2
15
5
1
6
;3
METHOD OF CLINICAL STUDY
Each patient had a weekly blood cell count, blood urea nitrogen determination, urinalysis, urine culture and sensitivity test, and the majority had a bacterial colony count. Forty-three patients had cephalin cholesterol flocculation test, 21 an alkaline phosphatase, and 13 a prothrombin time determination. All of the patients had excretory urogram and panendoscopic examination prior to negGram therapy. In 54 cases, 2 gm. negGram was given as the initial dose and 1 gm., 4 times daily thereafter for 2 weeks; in 19 patients the same amount of the drug was given for 1 week. Twenty-seven patients were given only 0.5 gm. 4 times daily, for a period of 3 weeks or more. Among the latter patients there were three who were treated for a period of 3, 5, and 6 months respectively before their urine cultures became negative. They had Proteus species in their urine which were resistant to all the common antibacterial agents and sensitive to negGram. METHOD OF LABORATORY STUDY
In the men, midstream urinary specimens were obtained. In the women and those men who were unable to void, specimens were collected by catheterization. The presence of five or more white blood cells per high power field of uncentrifuged urine was considered as evidence of pyuria. For bacterial colony count, 0.1 cc urine was seeded onto blood agar plates. 5 If, on microscopic examination, the urine showed too many bacteria, it was then appropriately diluted for culturing. Part of the urine was centrifuged, de5 Sierp, M. and Draper, J. W.: The bacteriological evaluation of 2, 4-dimethoxy-6-sulfanilamido-l, 3-diazine (madribon®J in various urological disorders associated with urinary tract infection. Ann. N. Y. Acad. Sci., 82: 92-104, 1959.
* Organism considered suppressed when at least tenfold reducti0n in final colony count as compared with initial count.
canted, and inoculated into the various broth media for identification of the organisms. On the following day, disk-sensitivity tests for negGram and the common antibacterial agents were performed. The organism was considered eradicated if it did not grow in the final culture, suppressed if there was at least 10-fold reduction in the colony count, and persistent when the last colony count did not show such a reduction. 5 • 6 COMPLICATIONS
There were 6 cases of skin rashes, two severe enough to warrant discontinuing the treatment. One of these patients was sensitive to many other drugs. Six patients suffered mild nausea during their complete course of therapy. In 1 case there was a moderate, temporary fall in the white blood cell count which we are of the opinion probably was related to cobalt therapy given prior to and during administration of negGram. One case with a colostomy had diarrhea after 3 of therapy. This patient had a previous hi,tory of several episodes of diarrhea. No significant changes in blood urea nitrogen, liver function tests, or prothrombin time (when performed) were noted. RESUUIB
Bacteriological results. There were 53 infections with single organisms, 31 with two, and 16 with three. 6 Kass, E. H.: Chemotherapeutic and antibiotic drugs in the management of infections of the urinary tract. Amer. J. Med., 18: 764, 1955.
554
AKBARI AND ASSOCIATES TABLE
2. Gram-positive organisms: Bacteriological results Result Total
Organism
Staphylococcus aureus (coagulase negative) Staphylococcus aureus (coagulase positive) Staphylococcus albus Streptococci (beta & gamma)
13 2 3 15
Eradicated
Suppressed*
Persisted
Newly Emerged
2
0 0
8 0 2 8
3 2 0 5
0
1 2
0 0
* Organism considered suppressed when at least tenfold reduction in final colony count as compared with initial count. TABLE
3. Clinical results-100 patients Total Cured
Improved
Unimproved
-- -- --- ---
Pyelonephritis Acute ..... ........ Chronic. ... Chronic with stones. Lower tract infections Acute. .... . . . . . . . . . Chronic. ..... . . . . . . Prostatitis ... . . . . . Acute. Chronic-. . . . . .......
1 24 5 7 45
I
1 12 1
0 0 8 (2)* 4 (2)* 2 (1) * 2 (1 )*
7 29
0 9
1 I 1
17
9
0 7 (2)*
0
0
4
4
-------100
60
23
17
* Cases with indwelling catheter.
Among 44 cases with Proteus infections, 35 (79.5 per cent) were eradicated, 1 suppressed, 5 persisted, and 3 newly emerged. Twenty of 33 infections (60.6 per cent) of Escherichia coli were eradicated, 1 suppressed, 8 persisted, and 4 newly emerged. Pseudomonas aeruginosa was eradicated in 5 instances (33.3 per cent), 1 suppressed, 6 persisted, and 3 newly emerged. In 21 cases of Aerobacter aerogenes, 5 (23.8 per cent) were eradicated, 2 suppressed, 12 persisted, and 2 newly emerged (table 1). Among the gTam-positive organisms, we found none to be sensitive to the drug in vitro. However, in vivo, 2 cases of streptococci, 2 cases of Staphylococcus aureus (coagulase negative), and 1 Staphylococcus albus were eradicated by negGram (table 2). The emergence occurred with streptococci (5 cases), E. coli (4 cases), Ps. aeruginosa (3 cases) and Staph. aureus (coagulase negative) (3 cases) (tables 1 and 2). In this study we considered an organism with a colony count above 100,000 as a pathogen.
Clinical results. Clinically, the results of treatment were considered excellent when there was complete disappearance of the symptoms, improved when the symptoms were markedly decreased, and unimproved if the symptoms persisted. Table 3 shows the details of the clinical results. Sixty cases, including all acute infections, had excellent results. Among 17 unimproved cases, five had indwelling catheters. DISCUSSION
Except in 9 cases of acute infections, all patients in this study had been previously exposed to various antibacterial agents. The majority of their organisms were found resistant to the usual drugs and, therefore, the bacteriological results obtained by negGram therapy were encouraging. Minimal side effects are also worthy of consideration. However, a more definitive and fair evaluation of the drug must include long-range followup study of the patients whose organisms were eradicated, in order to detect the incidence of recurrence and possible late complications. It should also be tried in patients with ordinary infections and not solely in the resistant and complicated types. As with other antimicrobial agents, the presence of an indwelling catheter or calculi makes sterilization of urine with negGram difficult. SUMMARY
The results of the treatment with negGram, a new antibacterial agent, in 9 cases of acute urinary infections and 91 cases of chronic and complicated patients are reported. The best bacterial results were obtained against Proteus species. In this group, 35 (79.5 per cent) of the cases had excellent results. Side effects were minimal.