Scot.

mel).

J., 1975 20: 248

CEPHAZOLIN TREATMENT OF PNEUMOCOCCAL PNEUMONIA AND URINARY TRACT INFECTIONS M. Kilpatrick, T. C. Cesario, L. Thrupp and J. G. Tilles University of California, Irvine, California

Summary. Ten cases ofpneumococcal pneumonia were treated with cephazolin 500 mg. q8h for at least 5 days. In every case therapy was accompanied by clinical improvement and eradication of the organism. Ten patients with E. coli bacteriuria (5 symptomatic) were treated with cephazolin 500 mg. q12h for 7 to 10 days. In every case the pathogen was eliminated during therapy but in one case bacteriologic relapse occurred following cessation of therapy. In 10 cases of bacteriuria caused by P. mirabilis, Klebsiella sp, Enterobacter, and Enterococcus, the urine became sterile during treatment, but relapse was common. Initial andfinal creatinine clearances obtained in 29 patients who received an average of 12.9 g. of cephazolin showed no tendency toward loss of renal function. Serial serum levels of cephazolin were determined following the first 500 mg. dose in 18 patients. The peak serum level occurred at one hour with a serum half life of approximately 2.2 hours. For 13 of these 18 patients serial serum levels were also obtained following the last dose of cephazolin. At this time the mean peak level occurred at 2 hours but again the serum half life was approximately 1.9 hours.

CEPHAZOLIN, a new derivative of 7aminocephalosporanic acid, is reported to have the following favourable qualities: remarkably high serum levels following intramuscular administration, prolonged serum half life, high potency in vitro against pyogenic Gram positive cocci of the upper respiratory tract as well; moderate potency in vitro against E coli and most Klebsiella, relatively good patient acceptability by intramuscular administration, and relatively little cross allergy with penicillin (Finland et al., 1973). Unfavourable qualities include high serum protein binding, poor in vitro activity against Pseudomonas, Serratia, and indole positive Proteus, considerable reduction of activity against high innocula of some bacteria in vitro, and lack of suitability for oral administration. The place of cephazolin as a 'broad spectrum' cephalosporin necessarily depends on the results of clinical efficacy studies. The following study was carried out in order to document the clinical efficacy, clinical pharmacology, and toxicology of cephazolin in acutely ill patients usually debilitated with other disease. Methods Population.

Patients

hospitalised

at

the

Orange County Medical Centre during the period December 1972 to January 1974, who denied antibiotic treatment during the previous 3 days were admitted to the study when meeting one of the following sets of criteria: Respiratory disease. Lower respiratory tract symptoms, fever, leucocytosis, and pulmonary infiltrate on X-ray plus a Gram stain of the sputum demonstrating polymorphonuclear leucocytes and a predominance of Gram positive cocci (19 patients). Urinary tract disease. Diagnosis of acute urinary tract infection on the basis of typical symptoms, fever, leucocytosis, and a positive Gram stain of the urine (15 patients) or asymptomatic bacteriuria with 2 or more consecutive urine cultures positive for the same single organism (6 patients). Soft tissue disease. Localized cellulitis and abscess accompanied by fever and peripheral leucocytosis (2 patients). Bacteriology.Organisms were isolated in the Clinical Microbiology Laboratory of the OCMC where sensitivity to cephazolin and other antibiotics was determined by the Kirby-Bauer method. Drug levels. For 18 patients serial sera were obtained over a 6-hour period at the

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Cephazolin treatment of Pneumococcal Pneumonia and Urinary Tract Infections

time of the first innoculation of cephazolin. With 13 of these 18 patients serial sera were also obtained following the final dose of cephazolin. Assay of the antibiotic was carried out in the University of California, Irvine, Infectious Disease Research Laboratory using the tube dilution method in the microtiter system and Streptococcus 98 as the indicator organism (Abramowicz et al., 1966). Untoward effects. All patients were examined daily for evidence of allergy or side effects to cephazolin. Parameters of kidney, liver, and bone marrow function were monitored via blood samples obtained at 3day intervals and analysed by the Clinical Pathology Laboratory of OCMC. Administration. Unless otherwise noted cephazolin was administered according to the following schedules: 1.0g. every 8 hours for infections with Staphylococcus aureus, 0.5 g. every 8 hours for non-staphylococcal respiratory infections; and 0.5 g. every 12 hours for urinary tract infections. Results Bacteria isolated. It can be seen in Table I that all of the primary pathogens isolated from specimens obtained before therapy proved to be sensitive to cephazolin save one. This latter organism, an enterococcus, was eliminated from the urine with cephazolin despite its in vitro resistance. Superinfecting bacteria whose association with disease required a change in antibiotic regimen included 6 Pseudomonas aeruginosa and an Enterobacter aerogenes all of which were resistant to cephazolin and a Proteus mirabilis and an Enterobacter aerogenes which were ultimately found to be sensitive to cephazolin. In addition, a viridans streptococcus, for which the MIC and MBC for cephazolin was 0.02 p,g. per ml. and 0.4 icg. per ml. respectively, persisted in pleural fluid despite high doses of cephazolin (See Clinical Findings). Clinical findings-respiratory infections. As seen in Table II in each of the 10 cases of pneumococcal pneumonia, the pathogen was eliminated with a concomitant improvement in symptoms, drop in fever, normalization of the leucocyte count, and a gradual resolution

of the X-ray infiltrate. In one patent with a cerebrovascular accident superinfection with Pseudomonas aeruginosa 2 days after a 5-day course of cephazolin led to septicaemia and death. In a patient with cirrhosis having an acute gastrointestinal bleed plus staphylococcal pneumonia and septicaemia, repeat cultures of blood and sputum were obtained and therapy switched from cephazolin to nafcillin at the time it was learned that the original blood cultures were positive for S. aureus. Although the repeat cultures did not grow staphylococcus, the patient succumbed after 48 hours because of continued gastrointestinal bleeding. A patient with a l3-haemolytic streptococcal pneumonia continued to have multiple pulmonary aspirations on therapy. Although the initial pathogen was rapidly eliminated, progressive pulmonary infiltrates were associated with Proteus mirabilis and Enterobacter aerogenes and led to a change in antibiotic regimen to gentamicin and chloromycetin. Nevertheless the patient died of pneumonia 5 days after the 6-day course of cephazolin. Three patients with acute pneumonia had rapid improvement of symptoms, fever, and leucocytosis and a gradual improvement in X-ray infiltrate on cephazolin therapy but no pathogen was ever isolated from the pre-therapy sputum. A patient each with staphylococcal and pneumococcal bronchitis had rapid resolution of all manifestations of acute respiratory disease following initiation of treatment with cephazolin. Two patients were treated for lung abscess. One, who presented with foul sputum, had resolution of the abscess after a total of 95.5 g. of cephazolin over 36 days. Since the initial sputum was cultured only aerobically and grew out normal throat flora, it is presumed that the patient had primary lung abscess with anaerobic bacteria. A second patient had multiple lung abscesses and pleural effusion which grew out Streptococcus viridans although the sputum had Streptococcus pneumoniae. After cephazolin 1.0 g. every 6 hours intramuscularly for 4 days and intravenously for 1 day, the pleural effusion continued to grow out Streptococcus viridans. At this time the serum had peak and trough cidal activity for the streptococcus at dilutions of 1:128 and 1:8, respectively. After 249

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a total of 28 g. of cephazolin the patient was switched to penicillin G, 24 million units intravenously, and streptomycin, 0.5 g. intramuscularly, daily. After 12 days of the latter therapy the pleural fluid was found to be sterile. At completion of therapy lung showed cystic degeneration. Urinary tract infections. Ten patients with E. coli urinary tract infection had sterile urine in 24 to 48 hours. All 5 who had been symptomatic initially had simultaneous resolution of their symptoms. One patient had recurrence of the urinary tract infection with

a sensitive E. coli 16 days after therapy was discontinued and another patient had superinfection with Pseudomonas aeruginosa, during treatment, requiring a change of the antibiotic regimen to gentamicin. Four symptomatic patients with Proteus mirabilis urinary tract infections had rapid elimination of the infecting organism and resolution of symptoms with cephazolin treatment. Recurrence with the same organism occurred within 2 weeks for one patient and one month for another. In the latter case a second course of cephazolin again sterilized the urine but the

250

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IV

Vt

...

Sub total

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

S. aureus Unknown '2

E. coli P. mirabilis Other enterics? Enteroccocus

Pneumococcus Other BacteriaNon-bacterial

Agent

41

2

1 1

20

1

1 35

36

1

1

1

20

1

20

10 5 4

10 5 4

14

15

19 10 5 4 1

2 15

2 1

10 2 16

Eliminated Persisted

10 2

Isolated

Original Organism

10 2 3 2 2

Total

Cases

5

5

1 3 1

8

6

28 3'0

P

2

P 13

Super infection with new Recurred organism

CASES TREATED

377

2

1 1

207

1

107 5 4"

15

9 0 3 2 1

Cure

J

3

1 2

Death

Clinical outcome

Pseudomonas aeruginosa. Staphylococcus aureus and B haemolytic streptococcus. Combined infection with Proteus mirabilis and Enterobacter aerogenes, Final reading of initial chest X-ray indicated no infiltrate. Organisms of a primary lung abscess presumably eliminated but not documented. Streptococcus viridans. Five patients had asymptomatic E. coli bacteriuria. Both Pseudomonas aeruginosa. Klebsiella, Klebsiella plus E. coli, E. coli plus Proteus rettgeri and Enterobacter agglomerans, Three Pseudomonas aeruginosa and one Enterbacter aerogenes. One patient had asymptomatic bacteriuria with E. coli and P. rettgeri. No growth; Gram stain demonstrated Gram positive cocci and polymorphonuclear leucocytes; lesion behaved clinicallyasexpectedforinfection with S. aureus.

Total

Sub total

Soft tissue infection

Sub total

Urinary tract infection

BronchitisLung abscess

Pneumonia

Respiratory disease

Tablell.

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Kilpatrick, Cesario, Thrupp and Tilles

organism recurred when it was discontinued. Superinfection with Pseudomonas aeruginosa occurred in 2 other patients while on therapy. One patient with Klebsiella, one with both Klebsiella and E coli and a third with Proteus rettgeri and E coli, had elimination of initial organisms and any symptoms present on cephazolin therapy, but subsequently had superinfection, in each case, with Pseudomonas. A patient with infection with Enterobacter agglomerans had recurrence with Enterobacter aerogenes 4 days after completion of the course of cephazolin. A single patient with enterococcus infection had rapid resolution of symptoms and bacteriuria on therapy. Soft tissue infections. Two patients with abscesses and systemic manifestations of infection were treated concurrently with incision and drainage and cephazolin therapy. From one, who subsequently was discovered to have received a previous single dose of nafcillin, Staphylococcus aureus was grown from the pre-cephazolin sample. From the other, whose initial specimen had Gram positive cocci and polymorphonuclear leucocytes on Gram stain, there was no growth on culture. Both patients responded well to the treatment given. Drug levels. The mean serum level during the 6 hours following the initial dose of 0.5 g. cephazolin intramuscularly is plotted for 18 patients in Figure 1. Similar data following the final dose in 13 patients is also plotted. It can be seen that following the initial dose the peak occurred in one hour and the half life was about 2.2 hours while for the final dose the peak occurred at 2 hours and the half life was approximately 1.9 hours. It is apparent that there was very little evidence of accumulation of the drug after an average of 6.6 days of therapy. The relation of serum level to renal function is shown in Figure 2 where the initial and final peak serum levels are plotted respectively, versus the initial and final creatinine clearances. Toxicology. Monitoring of blood for marrow and liver toxicity revealed a single patient who transiently had both unexplained rise in serum glutamic oxaloacetic transaminase to 77 and appearance of haemosiderin in the urine. These abnormalities were believed

to be unrelated to the cephazolin therapy. Renal function was measured by serial determination of creatinine clearance and urinanalysis. A plot of the initial versus the final creatinine clearance for 29 patients who received an average of 12.9 g. of cephazolin is shown in Figure 3. It is seen that there is no significant trend toward a loss of glomerular filtration as measured by this test. Similarly, serial urinanalyses revealed no development of proteinuria, casts, or haematuria attributable to drug toxicity. A 69-yearold patient with a history of allergic skin rash to penicillin G, who received a second course of cephazolin (0.5 g. every 12 hours) for a recurrence of a symptomatic Proteus pyelonephritis one month after the initial treatment, had an episode of renal papillary necrosis on the final day of treatment one week after an 24

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Cephazolin treatment of pneumococcal pneumonia and urinary tract infections.

Ten cases of pneumococcal pneumonia were treated with cephazolin 500 mg. q8h for at least 5 days. In every case therapy was accompanied by clinical im...
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