Cephaloridine compared with penicillin and streptomycin in chronic purulent bronchitis

Brit. oT. Dis. Chest (t967) 6x, xol.

Cephaloridine compared with Penicillin and Streptomycin in chronic purulent Bronchitis Controlled Trials of increasing Dosage of Cephaloridine A. PxN~s, H. RAAFAT, K. PLUCINSKI, J . S. B. GR~ENFX~LD, AND W. D. LINSELL Ware Park and Herts & Essex Hospitals

CEPHALORIDINE is effective in vitro against Hcemophilus influenz¢ and Streptococcus pneumonice, perhaps the chief pathogens in purulent infections of the bronchi. As cephaloridine is highly bactericidal and very well tolerated it seemed a promising drug to try in patients with severe purulent exacerbations of bronchial infections. We thought it could be helpful in two groups of patients. The first are those for w h o m other antibiotics in high dosage fail while the patients are still ill from the effects of unsuppressed infection: we encounter m a n y such as these. The second are patients with previous hypersensitivity reactions to penicillin who therefore could be given neither penicillin nor ampicillin; these were still seriously ill from infections which had not responded to tetracycline, chloramphenicol, or erythromycin. This, too, is common among our patients. We describe below a controlled trial of cephaloridine in patients of these two types. The Patients These suffered from chronic purulent bronchitis, from bronchiectasis, or from both. In m a n y the disorder was advanced, and m a n y were elderly and had often been transferred to our care from other hospitals where treatment had failed. To be eligible for the trial patients must have had persistent purulent sputum despite at least two fortnightly courses of two or more other antibiotics. These had been selected from daily doses of tetracycline 2-3 G., penicillin 6-i o mega units, ampicillin 4-6 G., chloramphenicol 2G., and erythromycin 2G. Few had been treated with streptomycin. The majority had received six or more such courses recently in our own or other hospitals. Those with active pulmonary tuberculosis, carcinoma of the lung, or an eosinophilia in the sputum of Io per cent. or more were excluded. Features of these patients are shown in Table I. All were in hospital throughout their treatment and later assessment. (Recelvedfor publication, December z966 )

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PINES, RAAFAT, PLUCINSKI~ GREENFIELD AND LINSELL

TABLE I. AGE, SEX, WEIGHT, INITIAL CLINICAL STATE, AND COMPLICATIONS IN THE PATIENTS INCLUDED IN THE THREE TRIALS

Cephaloridine

Penicillin and streptomycin

~st trial

znd trial

3rd trial

xst trial

~nd trial

3rd trial

31

35

34

31

34

32

7 15 9

9 x7 9

x2 2o 2

5 16 xo

II 17 8

9 19 5

27 4

32 3

34 o

27 4

31 3

32 o

5 7

5 23 7

4 25 6

3 2o 8

5 24 5

2 23 7

Good Moderate Poor

I 22 8

2 22 11

3 21 Io

3 x9 9

3 ~2 9

4 2i 9

Bronchiectasis Cor p u l m o n a l e

7 8

4 6

5 8

6 7

3 9

t Io

N u m b e r of p a t i e n t s

Age in years: U p to 60 6I-7o 71 a n d over Male Female

Weight: U p to 5 ° kg.

5 I-7O 71 a n d over

19

General state:

The Trials T o compare with cephaloridine, we chose a combination of penicillin and streptomycin. This is very widely used, and is given by intramuscular injection in the same way as cephaloridine. T h e dose of penicillin was 2,000,000 units twice daily for fourteen days, accompanied for the first seven days by 0"5 G. of streptomycin twice daily in the same injection. For reasons which will become clear later cephaloridine was given in ascending dosage. I n the first trial, this was i G. twice daily for fourteen days, in the second 2 G. twice daily, and in the third trial 2 G. three times daily for fourteen days. Routine treatment was the same for all patients as far as their state of illness would allow. This included breathing exercises, postural drainage, bronchodilators, respiratory stimulants where thought to be helpful, and optimistic encouragement. Patients were encouraged to leave their beds as soon as possible. As patients became eligible for these trials after other treatments failed, they were allocated by strict alternation to either treatment. T h e allocation was from a central list, held by a secretary: as patients were treated in three separate wards, each with its own clinician-in-charge, it was unlikely that the choice of treatment could be anticipated by the ward clinician entering each patient into the trial. T h e only exception was a history of hypersensitivity to

CEPHALORIDINE

COMPARED

WITH

PENICILLIN

AND

STREPTOMYCIN

IO3

penicillin: these patients were given cephaloridine and the next patient entered was allocated to the other group. Many with this hypersensitivity had been ill for long periods, had received little benefit from the antibiotics which they could safely be given, and had to be denied the improvement which penicillin and ampicillin might have yielded. This was the main advantage of choosing an alternating system of selection rather than randomization. The effect of treatment was assessed chiefly by changes in the character of the daily 24-hour specimen of sputum--its purulence to the naked eye and its quantity. This was done independently by an experienced and trained charge nurse who was completely unaware of what treatment each patient was having, whether he was in the trial or not, or if indeed he was being given any treatment at all. Four grades were used in assessing purulence--purulent (when'more than half of the specimen consisted of pus), muco-purulent (when less than half was pus), trace of pus (when most was mucoid), and mucoid (when no pus could be seen). Before the trial began and after its completion the bacteriology of the sputum was routinely assessed, as were the urine, blood urea, hmmoglobin, white count, and sedimentation rate. Pyrexia and radiographic evidence of consolidation were infrequent and were therefore not recorded in later cases in the trial. The maximal peak flow rate was recorded in the first patients entering the trial. However, many were too ill to give reliable readings at the beginning and changes were often inconstant and bizarre: they were not recorded later in the trial for these reasons. A "blind" clinical assessment was also carried out. Patients entered each trial once only, but they were eligible for the next stage of the trial if treatment failed or if the sputum became purulent again a fortnight or more after the end of treatment. Nineteen patients re-entered later stages of the trial. The study lasted from j a n u a r y 1965 to January 1966.

The first trial (Fig. x) Cephaloridine I G. was given to 31 patients twice daily for a fortnight and 31 were given penicillin together with streptomycin. This daily dose of cephaloridine has been described as effective in other infections (Murdoch et al., x964). Most patients were elderly males in moderate or poor general condition as judged clinically by the admitting physician and weighing between 51 and 7° kg. (Table I). Both groups were comparable in these basic features. Seven patients treated with cephaloridine had bronchiectasis and eight cor pulmonale. Six patients treated with penicillin and streptomycin had bronchiectasis and seven cor pulmonale. There were no withdrawals. At the end of the fortnight only four out of the 31 patients treated with cephaloridine had mucoid sputum, as opposed to 14 out of the 31 patients treated with penicillin and streptomycin. Penicillin and streptomycin was thus much more successful (P = o.oi) than cephaloridine in a dose of I G. twice daily in these severe cases of chronic disease. Since cephaloridine was well tolerated and non-toxic, it seemed justifiable to see the effect of doubling the dose. This was especially important since the failure of many other antibiotics had left many of our patients in desperate illness.

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PINES~ RAAFAT, PLUCINSKI, GREENFIELD AND LINSELL

56% 37./,

4O°/o

2~

Penicillin and $treptom]cin

~

4G

6G

daiLydose Cephaloridine

Fxo. I. Success rate of Gephaloridine in ascending dosage related to pooled rate for penicillin and streptomycin

The second trial (Fig. z) Cephaloridine 2 G. was given to 35 patients twice daily, and 34 received penicillin and streptomycin in the same doses as before for z4 days. In addition two patients were withdrawn from the cephaloridine group, one because of pulmonary tuberculosis and one because of self-discharge; and one patient was withdrawn from those treated with penicillin and streptomycin because of carcinoma of the lung. Again most were elderly men, in moderate or poor general condition and weighing between 51 and 7° kg. Both groups were comparable in these features (Table I). Four patients treated with cephaloridine had bronehiectasis and six cor pulmonale, whilst three treated with penicillin and streptomycin had bronchiectasis and nine cor pulmonale. With this double dose of cephaloridine, the sputum became mucoid by the fourteenth day in 14 out of 35 patients (4o per cent.) and in I I out of the 34 (33 per cent.) treated with penicillin and streptomycin. All the patients whose sputum had become mucoid were observed in hospital for another month to see if the sputum remained clear. On the seventh day after treatment had ended the sputum was clear in seven patients treated with cephaloridine and in five treated with penicillin and streptomycin. By the end of the month the sputum was still clear in three and two patients respectively. As many of our patients had such advanced and resistant infections, we tried to assess minor improvements in purulence and quantity of sputum in order to assess the action of each antibiotic regimen more fully. A points system was used to grade disappearance of pus in the sputum and diminution of quantity (Table II). The number of marks given for each category was according to its agreed clinical importance. Cephaloridine gained 7° points and penicillin and streptomycin 57 points. None of these differences reached statistical significance to the level P = o.o5. Cephaloridine had again been perfectly tolerated and no toxicity had been noted. It seemed possible that a further increase in the dosage of cephaloridine might add to the success-rate of this antibiotic. This could have been of great benefit to our unfortunate patients. To increase the doses of streptomycin in

GEPHALORIDINE

GOMPARED

WITH

PENICILLIN

IO5

AND STREPTOMYGIN

these elderly and sick patients would risk giving them severe and often permanent vestibular disturbances (Cawthorne and Ranger, I957; Edanson and Lundgren, I964). We therefore went on to make a further comparison of cephaloridine given as 6 G. daily as against the same dose of penicillin and streptomycin. TABLE II. POINTS SYSTEM

Factor in improvement

Sputum quantity reduced by 50% or more to t r a c e o r n i l

Sputum purulence reduced from purulent to mucopurulent ,, ,, ,, ,, ,, ,, trace of pus ,, ,, ,, ,, ,, ,, mucoid ,, still mucoid one week after treatment ended ,, ,, ,, ,, month ,, ,, ,,

Points

I 2

I 2 3 I 3

The third trial (Fig. I)

Cephaloridine was given as 2 G. three times daily to 34 patients and penicillin with streptomycin was given to 32 patients in the same dose as before, both for 14 days. T w o additional patients had to be withdrawn from the cephaloridine-treated group, one an asthmatic with an eosinophilia of 25 per cent. in the sputum and one having carcinoma of the lung, and one was withdrawn from the penicillin-and-streptomycin group because of carcinoma of t h e lung. All were men; their basic features were as in the other two trials and were comparable (Table I). Five patients in the cephaloridine group had extensive bronehiectasis as opposed to only one among the penicillin-and-streptomycin patients. Eight patients among the former were in cor pulmonale, and ten of the latter. In 19 out of 34 patients (56 per cent.) cephaloridine rendered the sputum mucoid. Penicillin and streptomycin were similarly successful in I I out of 32 patients (34 per cent.). Cephaloridine 6 G. daily was thus significantly more successful (P = o.o5). The successfully treated patients were observed for another month (Fig. 2). In I3 out of the 19 (66 per cent.) patients treated with cephaloridine the sputum was still mucoid a week later, and in seven (37 per cent.) it was still clear four weeks after treatment. No further antibiotics had been given. With penicillin and streptomycin, only two out of eleven patients still had mucoid sputum at either one or four weeks later. T h e difference is significant (P < o-o5) at one week but not at four weeks. Using our points system, cephaloridine gained 68 and penicillin and streptomycin 48; when the follow-up was included the points rose to IO2 and 56 respectively (P < o.o5). Thus cephaloridine 6 G. daily was much more successful than penicillin and streptomycin, both at the end of the fortnight's course of treatment and over the succeeding four weeks. The rate at which sputum became mucoid is shown in Table III. After seven days' treatment ten cephaloridine-treated patients showed mucoid sputum, as opposed to five given penicillin and streptomycin;

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PINI~S, R A A F A T , P L U G I N S K I , G R E E N F I E L D AND L I N S E L L

after 14 days' treatment the numbers were nineteen and eleven patients respectively. 19 11

Days after treatment:

0 7 28

0 7 26

PeniciRin and streptomycin

Cephatoridine 66 daily

FIG. 2. Follow-up after t r e a t m e n t . N u m b e r of patients c o n t i n u i n g to h a v e m u c o i d s p u t u m

TABLE I I I . NUMBER OF PATIENTS ACHIEVING MUCOID SPUTUM AT DAILY INTERVALS DURING TREATMENT IN THE THIRD T R I A L

Number o f days

z

~

3

4

5

6

7

8

9

zo

H

**2

x3

14

N u m b e r o f patients treated withcephaloridine

o

o

i

3

4

8

io

Ii

ix

13

t4

I8

19

19

N u m b e r of patients treated with penicillin a n d streptomycin

o

o

~

2

2

4

5

6

6

7

8

9

ii

Ii

"Blind" Clinical A s s e s s m e n t A clinical assessment was made by one of us at the beginning and end of each patient's treatment. This was in two grades or points of improvement or deterioration, taking into account changes in the patient's general state, res, piratory and pulse rates, blood pressure, and other respiratory and cardiac signs. The state of the sputum was ignored. The observer was completely unaware of what antibiotic treatment each of the patients assessed was having. In the three trials cephaloridine gained 9, 24, and 40 points successively, and penicillin with streptomycin 27, 23, and 24 points. These results correlate very closely with those of sputum assessment, as we found previously in a "doubleblind" trial oftetracyclines in similar patients (Pines et al., I964). Adding these points to those gained in sputum assessment, cephaloridine in a dose of Ggrarnmes daily was significantly superior (Io8 v. 72, P = 0"05). Toxicity Pain was complained of by nine patients with the injections of penicillin and streptomycin, and by one with the cephaloridine injections. No toxic effects

CEPHALORIDINE

COMPARED

WITH

PENICILLIN

AND STREPTOMYCIN

xo7

were found in our routine laboratory investigations. More detailed examinations conducted on the last few patients in the trial and in subsequent experience have shown signs of a transient renal reaction. After the first few days of treatment with 6 G. daily there was variable and sometimes massive outpouring of hyaline, and, infrequently, granular casts, occasionally with mild albuminuria and red and white cells and minor abnormalities of amino-acid output. These continued until the cephaloridine was stopped and then disappeared after a few days. Routine estimations of blood urea showed no adverse effects on renal function, and there has been no evidence of any other changes; those seen were mainly tubular and are in themselves of uncertain and doubtful significance. They will be described in detail elsewhere (Linsell et al., 1967). There was no obvious clinical manifestation of this or of other toxicity. Of the patients treated with cephaloridine, 29 had had previous reactions to penicillin. None reacted to cephaloridine. One patient without a previous history of drug allergy had a violent morbiUiform eruption on the 13th day of treatment with cephaloridine I G. twice daily. This subsided when she was given prednisolone.

Bacteriology During the 2o 3 courses of cephaloridine or penicillin and streptomycin the following potential pathogens were isolated from the sputum: H. influenzcein 24 (I2 per cent.), S. pneumoni¢ in 15 (7"5 per cent.), Escherickia coli in 2x (IO per cent.), Pseudomonas pyoeyanea in 19 (9"5 per cent.), Staphylococcus aureus in 19 (9"5 per cent.), Proteus spp. in I8 (9 per cent.) and Klebsiellapneumoniee in 9 (4"5 per cent.). These findings were too sporadic to allow analysis in relation to the results of either treatment. The isolation rates of H. influenzce and S. pneumonice are low in comparison to many published results (May, 1965). This may be because previous chemotherapy had suppressed a proportion of these organisms and made their isolation much more difficult. Whether organisms apart from H. influenzce and S. Pneumonice are important in these bronchial infections is doubtful (May, I965). The bacteriological sputum specimens were also assessed completely "blindly" by the bacteriological technician for the presence or absence of pus at the beginning and end of treatment. In the 197 specimens there was agreement with the ward assessment in 18o. In the 17 cases of disagreement, the ward assessment was preferred since the whole 24-hour specimen could be examined.

Discussion When cephaloridine has been used in individual patients with chest infections, the results have sometimes been successful (Murdoch et al., 1964; Sanchez Vegas, 1965; Gherardi et al., 1965; Villafane et al., 1965; and d'Ovidio et al., 1965). No controlled comparison with other antibiotics has yet been published, as far as we are aware. It is only in such a comparison that the place of cephaloridine can be established in the treatment of chronic purulent infections of the bronchi.

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PINES, RAAFAT, PLUQINSKI, GREENFIELD AND LINSELL

We have shown that in our patients with particularly resistant bronchial infections the effect of cephaloridine increases with the dose given. The best results were obtained with 6 G. daily, and were superior to those given by penicillin with streptomycin. When the numbers of successes were compared statistically in the three trials, in separate categories for age, pre-trial condition, weight, and sex, no significant differences appeared which were in disagreement with the results which have been described. Some of the patients successfully treated with 6 G. daily ofcephaloridine said that they had not felt so well for years. Very few of the patients treated with other regimens volunteered similar praise. The strictly alternate and independent allocation of treatment in our trial should not have allowed bias to enter into the selection of treatment. Though theoretically better, randomization would not have allowed 29 of our patients with penicillin sensitivity to receive the possible benefit of cephaloridine; their often desperate condition and the failure of so many other antibiotic treatments must be remembered here. Solutions of cephaloridine are quite distinct from those of penicillin with streptomycin--they are yellow and may precipitate almost immediately after mixing--and a "double-blind" trial was consequently impracticable; in any event the responses of both the patient and his sputum to treatment were assessed completely independently and "blindly", and no other factor was counted in assessing response. Why our patients required such a high dose of cephaloridine to clear their infection is uncertain. The minimum inhibitory concentration for H. influenzre, which is widely held to be the chief pathogen in chronic purulent bronchitis (Mulder, i938; May, I965) , varies considerably (Jones and Davis, r965). Perhaps the persistent and severe infections we were treating included many where the minimum inhibitory concentration was high: we have no data on this. In these severe and chronic infections of the bronchi there may be difficulty in penetration of antibiotics from the blood-stream to the areas of infection (Pines et al., I965) , so that high doses are required to overcome the barriers of fibrosis and diminished blood supply. Similarly, bacteria lurking in the minute abcesses described by Reid (I954), or the deeper layers of the bronchial mucous membrane (Hers and Mulder, i953) , may be difficult to reach. The advantage of the bactericidal effect of high dosage cephaloridine is shown in the follow-up. Among the patients whose sputum became mucoid, two-thirds were still free of purulent sputum a week later and a third a month after treatment. This effect was superior to the other regimens and is comparable to that of ampicillin 4 G. daily in similar patients (May, I964; Pines, I964). We are at present comparing cephaloridine and ampicillin in high dosage in a controlled trial. Our routine bacteriological investigations did not help in assessing the success or failure of either regimen. The uselessness of such routine investigations in most purulent exacerbations of bronchitis or bronchiectasis has often been emphasized (Scadding, 1966; Crofton, 1966). Apart from a transient sensitivity rash in one patient, there were no other obvious reactions to cephaloridine, even from the 29 patients who had had a history of penicillin sensitivity. With special investigations which are described

CEPHALORIDINE

COMPARED

WITH

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AND STREPTOMYCIN

lO9

elsewhere, we have detected transient urinary changes of doubtful and uncertain significance during the administration of 6 G. cephaloridine daily. Urinary cells and casts may be induced by simple analgesic drugs (Prescott, I965), but until more is known about these changes, cephaloridine 6 G. daily should probably be given only to patients suffering from severe illnesses, or where other antibiotics have failed and where any risks of this transient renal reaction are outweighed by the seriousness of the illness. In these circumstances we have shown that cephaloridine 6 G. daily will often prove of great benefit to these patients. In patients with severe chronic bronchitis, cephaloridine 4 G. daily has no obvious advantage over penicillin with streptomycin, except where there is hypersensitivity to penicillin.

Summary Cephaloridine in ascending doses and penicillin administered with streptomycin were compared in successive trials. The patients had chronic purulent bronchitis or bronchiectasis, resistant to all previous antibiotic treatment. In a dosage of 2 G. daily, cephaloridine was inferior to penicillin with streptomycin, in one of 4 G. it was equal and in one of 6 G. superior in effect. Transient renal changes caution the use of this last dose.

Acknowledgements We wish to thank: the nursing, pathological and secretarial staffs of Ware Park and the Herts & Essex Hospitals for their help; Drs E. Snell and R. Foord, Glaxo Laboratories Ltd, for their great help and for supplies of Cephaloridine (Ceporin) and Penicillin combined with Streptomycin (Crystamycin); Dr M. E. Solari, Chelsea College of Science and Technology, and Mr Michael Hill, London School of Hygiene and Tropical Medicine, for statistical help; Professor J. W. Crofton, University of Edinburgh, for criticism; the physicians who sent us their patients. References CAWTHORNE, T., & RANGER, D. (1957). Brit. reed. 07., i, 1444. CROFTON, J. (i966). Brit. reed. o7., i, 783 . ERLANSON, P., & LUNDOREN, A. ('1964). Aeta reed. seand., 176, 147. GHERARDI, C. R., MAZZEI, C. M., DIEZ, E., & RECHNIEWSKI, C. (1965). Pren. radd. argent., 52, 1916. HERS, J. F. P., & MULDER,J. (1953). 07. Path. Bact., 66, 1o3. JONES, D. M., & DAVIS,P. (I965). Brit. med. 3 , i, 448. LINSELL,W. D., PINES, A., & HAYDEN,J. W. (I967). o7. din. Path., to be published. MAY, J. R. (1964). Lancet, ii, 444. MAY, J. R. (i965). Brit. 07. Dis. Chest, 59, 57. MULDER,J. (1938). Acta med. stand., 94, 98. MURDOCH, J. McC., SPEIRS, C. F., GEDDES, A. M., & WALLACE, E. T. (I964). Brit. reed. 07, ii, I238. D'OvlDIO, F. R., BUSTOS,J. C., D'OvlDIO, E., & BARRIONUEVO, E. (1965). Pren. rndd. argent., 52, I928. PINES, A. (I964). Lancet, ii, 445. PINES, A., BUNDI, R. S., GREENFIELD,J. S. B., & PLUClNSKI, K. 0965). Brit. 07. Dis. Chest, 59, 8 i. PINES, A., PLUClNSKI,K., GREENFIELD,J. S. B., & MITCHELL, R. C. (1964). Brit. med.~7., ii, 1495.

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PRESCOTT, L. F. (x965). Lancet, ii, 9I, REXD, L. M. (x954)- Lancet, i, 275. SANCHEZ VEGAS, J. (I965). Rev. UroL (Caracas), xT, 345SCADDING, J. G. (i966). Brit. reed. ft., i, 128i. VILLAFANE, C. M., SALVAREZZA, C., OBAID, 1~., CIAFARDONI, P., & FORTE, A. C. (x965). Pren. m~d. argent., 52, I924.

Erratum In the article by Dr Mithal on Primary Osteomyelitis of the First Rib which appeared in the January issue, the illustrations numbered (b) and (c) were inadvertently transposed. (The captions are correct as printed.)