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New Combinations of Antibiotics
1207
LEADING ARTICLES
in close agreement. Habituation to oleanresulted in the development of considerable resistance to that antibiotic but little or no change in the sensitivity to tetracycline or sigmamycin. Repeated subculture in the presence of tetracycline produced a lesser degree of resistance to the homologous agent and also some increase in resistance to sigmamycin but no change in sensitivity to oleandomycin. Habituation to sigmamycin little changed the sensitivity to oleandomycin ; there was some increase in resistance to the combination but this was less than the resulting increase in resistance to tetracycline. GARROD4 points out that apparently the smaller amount of the weaker antibiotic (oleandomycin) fails to interfere effectively in the reaction of the organism to the major component in the combination (tetracycline). FAIRBROTHER and SOUTHALL5 consider that these results confirm the claim that the mixture delays, in vitro, the emergence of resistant variants of Staph. aureus. JONES and FINLAND2 noted differences in cross-resistance to erythromycin, oleandomycin, and spiramycin among strains of Staph. aureus freshly isolated from patients ; whereas complete crossresistance to all three agents is known to develop in strains repeatedly subcultered in the presence of any one of them. These observations accord with those reported by GARROD4 and by FAIRBROTHER and SOUTHALL 5. GARROD referred to cross-resistance as being " double " when resistance involved both erythromycin and oleandomycin, and "dissociated" when it was to one agent only. It can be concluded only that oleandomycin and spiramycin are so inferior to erythromycin that their adoption for general use is unwarranted ; indiscriminate use of these weak erythromycin-like agents may produce a staphylococcal population resistant not only to them but also to erythromycin itself. But when strains of Staph. aureus are encountered that are sensitive to these agents but resistant to erythromycin, their use may be justified. Combinations of tetracycline with oleandomycin or spiramycin seem to have little to commend them ; for the clinician presenting them may tend not to provide an effective dose of either drug, and he may falsely feel secure because of a mistaken belief that the combination provides better or broader antibacterial activity. There is no evidence whatever that in vivo such combinations delay or prevent the emergence of resistant variants. Furthermore suppression of resistant variants cannot be expected unless the organism is sensitive to both antibiotics in a combination. JONES and FINLAND6 have used their in-vivo method to investigate the combination of erythromycin and chloramphenicol. This mixture did not appear to be synergistic. There is some in-vitro evidencethat this combination delays the emergence of erythromycin-resistant staphylococci, but there is no proof that the combination has the same action in vivo. It must also be remembered that one component of this combination is a potentially dangerous
results
THE LANCET LONDON:
SATURDAY, DECEMBER 14,
1957
New Combinations of Antibiotics IT is hard to
keep
up to date with the many
new
combinations of antibiotics, and it may be far from easy to assess their value, because the manufacturers sometimes introduce them without adequate laboratory study or clinical trial. We lately evaluated anti-2 biotic combinations,l and now JONES and FINLAND report a detailed study of members of the erythromycin group-erythromycin, oleandomycin, and spiramycin-alone and in combination with tetracycline. With either an agar or a broth-dilution technique they found that, in general, erythromycin was unques-
tionably superior to oleandomycin or spiramycin in its activity against staphylococci and other gram-positive coccal pathogens. They also showed that oleandomycin was more potent than spiramycin. JONES and FINLAND determined the activity in vitro of combinations of tetracycline with either erythromycin or oleandomycin or spiramycin in various proportions. The combination of tetracycline with erythromycin proved superior to combinations of tetracycline with either oleandomycin or spiramycin ; but none of the mixtures, in any of the ratios that
were
used,
was
active than the more potent single comclearly of the mixture on its own. Indeed for most ponent strains the pairs of antibiotics were more often than not found to be inferior to the better of the individual components. JONES and FINLAND determined the antibacterial activity in the plasma of healthy young men after oral administration of the various drugs alone and in combination. The results confirmed their in-vitro findings ; none of the combinations showed activity greater than that obtained from the same dose of the more active component of the pair. The most enthusiastic report of synergism between tetracycline and a member of the erythromycin group was that by ENGLISH et al.,3 whose claim for enhanced activity of a mixture of 2 parts of tetracycline with 1 part of oleandomycin led to such a combination being marketed under a trade name (’Sigmamycin ’). The in-vitro evidence for their claim was not strong, and it is obviously not supported by the work of ’JONES and FINLAND.2 In this country GARROD4 has failed to demonstrate any synergistic activity by such a mixture of tetracycline and oleandomycin against 70 strains of staphylococci ; and FAIRBROTHER and SOUTHALL 5 were similarly unable to show synergism, in vitro, against 165 fresh isolates of common pathogens which included 80 strains of Staphylococcus aureus, ENGLISH et al.3 also claimed that this combination. in vitro, retarded the emergence of antibiotic-resistant variants of one strain of Staph. aureus and one strain of Streptococcus pyogenes. To test this claim GARROD 4 habituated six strains and FAIRIBROTHER and SOUTHALL 5 three strains of Staph. aureus to sigmamycin, oleandomycin, and tetracycline ; and their more
1.
2. 3. 4. 5.
are
domycin
Lancet, July 27, 1957, p. 177. Jones, W. F., Finland, M. New Engl. J. Med. 1957, 257, 481, 536. English, A. R., et al. Antibiot. Chemother. 1956, 6, 511. Garrod, L. P. Brit. med. J. July 13, 1957, p. 57. Fairbrother, R. W., Southall, J. E. Lancet, Nov. 16, 1957, p. 974.
drug. should seek to exercise restraint in and particular care to conserve erythromycin for treatment of life-endangering staphylococcal infections acquired in hospital and
Meanwhile,
the
6. 7.
use
of all
we
antibiotics,
Jones, W. F., Finland, M. New Engl. J. Med. 1957, 257, 744. Wright, S. S., et al. J. Lab. clin. Med. 1953, 42, 877.
1208
thus liable to be resistant to the common antibiotics. If weak erythromycin-like drugs are to be unwisely adopted, we may rely for a time on novobiocin and vancomycin 8; but how long can the production of genuinely new antibiotics keep us ahead in the downhill race ?
" Acute
Nephritis "
A FEW years ago Prof. CLIFFORD WiLSON and Prof. JEAN HAMBURGER were invited to speak about nephritis " at a meeting of the Renal Association. In keeping with English usage Professor ’WrLSON spoke about glomerular nephritis. In France, however, the term nephrite has wider connotations, and Professor HAMBURGER discussed the classification of all renal diseases. There is nothing new about such a confusion in the nomenclature of renal disease; it is due partly to ignorance of their aetiology. What is the accepted meaning of the term " acute nephritis " ? Does it describe a disease, a syndrome, or certain histological changes ? Generally the term is synonymous with a disease-i.e., acute glomerular nephritis, in which infection with haemolytic streptococci is followed after about two weeks by the sudden onset of hypertension, cardiac failure with oedema, proteinuria, and hoematuria. The prognosis of this condition is well defined ; death occurs in a few days in about 3%, in a few months in 7%, and in a few years in another 10% ; the remaining 80% recover completely. In the acute phase the histological changes consist in an intense proliferation and inflammation of the glomerular tufts. There are other causes of sudden onset of hypertension, cardiac failure with cedema, proteinuria, and haematuria-for instance, polyarteritis nodosa, disseminated lupus erythematosus, and anaphylactoid purpura. In these conditions there may be no preceding infection ; and, though there are often certain histological similarities to acute glomerular nephritis, the natural history of subsequent events and the prognosis are different. Nevertheless the clinical features of acute glomerular nephritis clearly form a syndrome which may be found in several other disease processes. It would be of help if this syndrome could be defined by some term which does not imply any particular disease ; it is only confusing to call it " acute nephritis". Occasionally the reverse difficulty is evident. Should a condition be called acute nephritis if there is no preceding infection with haemolytic streptococci, if most of the clinical features of acute glomerular nephritis are absent, and if the histological changes are not those of acute glomerular nephritis ? BATES, JENNINGS, and EARLE 9 illustrate this problem in a paper entitled " Acute nephritis unrelated to group A haemolytic streptococcus infection." "
Ten cases are described in which the most prominent clinical feature was haematuria ; in eight this followed 24-48 hours after the onset of acute pharyngitis, but in two the pharyngitis followed the hsematuria. No patient had a rise in jugular venous pressure or dyspnoea. Only one patient had pretibial oedema, and two had mild periorbital oedema ; there is no mention of diuresis or loss of weight during recovery. Only one patient had a diastolic pressure above 90 mm. Hg. Titres of serumantibodies against haemolytic streptococci, including type8. Lancet, 1957, i, 723. 9. Bates, R. C., Jennings, R. B., 23, 510.
Earle,
D. P.
Amer. J. Med.
1957,
specific antibodies against type 12, were measured in all patients, and except for one equivocal response there was no evidence of a preceding streptococcal infection. Renal biopsies were successfully performed in nine patients, but the average interval between the onset of symptoms and the first biopsy was 34 days. This is too long to make a reasonable comparison with the usual case of acute streptococcal glomerular nephritis ; in which recovery is rapid. In two patients, however, biopsy was done within 10 days of the onset ; at the time of the biopsy one had microscopical haematuria but no proteinuria, and the other had gross haematuria and some protein in the urine ; in the first there were a few minor foci of hypercellularity in the glomerular tufts, and in the second there were no structural abnormalities, though red cells were seen in Bowman’s space. It is clear that these patients did not have the clinical syndrome associated with acute glomerular nephritis, and that they had not recently had an
infection with haemolytic streptococci. In addition, the histological findings in the two cases where biopsy was done near the onset of the haematuria were totally different from those which are found in biopsy specimens obtained at a similar time from unselected patients with acute (streptococcal) glomerular nephritis. HUTT, PINNIGER, and DE WARDENER 10 have described the renal-biopsy findings in fourteen cases of acute glomerular nephritis in which the interval between the onset of the disease and the biopsy was 9 days ; when proteinuria and heematuria were present the characteristic glomerular lesions were found, including proliferation of the cells of the glomerular of the basement memtufts, oedema and brane, and infiltration with polymorph cells. BATES et al. suspect that in their series the acute pharyngitis was due to a virus infection, and they tentatively suggest that the accompanying hsematuria was also viral in origin. This seems a very and it is probable explanation, interesting that this is the first time that such a disorder has been described. Whether this condition should be referred to as acute nephritis " is more debatable.
disruption
"
Annotations BENIGN MYALGIC ENCEPHALOMYELITIS
THE onset of benign myalgic encephalomyelitis is commonly insidious with lassitude and malaise, followed by headache and neck stiffness, sometimes with vertigo and vomiting. There may be paraesthesise of the face and limbs. Though the patient may shiver, fever is often absent and never severe. Changes in mental state, especially depression and difficulty in concentration, are characteristic, and can easily lead to a diagnosis of hysteria. The patient complains of weakness in a limb or limbs, but total paralysis of a muscle is rare. The muscles are painful, and the pain causes great distress. The patient is generally confined to bed after a few days, though the interval may be as long as several weeks. Physical examination suggests a diffuse disorder of the nervous system, causing cerebral, mid-brain, or spinal lesions. The weakness usually proves to be only slight or moderate, and the reflexes
are
normal
or
increased. There is sensory
loss, sometimes of glove-and-stocking distribution, sometimes of a bizarre type corresponding to neither segmental nor peripheral-nerve pattern. The muscles hardly ever waste. The cerebrospinal fluid (c.s.F.) is normal.
The
course
10. Hutt, M. S. R., clin. Path. 1957
of the disease is
Pinninger, ; p. 46.
J. L., de
protracted,
often
Wardener, H. E. Int. Congr.
LEADING ARTICLES
in close agreement. Habituation to oleanresulted in the development of considerable resistance to that antibiotic but little or no change in the sensitivity to tetracycline or sigmamycin. Repeated subculture in the presence of tetracycline produced a lesser degree of resistance to the homologous agent and also some increase in resistance to sigmamycin but no change in sensitivity to oleandomycin. Habituation to sigmamycin little changed the sensitivity to oleandomycin ; there was some increase in resistance to the combination but this was less than the resulting increase in resistance to tetracycline. GARROD4 points out that apparently the smaller amount of the weaker antibiotic (oleandomycin) fails to interfere effectively in the reaction of the organism to the major component in the combination (tetracycline). FAIRBROTHER and SOUTHALL5 consider that these results confirm the claim that the mixture delays, in vitro, the emergence of resistant variants of Staph. aureus. JONES and FINLAND2 noted differences in cross-resistance to erythromycin, oleandomycin, and spiramycin among strains of Staph. aureus freshly isolated from patients ; whereas complete crossresistance to all three agents is known to develop in strains repeatedly subcultered in the presence of any one of them. These observations accord with those reported by GARROD4 and by FAIRBROTHER and SOUTHALL 5. GARROD referred to cross-resistance as being " double " when resistance involved both erythromycin and oleandomycin, and "dissociated" when it was to one agent only. It can be concluded only that oleandomycin and spiramycin are so inferior to erythromycin that their adoption for general use is unwarranted ; indiscriminate use of these weak erythromycin-like agents may produce a staphylococcal population resistant not only to them but also to erythromycin itself. But when strains of Staph. aureus are encountered that are sensitive to these agents but resistant to erythromycin, their use may be justified. Combinations of tetracycline with oleandomycin or spiramycin seem to have little to commend them ; for the clinician presenting them may tend not to provide an effective dose of either drug, and he may falsely feel secure because of a mistaken belief that the combination provides better or broader antibacterial activity. There is no evidence whatever that in vivo such combinations delay or prevent the emergence of resistant variants. Furthermore suppression of resistant variants cannot be expected unless the organism is sensitive to both antibiotics in a combination. JONES and FINLAND6 have used their in-vivo method to investigate the combination of erythromycin and chloramphenicol. This mixture did not appear to be synergistic. There is some in-vitro evidencethat this combination delays the emergence of erythromycin-resistant staphylococci, but there is no proof that the combination has the same action in vivo. It must also be remembered that one component of this combination is a potentially dangerous
results
THE LANCET LONDON:
SATURDAY, DECEMBER 14,
1957
New Combinations of Antibiotics IT is hard to
keep
up to date with the many
new
combinations of antibiotics, and it may be far from easy to assess their value, because the manufacturers sometimes introduce them without adequate laboratory study or clinical trial. We lately evaluated anti-2 biotic combinations,l and now JONES and FINLAND report a detailed study of members of the erythromycin group-erythromycin, oleandomycin, and spiramycin-alone and in combination with tetracycline. With either an agar or a broth-dilution technique they found that, in general, erythromycin was unques-
tionably superior to oleandomycin or spiramycin in its activity against staphylococci and other gram-positive coccal pathogens. They also showed that oleandomycin was more potent than spiramycin. JONES and FINLAND determined the activity in vitro of combinations of tetracycline with either erythromycin or oleandomycin or spiramycin in various proportions. The combination of tetracycline with erythromycin proved superior to combinations of tetracycline with either oleandomycin or spiramycin ; but none of the mixtures, in any of the ratios that
were
used,
was
active than the more potent single comclearly of the mixture on its own. Indeed for most ponent strains the pairs of antibiotics were more often than not found to be inferior to the better of the individual components. JONES and FINLAND determined the antibacterial activity in the plasma of healthy young men after oral administration of the various drugs alone and in combination. The results confirmed their in-vitro findings ; none of the combinations showed activity greater than that obtained from the same dose of the more active component of the pair. The most enthusiastic report of synergism between tetracycline and a member of the erythromycin group was that by ENGLISH et al.,3 whose claim for enhanced activity of a mixture of 2 parts of tetracycline with 1 part of oleandomycin led to such a combination being marketed under a trade name (’Sigmamycin ’). The in-vitro evidence for their claim was not strong, and it is obviously not supported by the work of ’JONES and FINLAND.2 In this country GARROD4 has failed to demonstrate any synergistic activity by such a mixture of tetracycline and oleandomycin against 70 strains of staphylococci ; and FAIRBROTHER and SOUTHALL 5 were similarly unable to show synergism, in vitro, against 165 fresh isolates of common pathogens which included 80 strains of Staphylococcus aureus, ENGLISH et al.3 also claimed that this combination. in vitro, retarded the emergence of antibiotic-resistant variants of one strain of Staph. aureus and one strain of Streptococcus pyogenes. To test this claim GARROD 4 habituated six strains and FAIRIBROTHER and SOUTHALL 5 three strains of Staph. aureus to sigmamycin, oleandomycin, and tetracycline ; and their more
1.
2. 3. 4. 5.
are
domycin
Lancet, July 27, 1957, p. 177. Jones, W. F., Finland, M. New Engl. J. Med. 1957, 257, 481, 536. English, A. R., et al. Antibiot. Chemother. 1956, 6, 511. Garrod, L. P. Brit. med. J. July 13, 1957, p. 57. Fairbrother, R. W., Southall, J. E. Lancet, Nov. 16, 1957, p. 974.
drug. should seek to exercise restraint in and particular care to conserve erythromycin for treatment of life-endangering staphylococcal infections acquired in hospital and
Meanwhile,
the
6. 7.
use
of all
we
antibiotics,
Jones, W. F., Finland, M. New Engl. J. Med. 1957, 257, 744. Wright, S. S., et al. J. Lab. clin. Med. 1953, 42, 877.
1208
thus liable to be resistant to the common antibiotics. If weak erythromycin-like drugs are to be unwisely adopted, we may rely for a time on novobiocin and vancomycin 8; but how long can the production of genuinely new antibiotics keep us ahead in the downhill race ?
" Acute
Nephritis "
A FEW years ago Prof. CLIFFORD WiLSON and Prof. JEAN HAMBURGER were invited to speak about nephritis " at a meeting of the Renal Association. In keeping with English usage Professor ’WrLSON spoke about glomerular nephritis. In France, however, the term nephrite has wider connotations, and Professor HAMBURGER discussed the classification of all renal diseases. There is nothing new about such a confusion in the nomenclature of renal disease; it is due partly to ignorance of their aetiology. What is the accepted meaning of the term " acute nephritis " ? Does it describe a disease, a syndrome, or certain histological changes ? Generally the term is synonymous with a disease-i.e., acute glomerular nephritis, in which infection with haemolytic streptococci is followed after about two weeks by the sudden onset of hypertension, cardiac failure with oedema, proteinuria, and hoematuria. The prognosis of this condition is well defined ; death occurs in a few days in about 3%, in a few months in 7%, and in a few years in another 10% ; the remaining 80% recover completely. In the acute phase the histological changes consist in an intense proliferation and inflammation of the glomerular tufts. There are other causes of sudden onset of hypertension, cardiac failure with cedema, proteinuria, and haematuria-for instance, polyarteritis nodosa, disseminated lupus erythematosus, and anaphylactoid purpura. In these conditions there may be no preceding infection ; and, though there are often certain histological similarities to acute glomerular nephritis, the natural history of subsequent events and the prognosis are different. Nevertheless the clinical features of acute glomerular nephritis clearly form a syndrome which may be found in several other disease processes. It would be of help if this syndrome could be defined by some term which does not imply any particular disease ; it is only confusing to call it " acute nephritis". Occasionally the reverse difficulty is evident. Should a condition be called acute nephritis if there is no preceding infection with haemolytic streptococci, if most of the clinical features of acute glomerular nephritis are absent, and if the histological changes are not those of acute glomerular nephritis ? BATES, JENNINGS, and EARLE 9 illustrate this problem in a paper entitled " Acute nephritis unrelated to group A haemolytic streptococcus infection." "
Ten cases are described in which the most prominent clinical feature was haematuria ; in eight this followed 24-48 hours after the onset of acute pharyngitis, but in two the pharyngitis followed the hsematuria. No patient had a rise in jugular venous pressure or dyspnoea. Only one patient had pretibial oedema, and two had mild periorbital oedema ; there is no mention of diuresis or loss of weight during recovery. Only one patient had a diastolic pressure above 90 mm. Hg. Titres of serumantibodies against haemolytic streptococci, including type8. Lancet, 1957, i, 723. 9. Bates, R. C., Jennings, R. B., 23, 510.
Earle,
D. P.
Amer. J. Med.
1957,
specific antibodies against type 12, were measured in all patients, and except for one equivocal response there was no evidence of a preceding streptococcal infection. Renal biopsies were successfully performed in nine patients, but the average interval between the onset of symptoms and the first biopsy was 34 days. This is too long to make a reasonable comparison with the usual case of acute streptococcal glomerular nephritis ; in which recovery is rapid. In two patients, however, biopsy was done within 10 days of the onset ; at the time of the biopsy one had microscopical haematuria but no proteinuria, and the other had gross haematuria and some protein in the urine ; in the first there were a few minor foci of hypercellularity in the glomerular tufts, and in the second there were no structural abnormalities, though red cells were seen in Bowman’s space. It is clear that these patients did not have the clinical syndrome associated with acute glomerular nephritis, and that they had not recently had an
infection with haemolytic streptococci. In addition, the histological findings in the two cases where biopsy was done near the onset of the haematuria were totally different from those which are found in biopsy specimens obtained at a similar time from unselected patients with acute (streptococcal) glomerular nephritis. HUTT, PINNIGER, and DE WARDENER 10 have described the renal-biopsy findings in fourteen cases of acute glomerular nephritis in which the interval between the onset of the disease and the biopsy was 9 days ; when proteinuria and heematuria were present the characteristic glomerular lesions were found, including proliferation of the cells of the glomerular of the basement memtufts, oedema and brane, and infiltration with polymorph cells. BATES et al. suspect that in their series the acute pharyngitis was due to a virus infection, and they tentatively suggest that the accompanying hsematuria was also viral in origin. This seems a very and it is probable explanation, interesting that this is the first time that such a disorder has been described. Whether this condition should be referred to as acute nephritis " is more debatable.
disruption
"
Annotations BENIGN MYALGIC ENCEPHALOMYELITIS
THE onset of benign myalgic encephalomyelitis is commonly insidious with lassitude and malaise, followed by headache and neck stiffness, sometimes with vertigo and vomiting. There may be paraesthesise of the face and limbs. Though the patient may shiver, fever is often absent and never severe. Changes in mental state, especially depression and difficulty in concentration, are characteristic, and can easily lead to a diagnosis of hysteria. The patient complains of weakness in a limb or limbs, but total paralysis of a muscle is rare. The muscles are painful, and the pain causes great distress. The patient is generally confined to bed after a few days, though the interval may be as long as several weeks. Physical examination suggests a diffuse disorder of the nervous system, causing cerebral, mid-brain, or spinal lesions. The weakness usually proves to be only slight or moderate, and the reflexes
are
normal
or
increased. There is sensory
loss, sometimes of glove-and-stocking distribution, sometimes of a bizarre type corresponding to neither segmental nor peripheral-nerve pattern. The muscles hardly ever waste. The cerebrospinal fluid (c.s.F.) is normal.
The
course
10. Hutt, M. S. R., clin. Path. 1957
of the disease is
Pinninger, ; p. 46.
J. L., de
protracted,
often
Wardener, H. E. Int. Congr.