THE USE AND ABUSE OF ANTIBIOTICS

been able to keep ahead of pharmacological progress by becoming resistant to each new antibiotic that has been introduced. Until recently we have been able to keep the situation under partial control because new antibiotics have generally appeared in time. But we are now face to face with the third disadvantage of anti- biotics. That despite the multiplicity of names given to them, there are in fact very few anti- biotics. Indeed not more than about a dozen all told.

This paucity is due, fundamentally, to the fact that antibiotics come from moulds, and it is only the very exceptional mould that can produce a useful antibiotic at all. Indeed tens of thousands of moulds must have been examined to find the 12 which produce antibiotics that are of value. It is, therefore, wishful thinking to assume that many more antibiotics are likely to become available from naturally occurring moulds in future years. Nor are we entitled to assume too readily that the chemists will come to the rescue and evolve new antibiotics in the test tube for use in the immediate future.

Thus we are faced with a situation that is, as far as I know, completely new to medicine. That with a very limited number of therapeutic sub-

727 stances available, we are trying to combat aetiological agents that can escape from our therapeutic control by not only becoming resis- tant to each substance as soon as they encounter it, but by becoming disseminated far and wide in the community.

Because of this the treatment of infections by antibiotics is by no means so simple as are many other forms of treatment. For it necessitates not only treatment of the infection itself, but an awareness on the part of the physician of the consequences both to the patient he is treating, and to possibly innumerable patients in the future, if the infecting organisms become resistant. The particular techniques the physician can employ to prevent the emergence of resistant strains and to control them if they do, will, I have no doubt, be referred to by subsequent speakers. But to my mind, the most important aspect of all, is that the phycisian must realize every time he uses an antibiotic that powerful weapon though it may be, the organisms it is called upon to combat can, unless carefully controlled, react so violently and successfully that the antibiotic may soon become useless.

It is for this reason that we are met here to- day to discuss the uses and abuses of antibiotics.

THE USE AND ABUSE OF ANTIBIOTICS-continued:

DRUG-RESISTANT STAPHYLOCOCCAL INFECTION BY

MARY BARBER, M.D. Postgraduate Medical School of London

ABOUT 25 years ago, prontosil was first used in the treatment of puerperal sepsis (Colebrook and Kenny, 1936). It is perhaps difficult for young obstetricians today to appreciate the drama of this. But, prior to the introduction of the sulphonamides, if a patient became infected with a haemolytic streptococcus in the puerperium she was expected to die, and the curative effect of prontosil was, in the words of Colebrook (1956), “something we had never seen in ten years experience of the disease”.

Today, I shall speak mainly about one of the unfortunate effects of the use, or perhaps I should say, misuse, of sulphonamides and anti- biotics, namely, drug-resistant staphylococcal infection. But, in order to put this in true perspective, I wish first to draw attention to the remarkable fall in the incidence and mortality of infections since 1935. Although it cannot be claimed that antibiotics are solely responsible for this, it is certain that they have played a major part.

728 JOURNAL OF OBSTETRICS AND GYNAECOLOGY

Sulphonamides 1800

Rnicillin

Streptomycin ./, jhloromphenicol

I200 tetracycines

I 0 0 0 I b

Ot------ 1930 1935 1940 1945 1950 1955

FIG. 1 Deaths from all infective and parasitic diseases per

million living in England and Wales, 1930 to 1957.

Infection d u r q childbirth and the pwrmum

I 1930 1935 1940 1945 1950 1955

FIG. 2 Puerperal pyrexia. Deaths per 100,OOO total births and incidence per 100,OOO population in England and Wales,

1930 to 1957.

Figure 1 shows the number of deaths per million living in England and Wales from all forms of infectious disease, between 1930 and 1957. It will be seen that since the introduction of antibiotics the mortality from infectious diseases has fallen by more than 80 per cent. It is of interest to note that in 1934 the number of deaths from infection was ten times the number of deaths on the road. By 1957 the figures were almost equal, although deaths on the road in that year were no higher than in 1934.

Figure 2 shows the deaths from puerperal infection per 100,000 total births in England and Wales for the same period. It will be seen that deaths from this condition have fallen to a very low level indeed since the introduction of sulphonamides. The incidence of puerperal pyrexia per 100,000 population is also shown and it will be seen that after an initial fall, there was apparently a sharp increase in 1951. It will not be necessary for me to explain to this audience that the increase reflects a change in the defini- tion of puerperal pyrexia for the purposes of notification, rather than a true increase in the incidence of infection.

EMERGENCE OF DRUG-RESISTANT STAPHY- LOCOCCAL INFECTION IN HOSPITALS

Not all bacteria, however, have taken the attack lying down, and certain species, notably Staph. aureus, Myco. tuberculosis and coliform bacilli, have shown a quite remarkable capacity to adapt themselves to the presence of anti- biotics. With the staphylococcus, indeed, there has been a neck and neck race between the discovery of new anti-staphylococcal agents and the capacity of the staphylococcus to breed strains resistant to previous ones.

A rapid and progressive increase in the incidence of drug-resistant staphylococcal infec- tion has been reported from hospitals all over the world in the last ten years or so. Figures 3 to 6 give examples from London, Paris, Sydney and Washington. It will be seen that by 1951 or earlier, the incidence of staphylococcal infection resistant to penicillin was over 50 per cent in all four hospitals. Since the tetracycline antibiotics were not introduced until after this had happened

THE USE AND ABUSE OF ANTIBIOTICS

it was penicillin-resistant staphylococci that became resistant to these antibiotics, so that hospital staphylococci tended to be resistant to both penicillin and the tetracyclines.

L 1946 l9JT 1948

,Chlortel Inlroducad I 953 o,o l e t Ras Inlaction

6o t

5 0

10 2o I

1955 IQ5T

FIG. 3 Increasing incidence of staphylococcal infection in a London hospital resistant to penicillin, 1946 to 1948 (from Barber and Rozwadowska-Dowzenko, 1948) and

tetracycline, 1955 to 1957.

- Penicillin

5 0 t

FIG. 4 Increasing incidence of drug-resistant staphylococcal infection among out-patients attending a hospital in Paris, 1948 to 1952 (based on the figures published by Chabbert,

Terrial and Schutzenberger, 1953).

OIO

70

60

50

4 0

30

20

10

729

Penicillin P-

Jan. Apr. Jul. Oct. Jan. 1951 19 5 2

FIG. 5 Increasing incidence of drug-resistant staphylococcal infection in a hospital in Sydney, Australia, 1951 to 1952 (based on the figures published by Rountree and

Thomson, 1952).

The situation with regard to streptomycin and chloramphenicol, which were introduced in 1944 and 1948 respectively, is rather different, since neither have been used extensively in general hospitals. Streptomycin has been reserved for the treatment of tuberculosis or acute infections for which there is no other equally effective drug, owing to the rapidity with which most bacteria can become resistant to it. In spite of this restriction, in many hospitals the prevalent staphylococcus is resistant to this antibiotic, as well as to penicillin and the tetracyclines.

The use of chloramphenicol has been kept low because of its possible effect on the bone marrow. This has meant that in most hospitals chloram- phenicol-resistant staphylococci are rare. It will be seen from Fig. 6 that in a hospital in Seattle,

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Epidemiological studies, including bacterio- phage typing of strains, have shown that the rapid increase in the incidence of drug-resistant staphylococci in hospitals is the result of two factors, namely, the extensive use of antibiotics and cross-infection. Thus in the first place, nearly all the drug-resistant strains emerging in a hospital or department are of one or two phage types, which have been “passaged” from patient to patient in the presence of the antibiotic to which they have become resistant.

730

O/O I

7 0

60

so

40

30

20

10

I

I951 1953 FIG. 6

Tncreasing incidence of drug-resistant staphylococcal infection in a hospital in Seattle, Washington, 1951 to 1953 (based on the figures published by Kirby and Ahern,

1953).

Washington, the incidence of chloramphenicol- resistant staphylococcal infection fell from 20 per cent to 6 per cent between August 1951 and April 1953, and this was associated with a drastic reduction in the use of the antibiotic, following reports of bone marrow damage.

By the time erythromycin arrived on the scenes, the warning had been sounded, and in most hospitals this antibiotic has been kept in reserve for infections resistant to other drugs. Even so erythromycin-resistant staphylococcal infection is not uncommon, since staphylococci develop resistance to erythromycin so rapidly that a gross change may occur during the treat- ment of a single case.

INFECTION IN MATERNITY DEPARTMENTS Maternity departments are no exception and,

even where there is no gross sepsis, the babies usually go home carrying drug-resistant Staph. pyogenes in the nasopharynx. The strains isolated tend to be resistant to penicillin only and are frequently of phage type 52A (Group 1). In this they differ from those responsible for most cases of surgical cross infection, which are usually multiple resistant strains of phage group 111 or type 80 (Barber and Burston, 1955; Shooter et al., 1958). The maternity strains, however, frequently resemble those carried by a large proportion of the nursing staff.

Examples from two maternity units will illustrate this. The first study was undertaken in a maternity hospital where there had been an outbreak of severe staphylococcal infection among the babies, due to a penicillin-resistant staphylococcus of phage type 52A. Similar strains were isolated from the conjunctiva of 16 of 35 healthy babies and from the noses of more than half of the nursing staff. The latter were studied repeatedly over an eight-month period, and it was found that the nasal carriage remained constant, in spite of the fact that the nurses themselves were continually changing, as the hospital was a training school for pupil mid- wives who came for a period of one to three months. When the nasal carriage rate of penicillin-resistant Staph. pyogenes was studied in relation to the length of time the nurses had been in the hospital, it was found, as shown in Fig. 7, that the two went closely together. Thus only 24 per cent of nurses who had been in the hospital for a fortnight or less carried such strains, whereas the incidence among nurses who had

73 1 THE USE AND ABUSE OF ANTIBIOTICS

STAPH PVOGENES

PENICILLIN-RESISTANT

% o f 6 o Nurser

4- 3 L i 1-14Dayr 6 Weeks 3Months

M A T E R N I T Y N UA S E S

FIG. 7 Nasal carrier state among nurses at a maternity hospital

related to time since entry to the hospital.

been there three months or more was 67 per cent. The majority of all typeable penicillin-resistant strains belonged to phage type 52A, so that it is fairly clear that most of the pupil midwives were picking up the prevalent hospital staphylococcus after their arrival (Barber, Hayhoe and White- head, 1949).

The second study was carried out in a maternity unit where the sepsis rate was extremely low and such lesions as occurred were trivial. Nevertheless it will be seen from Fig. 8 that 61 per cent of the nurses and 65 per cent of

NASAL CARRIAGE. Staph Pyoqrnrs HA1 U N I T I O > Z J

1 0 1 A L

P l Y I C I U I N 11SlSlANl

) M A C 1 l l P 1 52). P I N I C I I L I U 1 1 S I S 1 A U l

I.

1 0 , N U I S I S OOHLS11CS nh .drn#a%som .I 1m1<bwq. Ill6115 L I l U D l Y l S ---MOlYlRS

FIG. 8 Nasal carrier state of staff and patients in a maternity

department, where there was no gross sepsis.

the babies carried penicillin-resistant Staph. pyogenes in the nose, and that about a quarter of the mothers picked up penicillin-resistant staphylococci during their stay in hospital. Again, a large proportion of the penicillin- resistant strains belonged to phage type 52A (Barber et al., 1953).

Thus penicillin-resistant staphylococci appear to be freely disseminated even in a clean maternity unit. To what extent this means that we are sitting on a volcano it is difficult to say. There is some evidence to suggest that carrier strains, in the absence of sepsis, lose some of their virulence. An increase in the incidence of minor sepsis is probably a danger signal. Thus both Rountree and Freeman (1955) and Beaven and Burry (1956) describe outbreaks of severe neonatal infection due to strains which had apparently become of increased virulence by passage among babies suffering from minor infections, the incidence of which had been increasing. In both these studies, however, the infecting staphylococcus was a multiple resistant strain of phage group 111 (Beaven and Burry) or type 80 (Rountree and Freeman) similar to those occurring in surgical wards, and there is some evidence to suggest that such strains are of higher virulence than those resistant to penicillin only and of phage type 52A (Shooter et al., 1958; Barber er al., 1960).

PREVENTIVE MEASURES The question remains, what can be done to

improve the situation ? Since both cross-infection and the widespread use of antibiotics have played their part in the emergence of drug- resistant staphylococcal infection, both must be attended to. In this short communication, it is not possible even to outline measures for dealing with cross-infection, nor to obstetricians should this be necessary. But in view of the work referred to above, it is worth emphasizing that even minor neonatal sepsis should be taken seriously, that there should be as little contact as possible between maternity and surgical wards, and that nurses or doctors carrying multiple resistant staphylococci in the nose should be kept out of maternity units until their carrier state has been changed.

41

732

Finally, is it possible by a controlled antibiotic policy to reverse the drug-resistance of hospital staphylococci? A policy involving drastic restric- tion in the use of penicillin and the treatment of all infections with two drugs in combination has been carried out for two years at Hammersmith Hospital (see Barber et al., 1960). During the investigation, more than 5,000 patients were admitted to the surgical wards of the hospital and about 10 per cent were infected with staphylococci, occasionally before, but usually after admission to the hospital. At the beginning of the experiment only 12 per cent of the infections were sensitive to all antibiotics including penicillin; today the figure has risen to more than 50 per cent. During the same period the proportion of strains resistant to penicillin and the tetracyclines has been reduced from 70 per cent to 29 per cent.

That this experiment has not just been an academic exercise is shown by the fact that the mortality from staphylococcal sepsis fell steadily with the fall in the incidence of multiple- resistant infection and that, in fact, of 132 patients with penicillin-sensitive infections only 1 , a man 80 years old, died, whereas there were 23 deaths among 224 patients infected with multiple resistant strains.

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staphylococcal infection of greater severity than before the introduction of these powerful drugs. But, even with the versatile staphylococcus, the position is not hopeless, if we are prepared to take it seriously enough. A combined attack on cross-infection, including the provision of adequate isolation facilities, and on the misuse of antibiotics, would go far towards solving the problem.

CONCLUSION Today we reap the rewards of the indiscrimi-

nate use of antibiotics, in a problem of hospital

REFERENCES Barber, M., and Burston, J. (1955): Lancet, 2, 578. Barber, M., Dutton, A. A. C., Beard, M. A,, Elmes,

P. C., and Williams, R. S. (1960): Brit. med. J., 1, 1 1 . Barber, M.. Hayhoe, F. G . J., and Whitehead, J. E. M.

(1949): Lrlacet, 2, 1120. Barber, M., and Rozwadowska-Dowzenko, M. (1948):

Lancet, 2, 641. Barber, M., Wilson, B. D. R., Rippon, J. E., and

Williams, R. E. 0. (1953): J . Obstet. Gynaec. Brit. Emp., 60, 476.

Beaven, D. W., and Burry, A. F. (1956): Lancet, 2, 211. Chabbert, Y . , Terrial, G., and Schutzenberger, M . P.

(1953): Ann. Inst. Pusteur, 84, 952. Colebrook, L. (1956): Brit. med. J . , 1, 247. Colebrook, L., and Kenny, M. (1936): Lancet, 1, 1279. Kirby, W. M. M., and Ahern, J. J. (1953): Antibiot. and

Chemotheu., 3, 831. Rountree, P. M., and Freeman, B. M. (1955): Med. J .

Ausi., 2, 157. Rountree, P. M. , and Thomson, E. F. (1952): Lancer, 2,

262. Shooter, R. A., Smith, M. A., Griffiths, J. D., Brown,

M. E. A., Williams, R. E. O., Rippon, J. E., and Jevons, M. P. (1958): Brit. med. J . , 1, 607.

THE USE AND ABUSE OF ANTIBIOTICS-continued:

B. W. LACEY, B.Sc., M.D. Westminster Hospital, London

DR. BARBER has just emphasized the inter- dependence of antibiotic usage and cross- infection and the urgent need to control both if infection in the maternity unit is to be reduced to an acceptable minimum. It seems to me that this problem resembles that of cancer, and indeed many others in medicine, in that although many factors are known their relative im- portance and causal relationships are very

difficult to assess. I propose therefore only to present a perspective of the problem from a bacteriologist’s point of view, not of course as something established or even generally accept- able, because there is no such thing, but largely as a basis for discussion.

The amount of infection in a maternity unit can conveniently be regarded as the product of the following: