Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Current Medical Research and Opinion
Vol. 4, No. 8, 1977
Treatment of acute bacterial infections of the upper respiratory tract
M. S. Nadkarni,* M.D., P. A. Shah,** M.S.,F.R.C.S.,
Curr. Med. Res. Opin., (1977), 4, 544.
and
S. Thakurdesai, M.Sc. Department of Microbiology, Grant Medical College, and Sir. J . J . Group of Hospitals, Bombay, India Received: 18th December 1976
Summary A n open comparative study was carried out to assess the effectiveness of 4 antibiotic regimens in eradicating acute bacterial infections of the upper respiratory tract. Patients in each treatment group had similar physical parameters, severity of disease and bacterial pathogens, and were treatedfor 10 days with either erythromycin estolate, erythromycin stearate, ampicillin or oxytetracycline in the recommended dosage. Each patient was reviewed daily by physical examination and the bacteriological findings from throat swab andsalivary washings. The results showed that erythromycin stearate produced more rapid bacterial eradication and clinical resolution of symptoms and fever than with the other antibiotic preparations, and was well tolerated by most patients. Key words: Erythromycin - ampicillin - oxytetracycline - upper respiratory infections
Introduction Soon after its introduction in the mid-1940s penicillin became accepted as the therapy of choice for Gram-positive coccal infections of the respiratory tract. For some time it was the only antibiotic available for this or any other purpose and it attained a very high level of use throughout the world. Whilst its efficacy for streptococcal infections continued unimpaired, penicillin became progressively less useful for the treatment of staphylococcal infections owing to the rapid and extensive emergence of resistant strains, both in hospital and more recently in community strains.’ * Because of this, there was a swing to the empirical use of other antibacterial agents as they were developed, particularly chloramphenicol until its hazards became apparent, and then the choice increasingly favoured the tetracyclines. In their turn the tetracyclines have lost much of their therapeutic efficacybecause of the increasing incidence of resistance in both staphylococci and streptococci and more recently in pneumococci.’ 4.23 With the introduction of ampicillin, a penicillin with Gram-negative antibacterial activity, it has been used empirically as an alternative to both tetracycline and penicillin, although it is much less effective than ordinary penicillin against Grampositive cocci.’ Still more recently, recognition of the phenomenon of transferrable *Professor and Head of Department of Microbiology, **Assistant Honorary Ear, Nose and Throat Surgeon, Sir J. J. Group of Hospitals 544
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah and S. Thakurdesai
drug resistance in the Enterobacteriaceae has thrown doubt upon the wisdom of using either tetracycline or ampicillin as the treatment of choice for Gram-positive infections. Indeed, it has become evident that if these ‘broad-spectrum’ antibiotics are to retain any value in the therapy of Gram-negative infections of the lower bowel their indiscriminateuse in the treatment of respiratory tract infections,where a more specific antibiotic may be employed, must be drastically curtailed.’ 1 Several authorities2.lg have urged constraint in their use and a Leading Article9 on this subject questioned whether the possible effect of tetracycline and ampicillin on the bowel flora should not deter doctors from prescribing them, for example in mild infections of the respiratory tract. We decided, therefore, to compare the clinical efficacy of relatively narrowspectrum antibiotics with that of tetracycline and ampicillin in the treatment of mild respiratory tract infections, in the hope of finding a more selective antibiotic which would be effective as an empirical initial therapy, i.e. when prior bacteriological identification and antibiotic sensitivity testing are not immediately or conveniently practicable for one reason or another. In the choice of suitable and available narrowspectrum antibiotics we considered that benzyl penicillin and phenoxymethyl penicillin must be excluded because they cannot be expected to be uniformly efficacious in the treatment of staphylococcal infections. Lincomycin and clindamycin were considered unsuitable for routine use because of their reported toxicity.20-z4 Sulphonamides are no longer indicated in the treatment of streptococcal infection2’ and sulphonamide-trimethoprim combinations have yet to be proved capable of safe and sustained efficacyagainst sulphonamide-resistantstrains, a capacity mandatory in any empirical therapy. It was decided, therefore, to compare the clinical use of erythromycin, which we regard as a fairly narrow-range antibiotic, with ampicillin and oxytetracycline, the broad-spectrum antibiotics commonly used in empirical treatment. Erythromycin is available both as the propionyl ester (‘Althrocin’) and as the stearate (‘Erythrocin’t). Our study was designed to ascertain the causative organisms in acute upper respiratory tract infections seen at our hospital and to observe the efficacy of the four antibiotic preparations (two narrow and two broad-spectrum) in the clinical relief of these infections and in bacteriological clearance of the pathogen involved. All were prescribed according to manufacturers’ instructions.
Methods and materials In order to eliminate any bias due to the spontaneous remission of viral respiratory tract infections, it was decided to admit to the study only cases with bacteriologically confirmed acute bacterial infections of the upper respiratory tract. All the patients considered for admission to the study were examined by one of us in the Ear, Nose and Throat Out-Patients Department of the Sir J. J. Group of Hospitals, Bombay. Clinical criteria for admission to the study dictated admission of only adult patients ttrade mark, Abbott
545
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Treatment of acute bacterial infections of the upper respiratory tract
with fever greater than 98.6”F, together with symptoms and clinical signs of acute tonsillar o r pharyngeal infections. Exposure to any antibiotic within the preceding 7 days excluded admission. Suitable patients underwent a clinical examination at which throat swab and salivary washings were taken for culture and subsequent antibiotic sensitivity testing of the isolates. The salivary washings were collected by rinsing the mouth with 10 ml sterile normal saline. Care was taken to ensure that the patient did not take any hot or cold drinks for 30 minutes before the collection of the washings. Salivary stimulants were not used. The throat swabs were obtained under direct vision either from the affected tonsil in the case of patients with tonsillitis or from the posterior pharyngeal wall in cases of pharyngitis. In each case, specimens were collected on sterile cotton wool swabs. Specimens were incubated overnight on blood agar, trypticose soy broth and MacConkey’s medium. I n addition, a sample of blood was collected in an oxalate tube for haemoglobin estimation, total and differential white cell count, and packed cell volume. Patients considered suitable for inclusion in the study were requested to return the following day for specific antibiotic therapy. At this visit they were required to provide a stool sample. This was inoculated onto MacConkey’s medium, incubated overnight, any growth examined, and sensitivities to the antibiotics involved in the study determined. The selected patients were allocated by stratification on the basis of initial culture to one or other of the 4 groups to undergo therapy with the test antibiotics, thereby ensuring equal distribution of treatments amongst the pathogens isolated. Patients returned daily for 7 days to the clinic and again on the 10th study day. At each attendance, clinical assessment was undertaken by the same investigator and a further throat swab and salivary washing obtained. In order to ensure compliance with regard to medication, treatment was dispensed daily and a note made of any side-effects during the preceding 24 hours. Symptoms such as abdominal pain, nausea, vomiting, diarrhoea, constipation or rash were solicited at each attendance. The stool culture, which was intended to reveal any change in bowel flora due to antibiotic therapy, was repeated only on the 5th and 10th day. The time required for clinical cure was defined as the first examination at which the patient was asymptomatic, apyrexial, and at which physical examination was negative. The time required for bacteriological cure was defined as the day on which the initial pathogen had been eradicated without subsequent recurrence. If the symptoms were not resolved or the patient failed to become apyrexial by the 10th day, the case was classified as a clinical failure for the treatment applied. Similarly, if the initial pathogen was still demonstrable on the 10th day, either from throat swab or salivary washings, the case was considered a bacteriological failure for the antibiotic used.
Results Initially, 125 patients fulfilled the criteria for inclusion in the study. Of these, 14 (1 1 %) failed to complete the 10-day review and were excluded from the final analysis. 546
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah and S. Thakurdesai
Analysis of the 4 treatment groups on the basis of age, sex, height and weight demonstrated no statistically significant difference between the groups with regard to physical characteristics. Haemoglobin, haematocrit readings, height and weight were considered indications of nutritional status. Again, there was no statistical difference between the 4 groups. Fever present at the first consultation together with total white cell count and polymorphonuclear count were considered as indications of the severity of the bacterial infection. In this respect, no statistically significant difference was detected between the 4 groups. We considered that the initial white cell count might give some indication of bacterial aetiology of the infection. However, there was no reasonable degree of correlation between the pathogen isolated and the initial body temperature or the white cell count. In summary, therefore, the treatment groups were considered comparable in respect of physical characteristics, severity of infection and bacterial aetiology of the disease process, the only demonstrated variable between the 4 groups being the particular therapeutic regimen used. Table 1 summarizes the comparative sensitivity of the throat swab and salivary washings as an indicator of bacterial eradication. It will be seen that the throat swab was more sensitive than salivary washings. With regard to clinical cure, fever was slightly more sensitive than symptomatology in the definition of clinical cure. Table I. Comparative sensitivity of different methods of assessing bacteriological and clinical cure in 111 patients
Assessment Bacterial eradication Throat swab more sensitive Salivary washings more sensitive Equal in sensitivity Clinical cure Fever more sensitive Symptoms more sensitive Equal in sensitivity
No. patients
43 7 61
44 28 39
Table I1 gives details of the overall clinical and bacteriological cure in the 4 treatment groups together with a distribution of organisms between the treatment groups. Using a Chi-squared test for independence there was no statistical difference in the distribution of organisms among the treatment groups. Infecting organisms isolated included Streptococcus pyogenes, Staphylococcus pyogenes, Diplococcus pneumoniae, Streptococcus viridans, separately and in combination. Streptococcus viridans was only considered to be pathogenic where it was the principal organism isolated as a heavy growth; the clinical findings supported this diagnosis. Clinical resolution is illustrated in Figures 1 and 2. From Figure 1 it will be seen that erythromycin stearate caused a significantly more rapid subsidence in fever than the other antibiotics. The erythromycin stearate group showed a significantly greater number ofpatients apyrexial thaneithertheampicillin (p < 0.01) or the oxytetracycline (p = 0.03) group on the second treatment day. 547
Treatment of acute bacterial infections of the upper respiratory tract
Table II. Overall assessment of ‘cure-rate’ and distribution of organisms in 4 treatment groups: number of patients
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Assessment
Erythromycin Erythromycin stearate estolate
Ampicillin
Oxytetracycline
25
29
21 1
29
23 2
21 8
26 2
14
Distribution of organisms isolated Streptococcus viridans
6
Mixed infection
5
Staphylococcus pyogenes
Pneumococcus
4 5
Streptococcus pyogenes
5
5 6 5 5 8
5 5 5 5 8
I 5 5 6 6
Clinical assessment: Day I0
Success Failure Bacteriological assessment: Day 10
Success Failure
15
Figure 1. Comparative rapidity of clinical cure in 4 treatment groups: reduction of fever 100
90 80 70
60 50 40 0 Erythromycin stearate
30
0
Erythromycin estolate
A Ampicillin
20
o Oxytetracycline
10 0 0
1
2
3
4
5
6
10
Treatment day
Although more patients on erythromycin stearate were apyrexial than those on erythromycin estolate, the results did not reach statistical significance. Figure 2 demonstrates the resolution of symptoms and duration of treatment. There was no significant difference between symptomatic relief and the drug used. 548
M . S. Nadkarni, P. A. Shah and S. Thakurdesai
Figure 2. Comparative rapidity of elimicaI cure in 4 treatment groups: relief of symptoms
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
100
-
90
n
80
a
70
v1
0 C
.-
-E
.-0
a
E
?:
60
c
-E .-i9
50
m M
40 30
D Erythromycin stearate
20
A Ampicillin
-m
G’
u
Erythromycin estolatc 0 Oxytetracycline
10
0 0
1
2
3
4
5
6
10
Treatment day
Figure 3 compares the rapidity of bacterial eradication among the preparations used. By Day 3 , 9 out of 25 patients treated with erythromycin stearate had demonstrated bacterial eradication compared with only 2 of 29 treated with oxytetracycline (p =0.02). Nine patients out of 29 treated with erythromycin estolate and 8 out of 28 treated with ampicillin had also demonstrated a significantly better bacteriological cure rate than the oxytetracycline group (p =0.04). Bacteriologicalcure rates with erythromycin stearate were significantlybetter than with erythromycin estolate on Day 4 (p = 0.03) and Day 5 (p =0.05). Additionally, ampicillin and erythromycin stearate were both significantly superior to oxytetracycline (p < 0.01), although the results with ampicillin were not superior to those obtained with erythromycin estolate. At the conclusion of treatment both ampicillin and erythromycin stearate were still significantly superior to oxytetracycline in terms of bacterial eradication (p < 0.01). No important difference was apparent in the incidence of side-effects, but they appeared to have been rather more troublesome amongst those patients treated with oxytetracycline (Table In). Diminution of bowel flora was demonstrable following dosage of all 4 antibiotic preparations, but the post-therapy antibiotic sensitivitytesting did not demonstrate a particular pattern for any of them. 549
Treatment of acute bacterial infections of the upper respiratory tract
Figure 3. Comparative rapidity of bacterial eradication in 4 treatment groups
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
loo
1
90 -
80 -
60 50 70
40
-
30
-
0
Erythromycin stearate Erythromycin estohte
A
.Ampicillin
[.I
"1
o Oxytetracycline
10
Treatment day Table Ill. Number of patients reporting side-effects Side-effect
Erythromycin stearate
Nausea
8
Constipation Diarrhoea
1
Abdominal pain
2
Rash
1
No. side-effects
12
Erythromycin estolate
Ampicillin
Oxytetracycline
11
11
11
1
3
3 3
5
2
3 1
17
16
21
Discussion The design of the study ensured that the pathogens isolated from the throat swabs were equally represented in each of the 4 treatment groups. Analysis at the conclusion of the study of the physical characteristics, haematological parameters and initial clinical findings of the patients revealed that the 4 treatment groups were comparable and that the only variable in the study was the therapeutic regimen utilized. The 550
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah, and S. Thakurdesai
bacteriological procedures applied to the salivary washings and throat swabs were identical and under the control of one of us so that we were able to ensure uniformity of laboratory standards. In undertaking both salivary washings and routine throat swabs we could not confirm the findings of Ross’ who, following a study in children with streptococcal infections, suggested that salivary cultures were superior to throat swabs in assessing bacterial eradication. In our study, only in 1 of the 27 patients with Streptococcusp~~ogenes infections did the salivary washings prove more sensitive than the throat swab. Throughout the series of 11 1 infections the salivary washings proved more sensitive only for 7 isolates compared with 43 throat swabs (Table I). In medical practice, microbiological culture and antibiotic sensitivity testing are not routinely undertaken in our country owing to the expense involved and to the relatively large patient population. Even in more affluent societies there is a tendency to neglect this desirable prelude to antibacterial therapy, and Lakes reported that only 3.4 % of patients with acute infections were referred for microbiological study. Most clinical studies on antibiotic treatment include only pre- and post-therapy cultures, but in studying the efficacy of a group of antibiotics we considered it essential to undertake daily cultures in addition to physical examination. The results of our study show differences in the achievement of clinical resolution and of bacterial eradication in the 4 treatment groups. Figure 2 illustrates the time taken for symptomatic relief to occur and shows no statistical difference between the 4 groups. Figure 1 compares the daily cumulative percentage of patients becoming apyrexial following treatment. Erythromycin stearate effected a more rapid return to normal temperature than the other 3 antibiotic preparations. The most striking difference in the results of the 4 treatment groups was seen in the rate of bacterial eradication (Figure 3). Following 10 days treatment with oxytetracycline, only 15 (5 1.7 %) of 29 demonstrated bacteriological cure, although all had undergone clinical resolution by the 10th day. Organisms persisting included Pneumococcus (3 cases), Streptococcus (3 cases) and Staphylococcus (2 cases). This represents an unacceptable bacteriological failure rate in patients with upper respiratory tract infections and is in agreement with the experience of other authors who suggest that over the years resistance to tetracycline has become so frequent in strains of haemolytic streptococci and pneumococci that this antibiotic should no longer be used as the primary treatment of sore throats or pneumococcal pneumonia.’ . 4 Tetracycline-resistant strains of Streptococcusp~ogenes were first noted in hospital isolates in 1952;’2 since then, there has been avarying incidence of resistant strains of up to 40 % isolated from domiciliary patients.23 Recently, the incidence of Streptococcuspneumoniae resistant to tetracycline has increased and up to 30 % of isolates in a recent study demonstrated minimum inhibitory concentrations greater than 2.0 mcg/ml to tetracycline, whilst erythromycin was shown to inhibit all strains at a concentration of less than 0.03 mcg/ml.l The failure of tetracycline in our study can be directly attributed to bacterial resistance, but this is not so with the erythromycin estolate group. Whilst clinical resolution occurred in all 29 patients treated with erythromycin estolate, 8 patients failed to demonstrate bacterial eradication of the primary isolate (2 cases of Strepto551
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Treatment of acute bacterial infections of the upper respiratory tract
coccus pyogenes and 1 case of Streptococcus pneumoniae),giving an overall cure rate of 72 %. Furthermore, the response to erythromycin estolate was slower than to either ampicillin or erythromycin stearate. Erythromycin estolate, being absorbed as the ester, requires hydrolysis to erythromycin base before it can exhibit bacterial activity.6 A percentage of erythromycin estolate may be excreted unchanged in the urine as hydrolysis may not have occurred prior to excretion.3 It is suggested that this is the reason for the slow response with this antibiotic, although at the 10-day review there was no statistical difference between the bacterial eradication obtained with erythromycin stearate, ampicillin or erythromycin estolate. Both erythromycin stearate and ampicillin were statistically superior to oxytetracycline in the rate and degree of eradication. The results obtained with ampicillin therapy were considerably better than those with oxytetracycline. Symptomatic relief occurred within 6 days in all 28 patients treated, and only 2 failed to demonstrate bacteriological cure by the 10th day (1 case of Streptococczrspyogenes infection), an overall success rate of 93 %. Whilst the speed of bacterial eradication with ampicillin was slower than with erythromycin stearate, this difference was not statistically significant. Erythromycin stearate gave the fastest bacterial eradication, and clinical resolution had been obtained in all patients by the 7th day, all being apyrexial by the 5th day. Only 2 of the 25 patients treated with erythromycin stearate failed t o demonstrate bacterial eradication by the 10th day (1 Streptococcus viridans, 1 mixed infection), an overall success rate of 92 %. The changes in the antibiograms of Escherichia cofi in our patients were similar with all 4 treatments. This does not conform with the findings of other worker^,^,'-^^ who have demonstrated in patients receiving courses of tetracycline, strong selection not only for strains of E. coli resistant to tetracycline but also for strains showing multiple resistance, the frequency of resistance to ampicillin, streptomycin, chloramphenicol and sulphonamides in E. coli increasing in patients treated with tetracycline. Knothe and Wiedemann’ treated 8 volunteers as out-patients with tetracycline in doses of 0.5 g twice daily. Tetracycline-resistant E. coli appeared in all the subjects within 24 hours ofcommencing treatment. In the same study, treatment with erythromycin ethylsuccinate or erythromycin stearate did not affect E. coli and there was no selection of R-factor bearing strains. Although selection of resistant strains in the bowel by ampicillin and amoxicillin therapy is not as strong as by tetracyclines, it is still significant. In our series the incidence of side-effects with the 4 antibiotics was similar, although it appeared that they were slightly more numerous and troublesome with oxytetracycline. The major reported side-effect of ampicillin therapy is allergy and skin eruption, which is greater following treatment with ampicillin than with other penicillins.22 In addition, this effect is more common in patients suffering from infectious mononucleosis or viral diseases. Because all our patients suffered from bacterial infections, the incidence of this side-effect in our series was comparatively low. In selecting an antibiotic for treatment of simple infections such as acute sore throat, therapy should be directed at patient care and protection of the environment. 5 52
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah and S. Thakurdesai
Antibiotics should be selected which are efficacious, have minimal side-effects, are unlikely to produce resistance, and which are without influence on the commensal organisms in the alimentary tract. Erythromycin stearate (‘Erythrocin’) in this study demonstrated statistically significant superiority over both tetracycline and erythromycin estolate in rapidity of bacterial eradication. In addition, this antibiotic proved to be remarkably free from adverse side-effects, exerted no influence on bowel flora, and was well tolerated by the majority of patients with the exception of a few who experienced gastro-intestinal disturbance. Bacterial resistance to erythromycin stearate amongst Gram-positive organisms is remarkably low and confined to an 8 % incidence amongst out-patient staphylococci.1* Early fears that erythromycin-resistant strains of Staphylococcus aureus would rapidly emerge if erythromycin was used frequently have not been substantiated. In a recent study of 15-months’ continual use of an empirical treatment for throat and skin infections, erythromycin-resistant staphylococci did not appear.’ Strains of Streptococcus pyogenes resistant to erythromycin continue to be rare : Robertson1 5 found only 8 strains in over 6000 isolates. Strains of Streptococcus pneumoniae resistant to erythromycin have been reported but do not appear to be at all common. The indiscriminate use of antibiotics is to be condemned and, where possible, a selective antibiotic is to be preferred to a broad-spectrum one, provided that clinical efficacy can be demonstrated. The results of this study have clearly demonstrated the efficacy of erythromycin stearate (‘Erythrocin’) in the treatment of bacterial infections of the upper respiratory tract. I n fact, the spectrum of the drug covers the majority of bacteria responsible for respiratory tract infections and includes such organisms as Corynebacterium diphtheriae and Bordetellapertussis, which are commonly associated with troublesome infections in the tropical climate, and for which erythromycin is recognized as the treatment of choice. As erythromycin is the most effective agent for the treatment of Mycoplasma pneumoniae, a common cause of upper respiratory tract infections in temperate climates, its spectrum demonstrably covers all the important pathogens causing acute upper respiratory tract infections.
Acknowledgements We would like to acknowledge the help of the Medical and Nursing staff of the Sir J. J. Hospital, Bombay. Our sincere thanks go to Drs. C. E. Cook and M. A. Neaverson of Abbott Laboratories, who supported the study, and to Mr. H. Frush who undertook the statistical analysis.
References
1. Ball, A. P., Gray, J. A., and McC Murdoch, J., (1975). Antibacterial drugs today. Curr. Therapeutics, 16,97. 2. Christie, A. B., (1970). Advances in the treatment of infectious diseases.Practitioner, 205,516. 3. Chun, A. H., and Wiegand, R. G., (1971). In: Proc. Acad. Pharmacol. Sci. Symposium, Am. Pharmacol. Assoc. 4. Committee on Drugs, (1975). Requiem for tetracyclines.Pediatrics, 55, 142. 5 . Datta, N., Faiers, M. C., Reeves, D. S., Brudtt, W., 0rskov, F., and 0rskov, I., (1971). R-factors in Escherichiu coli in faeces after oral chemotherapy in general practice. Lancet, 1, 312. 553
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Treatment of acute bacterial infections of the upper respiratory tract
6. Kavanagh, F., and Dennim, L. J., (1963). “Analytical Microbiology”. Academic Press, Indianapolis. 7. Knothe, H., and Wiedemann, B., (1975). Development of resistant enterobacteria in the bowel after treatment with tetracycline and erythromycin. In: Proc. 9th Int. Cong. Chemotherapy, London. Abst. No. M. 353. Plenum, New York. 8. Lake, B., (1971). Ampicillin in acute infections of general practice: a controlled trial. Med. J . Aust., 1,636. 9. Leading article, (1968). Transferable antibiotic resistance on Teesside. Br. Med. J., 1, 263. 10. Loosli, C. G., (1968). Synergism between respiratory viruses and bacteria. Yale J. Eiol. Med., 40,522. 11. Lowbury, E. J., (1975). Rationale for controlling the emergence of drug resistance. In: Proc. 9th Int. Cong. Chemotherapy, 3,187. Eds.: J. Williams and A. M. Geddes. Plenum, New York. 12. Lowbury, E. J., and Cason, J. S., (1954). Aureomycin and erythromycin therapy for Streptococcus pyogenes in burns. Er. Med. J., 2,914. 13. Manners, B. T. B., Grob, P. R., Beyron, S. P. J., and Gibbs, F. J., (1976). An investigation of antibiotic resistance of Staphylococcus aureus in general practice. Practitioner, 216,439. 14. Mitchell, R. G., and Baber, K. G. (1965). Infections by tetracycline-resistant haemolytic streptococci. Lancet, 1,25. 15. Robertson, M. H., (1973). Tetracycline resistant beta-haemolytic streptococci in South West Essex; decline and fall. Br. Med. J., 3, 84. 16. Robson, H. G., (1975). Susceptibility of Streptococcus pneumoniae (Pneumococcus) to penicillin, erythromycin and tetracycline. In : Proc. 9th Int. Cong. Chemotherapy, London. Abst. No. M.489. Plenum, New York. 17. Ross, P. W., (1971). Beta-haemolytic streptococci in saliva. J. Hyg. (Camb.),69, 347. 18. Ross, S., Rodrigues, W., Controni, G., and Khan, W., (1974). Staphylococcal susceptibility to penicillin G. The changing patterns among community strains. J.A.M.A., 229, 1075. 19. Rubbo, S. D., (1969). Common sense in chemotherapy. Med. J . Aust., 1,431. 20. Scott, A. J., and Nicholson, G. I., (1974). The recognition of pseudomembranous colitis as a clinical entity. Aust. N.Z. J . Med., 4, 502. 21. Seifert, M. H., (1973). Use and abuse of antibiotic and chemotherapeutic remedies. Ill. Med. J., 144, 64. 22. Shapiro, S., Sloane, D., Siskind, V., and Lewis, G. P., (1969). Drug rash with ampicillin and other penicillins. Lancet, 2,969. 23. Shaw, E. J., (1974). Recent changes in bacterial resistance to antibiotics. Practitioner, 213, 487. 24. Tedesco, F. J., Stanley, R. J., and Alpers, D., (1971). Diagnostic features of clindamycinassociated seromembranous colitis. N. Engl. J. Med., 290,84.
554
Current Medical Research and Opinion
Vol. 4, No. 8, 1977
Treatment of acute bacterial infections of the upper respiratory tract
M. S. Nadkarni,* M.D., P. A. Shah,** M.S.,F.R.C.S.,
Curr. Med. Res. Opin., (1977), 4, 544.
and
S. Thakurdesai, M.Sc. Department of Microbiology, Grant Medical College, and Sir. J . J . Group of Hospitals, Bombay, India Received: 18th December 1976
Summary A n open comparative study was carried out to assess the effectiveness of 4 antibiotic regimens in eradicating acute bacterial infections of the upper respiratory tract. Patients in each treatment group had similar physical parameters, severity of disease and bacterial pathogens, and were treatedfor 10 days with either erythromycin estolate, erythromycin stearate, ampicillin or oxytetracycline in the recommended dosage. Each patient was reviewed daily by physical examination and the bacteriological findings from throat swab andsalivary washings. The results showed that erythromycin stearate produced more rapid bacterial eradication and clinical resolution of symptoms and fever than with the other antibiotic preparations, and was well tolerated by most patients. Key words: Erythromycin - ampicillin - oxytetracycline - upper respiratory infections
Introduction Soon after its introduction in the mid-1940s penicillin became accepted as the therapy of choice for Gram-positive coccal infections of the respiratory tract. For some time it was the only antibiotic available for this or any other purpose and it attained a very high level of use throughout the world. Whilst its efficacy for streptococcal infections continued unimpaired, penicillin became progressively less useful for the treatment of staphylococcal infections owing to the rapid and extensive emergence of resistant strains, both in hospital and more recently in community strains.’ * Because of this, there was a swing to the empirical use of other antibacterial agents as they were developed, particularly chloramphenicol until its hazards became apparent, and then the choice increasingly favoured the tetracyclines. In their turn the tetracyclines have lost much of their therapeutic efficacybecause of the increasing incidence of resistance in both staphylococci and streptococci and more recently in pneumococci.’ 4.23 With the introduction of ampicillin, a penicillin with Gram-negative antibacterial activity, it has been used empirically as an alternative to both tetracycline and penicillin, although it is much less effective than ordinary penicillin against Grampositive cocci.’ Still more recently, recognition of the phenomenon of transferrable *Professor and Head of Department of Microbiology, **Assistant Honorary Ear, Nose and Throat Surgeon, Sir J. J. Group of Hospitals 544
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah and S. Thakurdesai
drug resistance in the Enterobacteriaceae has thrown doubt upon the wisdom of using either tetracycline or ampicillin as the treatment of choice for Gram-positive infections. Indeed, it has become evident that if these ‘broad-spectrum’ antibiotics are to retain any value in the therapy of Gram-negative infections of the lower bowel their indiscriminateuse in the treatment of respiratory tract infections,where a more specific antibiotic may be employed, must be drastically curtailed.’ 1 Several authorities2.lg have urged constraint in their use and a Leading Article9 on this subject questioned whether the possible effect of tetracycline and ampicillin on the bowel flora should not deter doctors from prescribing them, for example in mild infections of the respiratory tract. We decided, therefore, to compare the clinical efficacy of relatively narrowspectrum antibiotics with that of tetracycline and ampicillin in the treatment of mild respiratory tract infections, in the hope of finding a more selective antibiotic which would be effective as an empirical initial therapy, i.e. when prior bacteriological identification and antibiotic sensitivity testing are not immediately or conveniently practicable for one reason or another. In the choice of suitable and available narrowspectrum antibiotics we considered that benzyl penicillin and phenoxymethyl penicillin must be excluded because they cannot be expected to be uniformly efficacious in the treatment of staphylococcal infections. Lincomycin and clindamycin were considered unsuitable for routine use because of their reported toxicity.20-z4 Sulphonamides are no longer indicated in the treatment of streptococcal infection2’ and sulphonamide-trimethoprim combinations have yet to be proved capable of safe and sustained efficacyagainst sulphonamide-resistantstrains, a capacity mandatory in any empirical therapy. It was decided, therefore, to compare the clinical use of erythromycin, which we regard as a fairly narrow-range antibiotic, with ampicillin and oxytetracycline, the broad-spectrum antibiotics commonly used in empirical treatment. Erythromycin is available both as the propionyl ester (‘Althrocin’) and as the stearate (‘Erythrocin’t). Our study was designed to ascertain the causative organisms in acute upper respiratory tract infections seen at our hospital and to observe the efficacy of the four antibiotic preparations (two narrow and two broad-spectrum) in the clinical relief of these infections and in bacteriological clearance of the pathogen involved. All were prescribed according to manufacturers’ instructions.
Methods and materials In order to eliminate any bias due to the spontaneous remission of viral respiratory tract infections, it was decided to admit to the study only cases with bacteriologically confirmed acute bacterial infections of the upper respiratory tract. All the patients considered for admission to the study were examined by one of us in the Ear, Nose and Throat Out-Patients Department of the Sir J. J. Group of Hospitals, Bombay. Clinical criteria for admission to the study dictated admission of only adult patients ttrade mark, Abbott
545
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Treatment of acute bacterial infections of the upper respiratory tract
with fever greater than 98.6”F, together with symptoms and clinical signs of acute tonsillar o r pharyngeal infections. Exposure to any antibiotic within the preceding 7 days excluded admission. Suitable patients underwent a clinical examination at which throat swab and salivary washings were taken for culture and subsequent antibiotic sensitivity testing of the isolates. The salivary washings were collected by rinsing the mouth with 10 ml sterile normal saline. Care was taken to ensure that the patient did not take any hot or cold drinks for 30 minutes before the collection of the washings. Salivary stimulants were not used. The throat swabs were obtained under direct vision either from the affected tonsil in the case of patients with tonsillitis or from the posterior pharyngeal wall in cases of pharyngitis. In each case, specimens were collected on sterile cotton wool swabs. Specimens were incubated overnight on blood agar, trypticose soy broth and MacConkey’s medium. I n addition, a sample of blood was collected in an oxalate tube for haemoglobin estimation, total and differential white cell count, and packed cell volume. Patients considered suitable for inclusion in the study were requested to return the following day for specific antibiotic therapy. At this visit they were required to provide a stool sample. This was inoculated onto MacConkey’s medium, incubated overnight, any growth examined, and sensitivities to the antibiotics involved in the study determined. The selected patients were allocated by stratification on the basis of initial culture to one or other of the 4 groups to undergo therapy with the test antibiotics, thereby ensuring equal distribution of treatments amongst the pathogens isolated. Patients returned daily for 7 days to the clinic and again on the 10th study day. At each attendance, clinical assessment was undertaken by the same investigator and a further throat swab and salivary washing obtained. In order to ensure compliance with regard to medication, treatment was dispensed daily and a note made of any side-effects during the preceding 24 hours. Symptoms such as abdominal pain, nausea, vomiting, diarrhoea, constipation or rash were solicited at each attendance. The stool culture, which was intended to reveal any change in bowel flora due to antibiotic therapy, was repeated only on the 5th and 10th day. The time required for clinical cure was defined as the first examination at which the patient was asymptomatic, apyrexial, and at which physical examination was negative. The time required for bacteriological cure was defined as the day on which the initial pathogen had been eradicated without subsequent recurrence. If the symptoms were not resolved or the patient failed to become apyrexial by the 10th day, the case was classified as a clinical failure for the treatment applied. Similarly, if the initial pathogen was still demonstrable on the 10th day, either from throat swab or salivary washings, the case was considered a bacteriological failure for the antibiotic used.
Results Initially, 125 patients fulfilled the criteria for inclusion in the study. Of these, 14 (1 1 %) failed to complete the 10-day review and were excluded from the final analysis. 546
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah and S. Thakurdesai
Analysis of the 4 treatment groups on the basis of age, sex, height and weight demonstrated no statistically significant difference between the groups with regard to physical characteristics. Haemoglobin, haematocrit readings, height and weight were considered indications of nutritional status. Again, there was no statistical difference between the 4 groups. Fever present at the first consultation together with total white cell count and polymorphonuclear count were considered as indications of the severity of the bacterial infection. In this respect, no statistically significant difference was detected between the 4 groups. We considered that the initial white cell count might give some indication of bacterial aetiology of the infection. However, there was no reasonable degree of correlation between the pathogen isolated and the initial body temperature or the white cell count. In summary, therefore, the treatment groups were considered comparable in respect of physical characteristics, severity of infection and bacterial aetiology of the disease process, the only demonstrated variable between the 4 groups being the particular therapeutic regimen used. Table 1 summarizes the comparative sensitivity of the throat swab and salivary washings as an indicator of bacterial eradication. It will be seen that the throat swab was more sensitive than salivary washings. With regard to clinical cure, fever was slightly more sensitive than symptomatology in the definition of clinical cure. Table I. Comparative sensitivity of different methods of assessing bacteriological and clinical cure in 111 patients
Assessment Bacterial eradication Throat swab more sensitive Salivary washings more sensitive Equal in sensitivity Clinical cure Fever more sensitive Symptoms more sensitive Equal in sensitivity
No. patients
43 7 61
44 28 39
Table I1 gives details of the overall clinical and bacteriological cure in the 4 treatment groups together with a distribution of organisms between the treatment groups. Using a Chi-squared test for independence there was no statistical difference in the distribution of organisms among the treatment groups. Infecting organisms isolated included Streptococcus pyogenes, Staphylococcus pyogenes, Diplococcus pneumoniae, Streptococcus viridans, separately and in combination. Streptococcus viridans was only considered to be pathogenic where it was the principal organism isolated as a heavy growth; the clinical findings supported this diagnosis. Clinical resolution is illustrated in Figures 1 and 2. From Figure 1 it will be seen that erythromycin stearate caused a significantly more rapid subsidence in fever than the other antibiotics. The erythromycin stearate group showed a significantly greater number ofpatients apyrexial thaneithertheampicillin (p < 0.01) or the oxytetracycline (p = 0.03) group on the second treatment day. 547
Treatment of acute bacterial infections of the upper respiratory tract
Table II. Overall assessment of ‘cure-rate’ and distribution of organisms in 4 treatment groups: number of patients
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Assessment
Erythromycin Erythromycin stearate estolate
Ampicillin
Oxytetracycline
25
29
21 1
29
23 2
21 8
26 2
14
Distribution of organisms isolated Streptococcus viridans
6
Mixed infection
5
Staphylococcus pyogenes
Pneumococcus
4 5
Streptococcus pyogenes
5
5 6 5 5 8
5 5 5 5 8
I 5 5 6 6
Clinical assessment: Day I0
Success Failure Bacteriological assessment: Day 10
Success Failure
15
Figure 1. Comparative rapidity of clinical cure in 4 treatment groups: reduction of fever 100
90 80 70
60 50 40 0 Erythromycin stearate
30
0
Erythromycin estolate
A Ampicillin
20
o Oxytetracycline
10 0 0
1
2
3
4
5
6
10
Treatment day
Although more patients on erythromycin stearate were apyrexial than those on erythromycin estolate, the results did not reach statistical significance. Figure 2 demonstrates the resolution of symptoms and duration of treatment. There was no significant difference between symptomatic relief and the drug used. 548
M . S. Nadkarni, P. A. Shah and S. Thakurdesai
Figure 2. Comparative rapidity of elimicaI cure in 4 treatment groups: relief of symptoms
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
100
-
90
n
80
a
70
v1
0 C
.-
-E
.-0
a
E
?:
60
c
-E .-i9
50
m M
40 30
D Erythromycin stearate
20
A Ampicillin
-m
G’
u
Erythromycin estolatc 0 Oxytetracycline
10
0 0
1
2
3
4
5
6
10
Treatment day
Figure 3 compares the rapidity of bacterial eradication among the preparations used. By Day 3 , 9 out of 25 patients treated with erythromycin stearate had demonstrated bacterial eradication compared with only 2 of 29 treated with oxytetracycline (p =0.02). Nine patients out of 29 treated with erythromycin estolate and 8 out of 28 treated with ampicillin had also demonstrated a significantly better bacteriological cure rate than the oxytetracycline group (p =0.04). Bacteriologicalcure rates with erythromycin stearate were significantlybetter than with erythromycin estolate on Day 4 (p = 0.03) and Day 5 (p =0.05). Additionally, ampicillin and erythromycin stearate were both significantly superior to oxytetracycline (p < 0.01), although the results with ampicillin were not superior to those obtained with erythromycin estolate. At the conclusion of treatment both ampicillin and erythromycin stearate were still significantly superior to oxytetracycline in terms of bacterial eradication (p < 0.01). No important difference was apparent in the incidence of side-effects, but they appeared to have been rather more troublesome amongst those patients treated with oxytetracycline (Table In). Diminution of bowel flora was demonstrable following dosage of all 4 antibiotic preparations, but the post-therapy antibiotic sensitivitytesting did not demonstrate a particular pattern for any of them. 549
Treatment of acute bacterial infections of the upper respiratory tract
Figure 3. Comparative rapidity of bacterial eradication in 4 treatment groups
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
loo
1
90 -
80 -
60 50 70
40
-
30
-
0
Erythromycin stearate Erythromycin estohte
A
.Ampicillin
[.I
"1
o Oxytetracycline
10
Treatment day Table Ill. Number of patients reporting side-effects Side-effect
Erythromycin stearate
Nausea
8
Constipation Diarrhoea
1
Abdominal pain
2
Rash
1
No. side-effects
12
Erythromycin estolate
Ampicillin
Oxytetracycline
11
11
11
1
3
3 3
5
2
3 1
17
16
21
Discussion The design of the study ensured that the pathogens isolated from the throat swabs were equally represented in each of the 4 treatment groups. Analysis at the conclusion of the study of the physical characteristics, haematological parameters and initial clinical findings of the patients revealed that the 4 treatment groups were comparable and that the only variable in the study was the therapeutic regimen utilized. The 550
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah, and S. Thakurdesai
bacteriological procedures applied to the salivary washings and throat swabs were identical and under the control of one of us so that we were able to ensure uniformity of laboratory standards. In undertaking both salivary washings and routine throat swabs we could not confirm the findings of Ross’ who, following a study in children with streptococcal infections, suggested that salivary cultures were superior to throat swabs in assessing bacterial eradication. In our study, only in 1 of the 27 patients with Streptococcusp~~ogenes infections did the salivary washings prove more sensitive than the throat swab. Throughout the series of 11 1 infections the salivary washings proved more sensitive only for 7 isolates compared with 43 throat swabs (Table I). In medical practice, microbiological culture and antibiotic sensitivity testing are not routinely undertaken in our country owing to the expense involved and to the relatively large patient population. Even in more affluent societies there is a tendency to neglect this desirable prelude to antibacterial therapy, and Lakes reported that only 3.4 % of patients with acute infections were referred for microbiological study. Most clinical studies on antibiotic treatment include only pre- and post-therapy cultures, but in studying the efficacy of a group of antibiotics we considered it essential to undertake daily cultures in addition to physical examination. The results of our study show differences in the achievement of clinical resolution and of bacterial eradication in the 4 treatment groups. Figure 2 illustrates the time taken for symptomatic relief to occur and shows no statistical difference between the 4 groups. Figure 1 compares the daily cumulative percentage of patients becoming apyrexial following treatment. Erythromycin stearate effected a more rapid return to normal temperature than the other 3 antibiotic preparations. The most striking difference in the results of the 4 treatment groups was seen in the rate of bacterial eradication (Figure 3). Following 10 days treatment with oxytetracycline, only 15 (5 1.7 %) of 29 demonstrated bacteriological cure, although all had undergone clinical resolution by the 10th day. Organisms persisting included Pneumococcus (3 cases), Streptococcus (3 cases) and Staphylococcus (2 cases). This represents an unacceptable bacteriological failure rate in patients with upper respiratory tract infections and is in agreement with the experience of other authors who suggest that over the years resistance to tetracycline has become so frequent in strains of haemolytic streptococci and pneumococci that this antibiotic should no longer be used as the primary treatment of sore throats or pneumococcal pneumonia.’ . 4 Tetracycline-resistant strains of Streptococcusp~ogenes were first noted in hospital isolates in 1952;’2 since then, there has been avarying incidence of resistant strains of up to 40 % isolated from domiciliary patients.23 Recently, the incidence of Streptococcuspneumoniae resistant to tetracycline has increased and up to 30 % of isolates in a recent study demonstrated minimum inhibitory concentrations greater than 2.0 mcg/ml to tetracycline, whilst erythromycin was shown to inhibit all strains at a concentration of less than 0.03 mcg/ml.l The failure of tetracycline in our study can be directly attributed to bacterial resistance, but this is not so with the erythromycin estolate group. Whilst clinical resolution occurred in all 29 patients treated with erythromycin estolate, 8 patients failed to demonstrate bacterial eradication of the primary isolate (2 cases of Strepto551
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Treatment of acute bacterial infections of the upper respiratory tract
coccus pyogenes and 1 case of Streptococcus pneumoniae),giving an overall cure rate of 72 %. Furthermore, the response to erythromycin estolate was slower than to either ampicillin or erythromycin stearate. Erythromycin estolate, being absorbed as the ester, requires hydrolysis to erythromycin base before it can exhibit bacterial activity.6 A percentage of erythromycin estolate may be excreted unchanged in the urine as hydrolysis may not have occurred prior to excretion.3 It is suggested that this is the reason for the slow response with this antibiotic, although at the 10-day review there was no statistical difference between the bacterial eradication obtained with erythromycin stearate, ampicillin or erythromycin estolate. Both erythromycin stearate and ampicillin were statistically superior to oxytetracycline in the rate and degree of eradication. The results obtained with ampicillin therapy were considerably better than those with oxytetracycline. Symptomatic relief occurred within 6 days in all 28 patients treated, and only 2 failed to demonstrate bacteriological cure by the 10th day (1 case of Streptococczrspyogenes infection), an overall success rate of 93 %. Whilst the speed of bacterial eradication with ampicillin was slower than with erythromycin stearate, this difference was not statistically significant. Erythromycin stearate gave the fastest bacterial eradication, and clinical resolution had been obtained in all patients by the 7th day, all being apyrexial by the 5th day. Only 2 of the 25 patients treated with erythromycin stearate failed t o demonstrate bacterial eradication by the 10th day (1 Streptococcus viridans, 1 mixed infection), an overall success rate of 92 %. The changes in the antibiograms of Escherichia cofi in our patients were similar with all 4 treatments. This does not conform with the findings of other worker^,^,'-^^ who have demonstrated in patients receiving courses of tetracycline, strong selection not only for strains of E. coli resistant to tetracycline but also for strains showing multiple resistance, the frequency of resistance to ampicillin, streptomycin, chloramphenicol and sulphonamides in E. coli increasing in patients treated with tetracycline. Knothe and Wiedemann’ treated 8 volunteers as out-patients with tetracycline in doses of 0.5 g twice daily. Tetracycline-resistant E. coli appeared in all the subjects within 24 hours ofcommencing treatment. In the same study, treatment with erythromycin ethylsuccinate or erythromycin stearate did not affect E. coli and there was no selection of R-factor bearing strains. Although selection of resistant strains in the bowel by ampicillin and amoxicillin therapy is not as strong as by tetracyclines, it is still significant. In our series the incidence of side-effects with the 4 antibiotics was similar, although it appeared that they were slightly more numerous and troublesome with oxytetracycline. The major reported side-effect of ampicillin therapy is allergy and skin eruption, which is greater following treatment with ampicillin than with other penicillins.22 In addition, this effect is more common in patients suffering from infectious mononucleosis or viral diseases. Because all our patients suffered from bacterial infections, the incidence of this side-effect in our series was comparatively low. In selecting an antibiotic for treatment of simple infections such as acute sore throat, therapy should be directed at patient care and protection of the environment. 5 52
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
M. S. Nadkarni, P. A. Shah and S. Thakurdesai
Antibiotics should be selected which are efficacious, have minimal side-effects, are unlikely to produce resistance, and which are without influence on the commensal organisms in the alimentary tract. Erythromycin stearate (‘Erythrocin’) in this study demonstrated statistically significant superiority over both tetracycline and erythromycin estolate in rapidity of bacterial eradication. In addition, this antibiotic proved to be remarkably free from adverse side-effects, exerted no influence on bowel flora, and was well tolerated by the majority of patients with the exception of a few who experienced gastro-intestinal disturbance. Bacterial resistance to erythromycin stearate amongst Gram-positive organisms is remarkably low and confined to an 8 % incidence amongst out-patient staphylococci.1* Early fears that erythromycin-resistant strains of Staphylococcus aureus would rapidly emerge if erythromycin was used frequently have not been substantiated. In a recent study of 15-months’ continual use of an empirical treatment for throat and skin infections, erythromycin-resistant staphylococci did not appear.’ Strains of Streptococcus pyogenes resistant to erythromycin continue to be rare : Robertson1 5 found only 8 strains in over 6000 isolates. Strains of Streptococcus pneumoniae resistant to erythromycin have been reported but do not appear to be at all common. The indiscriminate use of antibiotics is to be condemned and, where possible, a selective antibiotic is to be preferred to a broad-spectrum one, provided that clinical efficacy can be demonstrated. The results of this study have clearly demonstrated the efficacy of erythromycin stearate (‘Erythrocin’) in the treatment of bacterial infections of the upper respiratory tract. I n fact, the spectrum of the drug covers the majority of bacteria responsible for respiratory tract infections and includes such organisms as Corynebacterium diphtheriae and Bordetellapertussis, which are commonly associated with troublesome infections in the tropical climate, and for which erythromycin is recognized as the treatment of choice. As erythromycin is the most effective agent for the treatment of Mycoplasma pneumoniae, a common cause of upper respiratory tract infections in temperate climates, its spectrum demonstrably covers all the important pathogens causing acute upper respiratory tract infections.
Acknowledgements We would like to acknowledge the help of the Medical and Nursing staff of the Sir J. J. Hospital, Bombay. Our sincere thanks go to Drs. C. E. Cook and M. A. Neaverson of Abbott Laboratories, who supported the study, and to Mr. H. Frush who undertook the statistical analysis.
References
1. Ball, A. P., Gray, J. A., and McC Murdoch, J., (1975). Antibacterial drugs today. Curr. Therapeutics, 16,97. 2. Christie, A. B., (1970). Advances in the treatment of infectious diseases.Practitioner, 205,516. 3. Chun, A. H., and Wiegand, R. G., (1971). In: Proc. Acad. Pharmacol. Sci. Symposium, Am. Pharmacol. Assoc. 4. Committee on Drugs, (1975). Requiem for tetracyclines.Pediatrics, 55, 142. 5 . Datta, N., Faiers, M. C., Reeves, D. S., Brudtt, W., 0rskov, F., and 0rskov, I., (1971). R-factors in Escherichiu coli in faeces after oral chemotherapy in general practice. Lancet, 1, 312. 553
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 10/28/14 For personal use only.
Treatment of acute bacterial infections of the upper respiratory tract
6. Kavanagh, F., and Dennim, L. J., (1963). “Analytical Microbiology”. Academic Press, Indianapolis. 7. Knothe, H., and Wiedemann, B., (1975). Development of resistant enterobacteria in the bowel after treatment with tetracycline and erythromycin. In: Proc. 9th Int. Cong. Chemotherapy, London. Abst. No. M. 353. Plenum, New York. 8. Lake, B., (1971). Ampicillin in acute infections of general practice: a controlled trial. Med. J . Aust., 1,636. 9. Leading article, (1968). Transferable antibiotic resistance on Teesside. Br. Med. J., 1, 263. 10. Loosli, C. G., (1968). Synergism between respiratory viruses and bacteria. Yale J. Eiol. Med., 40,522. 11. Lowbury, E. J., (1975). Rationale for controlling the emergence of drug resistance. In: Proc. 9th Int. Cong. Chemotherapy, 3,187. Eds.: J. Williams and A. M. Geddes. Plenum, New York. 12. Lowbury, E. J., and Cason, J. S., (1954). Aureomycin and erythromycin therapy for Streptococcus pyogenes in burns. Er. Med. J., 2,914. 13. Manners, B. T. B., Grob, P. R., Beyron, S. P. J., and Gibbs, F. J., (1976). An investigation of antibiotic resistance of Staphylococcus aureus in general practice. Practitioner, 216,439. 14. Mitchell, R. G., and Baber, K. G. (1965). Infections by tetracycline-resistant haemolytic streptococci. Lancet, 1,25. 15. Robertson, M. H., (1973). Tetracycline resistant beta-haemolytic streptococci in South West Essex; decline and fall. Br. Med. J., 3, 84. 16. Robson, H. G., (1975). Susceptibility of Streptococcus pneumoniae (Pneumococcus) to penicillin, erythromycin and tetracycline. In : Proc. 9th Int. Cong. Chemotherapy, London. Abst. No. M.489. Plenum, New York. 17. Ross, P. W., (1971). Beta-haemolytic streptococci in saliva. J. Hyg. (Camb.),69, 347. 18. Ross, S., Rodrigues, W., Controni, G., and Khan, W., (1974). Staphylococcal susceptibility to penicillin G. The changing patterns among community strains. J.A.M.A., 229, 1075. 19. Rubbo, S. D., (1969). Common sense in chemotherapy. Med. J . Aust., 1,431. 20. Scott, A. J., and Nicholson, G. I., (1974). The recognition of pseudomembranous colitis as a clinical entity. Aust. N.Z. J . Med., 4, 502. 21. Seifert, M. H., (1973). Use and abuse of antibiotic and chemotherapeutic remedies. Ill. Med. J., 144, 64. 22. Shapiro, S., Sloane, D., Siskind, V., and Lewis, G. P., (1969). Drug rash with ampicillin and other penicillins. Lancet, 2,969. 23. Shaw, E. J., (1974). Recent changes in bacterial resistance to antibiotics. Practitioner, 213, 487. 24. Tedesco, F. J., Stanley, R. J., and Alpers, D., (1971). Diagnostic features of clindamycinassociated seromembranous colitis. N. Engl. J. Med., 290,84.
554
