1355
could elicit a hypersensitivity reaction at these sites. The fact that we were unable to relate skin hypersensitivity to the lesion formation after intravenous injection might be because of differences in response in the tissues compared to the skin. If the reaction
INFECTION CAUSED BY PROTEUS MIRABILIS STRAINS WITH TRANSFERABLE GENTAMICIN-RESISTANCE FACTORS
wholly or predominantly one of delayed hypersensitivity rather than an immediate type, this would explain the ineffectiveness of antihistamine treatment. However, anaphylactoid reactions have been observed in man5 after successive intralesional injections, so
Department of Microbiology, Central Middlesex Hospital,
was
pretreatment with antihistamine in these circumstances wise precaution.6 The results we have obtained in guineapigs reinforce our misgivings about use of B.C.G. intravenously. We feel that the vaccine should only be given by this route with extreme caution and in low doses, along the lines tried by Whittaker et aU The results may also be relevant to the side-effects reported after B.C.G. administration by some other routes.8 Fever, malaise, hepatic dysfunction, and jaundice have been most frequently associated with intralesional treatment,9 where rapid transfer into the bloodstream has been demonstraxed 1° There are reports of disseminated B.c.G. infection having occurred but where control was achieved by isoniazid or antibiotics.9,ll,12 Others have recognised the possible complication of hypersensitivity,6 and the seriousness of this has recently been underlined by reports of two deaths attributed to hypersensitivity after intralesional B.C.G.13,14 Morton’s group have controlled the complications due to hypersensitivity by pretreating with. antihistamines and aspirin and adjusting the dose of B.c.G. according to the patient’s degree of hypersensitivity. Morton’s experience of intralesional injection was with B.c.G. vaccine of the same manufacture as that used here, for which he stated a preference because of the high proportion of viable organisms compared with other preparations.13,14 This is in line with the conclusions from our guineapig experiments. The use of killed B.c.G. vaccine is therefore not advised.
may be
Requests for reprints should
be addressed to P. W. M.
REFERENCES
2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12.
13.
Zbar, B., Bernstein, I. D., Rapp, H. J. J. natn. Cancer Inst. 1971, 46, 831. Baldwin, R. W., Pimm, M. V. Eur. J. clin. biol. Res. 1971, 16, 875. Baldwin, R. W., Pimm, M. V. Br. J. Cancer, 1973, 27, 48. Baldwin, R. W., Pimm, M. V. Int. J. Cancer, 1973, 12, 420. Morton, D. L., Holmes, E. C., Eilber, F. R., Wood, W. C. Ann. intern. Med. 1971, 74, 587. Hunt, J. S., Silverstein, M. J., Sparks, F. C., Haskell, C. M., Pilch, Y. H., Morton, D. L. Lancet, 1973, ii, 820. Whittaker, J. A., Lilleyman, J. S., Jacobs, A., Balfour, I. ibid. 1973, ii, 1454. Bast, R. C., Zbar, B., Borsos, T., Rapp, H. J. New Engl. J. Med. 1974, 290, 1458. Sparks, F. C., Silverstein, M. J., Hunt, J. S., Haskell, C. M., Pilch, Y. H., Morton, D. L. ibid. 1973, 289, 827. Pinsky, C., Hirshant, Y., Oettgen, H. Proc. Am. Ass. Cancer Res. 1972, 13, 21. Mansell, P. W. A., Krementz, E. T. J. Am. med. Ass. 1973, 226, 1570. Grant, R. M., Mackie, R., Cochran, A. J., Murray, E. L., Hoyle, D., Ross, C. Lancet, 1974, ii, 1096. McKhann, C., Gunnarsson, A. in Neoplasm Immunity: BCG Vaccination (edited by R. G. Crispen); p. 31. Evanston, Illinois, 1974.
14.
London NW10 7NS
NAOMI DATTA
Department of Bacteriology, Royal Postgraduate Medical School, London W12 0HS
a
We thank Mrs Patricia J. Boulton for technical assistance and Dr A. T. A. Doble for his help in histological assessment.
1.
M. S. SHAFI
Spider, L. E., Wybran, J., Lieberman, R., Levinson, D., Epstein, W., Hendrickson, C. ibid. p. 45.
During a period of 10 weeks, four Summary patients in one hospital became infected with gentamicin-resistant Proteus mirabilis. In two of them, septicæmia associated with indwelling catheters
developed, one had urinary tract and wound infections, and in the fourth patient the organism was isolated from a superficial wound. The P. mirabilis strains showed multiple drug resistance. Strains from the first three patients were apparently identical and Their gentamicin were sensitive to tobramycin. resistance was not transferable to Escherichia coli K12, but could be transferred to another strain of P. mirabilis (PM13-3). The fourth strain was resistant to tobramycin; its gentamicin/tobramycin resistance was transferable to E. coli K12.
Introduction MANY infections in hospital patients are caused by gram-negative bacilli. In serious and possibly lifethreatening infections, gentamicin, sometimes in combination with other drugs, is often prescribed to provide effective cover against a wide range of
Gentamicin is used either when the causative organism is not known or because it has been shown to be the only effective drug to which the organism is sensitive. Although there have been reports of gentamicin resistance in Pseudomonas a-mginosa, such resistance has so far been uncommon among other aerobic gram-negative bacilli.2,3 Strains of Proteus mirabilis are generally more sensitive to antimicrobial drugs than strains of other Proteus spp. We describe four patients with infection caused by gentamicin-resistant P. mirabilis.
bacterial
Patients Patient 1.-A 62-year-old woman was admitted with head injury and multiple fractures resulting from a road accident. 12 days after admission she was transferred to the intensive-care unit because of renal failure. Septicxmia developed which was almost certainly derived from urinary-tract infection associated with an indwelling catheter. P. mirabilis, resistant to gentamicin as well as to other antimicrobial drugs, was isolated from a catheter specimen of urine and from the patient’s bloodstream (strain A). Treatment with gentamicin was started before the results of cultures were known. Subsequent cultures of blood did not yield bacterial growth. The patient recovered. Patient 2.-A 58-year-old man was admitted for investigation of polyneuritis. During his stay in hospital, flaccid paralysis involving the muscles of respiration
developed and he was transferred to the intensive-care unit. Septicaemia developed which, as in patient 1, was associated with an indwelling catheter. P. mirabilis re-
1356 PROPERTIES OF GENTAMICIN-RESISTANT P. MIRABILIS STRAINS
chloramphenicol and colistin; strain D was sensitive to these two drugs. The four strains were typed in the Cross Infection Reference Laboratory, Central Public Health Laboratory, Colindale, and were found to be of proticine type 2. When tested by Diene’s method, however, strain D was distinguishable from strains A, B, and C. The latter three strains were indistinguishable. Of the four strains, only D transferred gentamicin resistance to Escherichia coli K12 when tested as previously described.5 Gentamicin resistance was not transferable from strains A, B, and C to E. coli K12, but it was transferable to another strain of P. mirabilis PM13-3 (see
accompanying table). In each multiple drug resistance was transferred. Minimum inhibitory concentration (M.i.c.)
was
the lowest concentration
of
drug in diagnostic sensitivity test agar (Oxoid) to prevent visible growth from a surface inoculum of a 4-hour broth culture. Gm = gentamicin; Tb = tobramycin; Cb carbenicillin/ampicillin; Sm = streptomycin; Tc = tetracycline; Km = kanamycin; Cm = chloramphenicol; Su=sulphonamide; Tp=trimethoprim; Ct= colistin; Cp = cephaloridine. =
’PM13-3 is
a
mutant
case
of PM13" resistant
to
nalidixic acid and
rifampicin.
sistant to many antimicrobial drugs, including gentamicin, was isolated from his bloodstream (strain B) and from his urine. The patient was treated with gentamicin and benzyl penicillin. Subsequent blood-cultures proved negative, but the organism persisted in his urine. After antimicrobial treatment had been discontinued, septicaemia again developed and blood-cultures yielded an identical resistant strain of P. mirabilis. Because of the previous response to treatment with gentamicin and the apparent lack of any other effective antimicrobial drug, the patient was then treated with a combination of carbenicillin and gentamicin but he died. Patient 3.-A 69-year-old man was admitted with an abdominal aortic aneurysm, which was excised and replaced by an aorto-femoral graft. However, further aneurysms developed and he was operated upon again. After this he was transferred temporarily to the intensivecare unit before returning to a surgical ward. This patient had an indwelling catheter, and a urinary-tract infection developed which was treated by noxythiolin bladder washouts. P. mirabilis resistant to gentamicin, was isolated from his urine (strain C) and subsequently from his wound. The only antimicrobial therapy given was a short postoperative course of ampicillin and cloxacillin. The patient died. Patient 4.-A 62-year-old woman with severe rheumatoid arthritis was admitted to hospital for total hip replacement. 3 weeks after operation, when the dressing was removed, the wound appeared healthy, but about 10 cm. below the suture line there was excoriation of the skin (7 cm. x 10 cm.) where adhesive plaster had been applied. A strain of P. mirabilis (strain D) with multiple resistance was isolated from the site. Simple dry dressings were the wound healed. and applied superficial
Bacteriological Investigations The organisms isolated from all four patients were identified as typical P. mirabilis by the criteria of Cowan and Steely Disc diffusion tests showed all four strains to be resistant to ampicillin, carbenicillin,
cephaloridine, streptomycin, tetracycline, kanamycin, sulphonamide, and trimethoprim as well as to gentamicin. Strains A, B, and C were also resistant to
Discussion Strains of P. mirabilis (A, B, and C) from the first three patients were indistinguishable. The patients had been in the intensive-care unit at some time during the period of their stay in the hospital but not at the same time. Cross-infection was probable, but an identifiable source in the environment was not found. Strain D, from the fourth patient, was different and was isolated from a superficial lesion in a patient who had not been in the intensive-care unit. Because gentamicin-resistant bacteria are still rare in clinical practice, this drug is commonly used to treat life-threatening infections before the causative organism can be isolated and tested for drug sensitivity. Such routine use of gentamicin in hospitals, however, is likely to increase the frequency of resistant bacteria. Gentamicin resistance in bacteria arises either by mutation or by the acquisition of resistance (R) factors. Gentamicin R factors have been identified in several bacterial genera in various geographical 6-ro areas but have not previously been reported in the U.K. The presence of at least two types of gentamicin R factor in recent isolates of P. mirabilis in one hospital is disquieting. Each of the two types of R factor was harboured by a distinguishable strain of P. mirabilis. The R factor from these strains differed in their host ranges and also in their resistance patterns. Tobramycin is an aminoglycoside antibiotic closely related to gentamicin, having similar degree of toxicity but with greater activity against Ps. ceruginosa. Its activity against enterobacteria and staphylococci, however, is similar to that of gentamicin 11 Gentamicinresistant strains of Ps. ceruginosa and other aerobic gram-negative bacilli are often resistant also to tobramycin 12; laboratory selection using either drug results in resistance to both." Crowe and Sanders 13 reported that most resistant clinical isolates were resistant to both drugs, but some gentamicin-resistant strains were tobramycin sensitive, and a few gentamicin-sensitive strains were resistant to tobramycin. R factors have been identified which determine each of these three patterns of resistance," depending upon which of the aminoglycoside-inactivating enzymes is
produced.15 In the
with septicaemia, treatment with started before the causative organism was isolated and found to be resistant to this drug in vitro. The first patient recovered, but the second two
gentamicin
patients
was
1357
patient, although showing initial progress, eventually died. Only later were the strains tested against tobramycin and found to be susceptible to this drug. The presence of two types of R factor, with different patterns of resistance to gentamicin and tobramycin, indicates that results of in-vitro susceptibility tests against one drug cannot be applied to the other. Clearly, strains of aerobic gram-negative bacilli causing serious illness should be tested against each of these drugs separately before it is decided which is the more appropriate in a given clinical situation. Requests for reprints should be addressed
to
M. S. S.
REFERENCES
E. J. L., Ayliffe, G. A. J. Drug Resistance in Antimicrobial Therapy. No. 938, American Lecture Series, Springfield, Illinois, 1974. 2. Noone, P., Pattison, J. R., Davies, D. G. Postgrad. med. J. 1974, 1.
Lowbury,
3.
50, suppl. p. 9. Anderson, F. M., Datta, N., Shaw, E. J. Br. med. J. 1972, iii,
spective study at this centre has shown that the frequency of post-partum thromboembolism is much lower in Thai womenthan in women studied at the Mayo Clinic.2 We have studied the frequency of thromboembolic complications occurring after major surgery in Thai women. Postoperative thrombosis was determined by the 125I-fibrinogen test and subseThe results were compared quent phlebography. with those obtained by the same technique in women undergoing similar surgery at Oxford. Since identical equipment and the same source of radioactive fibrinogen (Amersham Radiochemical Centre, U.K.) were used in both studies, and the -people performing the test in Bangkok were trained in the methodology at Oxford, the results of the two studies could be directly compared. 169 women undergoing pelvic surgery at the Chulalongkorn Hospital Medical. School,
Bangkok,
were
studied.
82. 4. Cowan, S. T., Steel, K. J. Manual for the Identification of Medical Bacteria. London, 1974. 5. Datta, N. in Recent Advances in Clinical Pathology (edited by S. C. Dyke); p. 43. London, 1968. 6. Witchitz, J. L., Chabbert, Y. A. Annls Inst. Pasteur, Paris, 1972, 132, 367. 7. Lemosquet-Villemon, M., Morel, C., Freymuth, F. Path. Biol. 1972, 21, 227. 8. Martin, C. M., Ikari, N. S., Zimmerman, J., Waitz, A. J. J. infect. Dis. 1971, 124, suppl. p. 24. 9. Bryan, L. E., Semaka, S. D., van den Elzen, H. M., Kinnear, J. E., Whitehouse, R. L. S. Antimicrob. Ag. Chemother. 1973, 3, 625. 10. Jacoby, G. A. ibid. 1974, 6, 239. 11. Waterworth, P. M. J. clin. Path. 1972, 25, 979. 12. Brusch, J. L., Barza, M., Bergeron, M. G., Weinstein, L. Antimicrob. Ag. Chemother. 1972, 1, 280. 13. Crowe, C. C., Sanders, E. ibid. 1972, 2, 415. 14. Jacoby, G. A. ibid. 1974, 6, 807. 15. Benveniste, R., Davies, J. A. Rev. Biochem. 1973, 42, 471. 16. Coetzee, J. N. Ann. Rev. Microbiol. 1972, 26, 23.
POSTOPERATIVE THROMBOSIS IN THAI WOMEN V. POSHYACHINDA T. CHUMNIJARAKIJ Research Team on Clinical World Health Organisation Evaluation of Fertility Regulating Agents, Chulalongkorn Hospital and Medical School, Bangkok, Thailand The 125I-labelled fibrinogen infusion test and phlebography were used to detect evidence of the postoperative development of deep-vein thrombosis (D.V.T.) in the legs of 117 Thai women who had abdominal hysterectomy for benign conditions and of 52 who had major pelvic surgery for malignant disease of the ovary, uterus, and cervix. D.V.T. was demonstrated in 1·7% and 3·8%, respectively. Comparison of these results with an almost identical study in Oxford showed that D.V.T. was significantly more common in women in England— i.e., 12% and 35% in those with benign or malignant
Summary
diseases, respectively. Introduction CLINICIANS have long suspected that there are differences in the frequency of thromboembolism in different geographical regions, with low frequencies in Asian, Arab, and African populations. A retro-
Patients and Methods Patients undergoing either total abdominal hysterectomy for benign conditions or major pelvic surgery for malignant disease were admitted to the study. 117 patients underwent abdominal hysterectomy for benign conditions, while 52 women were operated on for malignant conditions of the ovary, uterus, and cervix.
Diagnosis
of
Leg-vein Thrombosis
Before l2sl_labelled fibrinogen was administered the uptake of radioactive iodine by the thyroid gland was blocked by 100 mg. potassium iodide, and this was continued daily for one week. One hour before the operation 100 ]Lei of 125I-Iabelled fibrinogen was injected intravenously. The level of 125l-labelled fibrinogen activity in the legs was measured using a Pitman 235 isotopelocalisation monitor.3 All measurements were made with the patients in the supine position with the legs elevated by 30° to avoid venous pooling of blood and also to allow The access to the posterior aspect of the calf muscle. limbs were examined four-six hours after operation and Venous thrombosis was on alternate days for seven days. said to have occurred when the count had increased by 20% when compared to the count at the same spot on the previous day, and to the count at the corresponding point on the opposite limb, providing that the activity When persisted and increased in the next few days. thrombosis was detected by 125I-labelled fibrinogen, percutaneous phlebography was carried out, as described elsewhere,4 to determine the exact site and extent of the thrombus.
Results
Postoperative D.v.T. was shown to have developed in the legs of 4 (2-4%) of the 169 women who received the radioactive 1251 fibrinogen. None of the positive cases had any clinical signs or symptoms of pulmonary embolism during the first 7 postoperative days. The accompanying table compares the results obtained in this study with results obtained in a similar study at Oxford.5 D.V.T. was shown to have developed postoperatively in 2 of the 117 patients with benign conditions and 2 of the 52 women with malignant disease. Thrombi were definitely demonstrated in the deep veins of the leg of 1 case by phlebography and not demonstrated in 2 cases. It was not possible to carry out the procedure in the remaining case.
could elicit a hypersensitivity reaction at these sites. The fact that we were unable to relate skin hypersensitivity to the lesion formation after intravenous injection might be because of differences in response in the tissues compared to the skin. If the reaction
INFECTION CAUSED BY PROTEUS MIRABILIS STRAINS WITH TRANSFERABLE GENTAMICIN-RESISTANCE FACTORS
wholly or predominantly one of delayed hypersensitivity rather than an immediate type, this would explain the ineffectiveness of antihistamine treatment. However, anaphylactoid reactions have been observed in man5 after successive intralesional injections, so
Department of Microbiology, Central Middlesex Hospital,
was
pretreatment with antihistamine in these circumstances wise precaution.6 The results we have obtained in guineapigs reinforce our misgivings about use of B.C.G. intravenously. We feel that the vaccine should only be given by this route with extreme caution and in low doses, along the lines tried by Whittaker et aU The results may also be relevant to the side-effects reported after B.C.G. administration by some other routes.8 Fever, malaise, hepatic dysfunction, and jaundice have been most frequently associated with intralesional treatment,9 where rapid transfer into the bloodstream has been demonstraxed 1° There are reports of disseminated B.c.G. infection having occurred but where control was achieved by isoniazid or antibiotics.9,ll,12 Others have recognised the possible complication of hypersensitivity,6 and the seriousness of this has recently been underlined by reports of two deaths attributed to hypersensitivity after intralesional B.C.G.13,14 Morton’s group have controlled the complications due to hypersensitivity by pretreating with. antihistamines and aspirin and adjusting the dose of B.c.G. according to the patient’s degree of hypersensitivity. Morton’s experience of intralesional injection was with B.c.G. vaccine of the same manufacture as that used here, for which he stated a preference because of the high proportion of viable organisms compared with other preparations.13,14 This is in line with the conclusions from our guineapig experiments. The use of killed B.c.G. vaccine is therefore not advised.
may be
Requests for reprints should
be addressed to P. W. M.
REFERENCES
2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12.
13.
Zbar, B., Bernstein, I. D., Rapp, H. J. J. natn. Cancer Inst. 1971, 46, 831. Baldwin, R. W., Pimm, M. V. Eur. J. clin. biol. Res. 1971, 16, 875. Baldwin, R. W., Pimm, M. V. Br. J. Cancer, 1973, 27, 48. Baldwin, R. W., Pimm, M. V. Int. J. Cancer, 1973, 12, 420. Morton, D. L., Holmes, E. C., Eilber, F. R., Wood, W. C. Ann. intern. Med. 1971, 74, 587. Hunt, J. S., Silverstein, M. J., Sparks, F. C., Haskell, C. M., Pilch, Y. H., Morton, D. L. Lancet, 1973, ii, 820. Whittaker, J. A., Lilleyman, J. S., Jacobs, A., Balfour, I. ibid. 1973, ii, 1454. Bast, R. C., Zbar, B., Borsos, T., Rapp, H. J. New Engl. J. Med. 1974, 290, 1458. Sparks, F. C., Silverstein, M. J., Hunt, J. S., Haskell, C. M., Pilch, Y. H., Morton, D. L. ibid. 1973, 289, 827. Pinsky, C., Hirshant, Y., Oettgen, H. Proc. Am. Ass. Cancer Res. 1972, 13, 21. Mansell, P. W. A., Krementz, E. T. J. Am. med. Ass. 1973, 226, 1570. Grant, R. M., Mackie, R., Cochran, A. J., Murray, E. L., Hoyle, D., Ross, C. Lancet, 1974, ii, 1096. McKhann, C., Gunnarsson, A. in Neoplasm Immunity: BCG Vaccination (edited by R. G. Crispen); p. 31. Evanston, Illinois, 1974.
14.
London NW10 7NS
NAOMI DATTA
Department of Bacteriology, Royal Postgraduate Medical School, London W12 0HS
a
We thank Mrs Patricia J. Boulton for technical assistance and Dr A. T. A. Doble for his help in histological assessment.
1.
M. S. SHAFI
Spider, L. E., Wybran, J., Lieberman, R., Levinson, D., Epstein, W., Hendrickson, C. ibid. p. 45.
During a period of 10 weeks, four Summary patients in one hospital became infected with gentamicin-resistant Proteus mirabilis. In two of them, septicæmia associated with indwelling catheters
developed, one had urinary tract and wound infections, and in the fourth patient the organism was isolated from a superficial wound. The P. mirabilis strains showed multiple drug resistance. Strains from the first three patients were apparently identical and Their gentamicin were sensitive to tobramycin. resistance was not transferable to Escherichia coli K12, but could be transferred to another strain of P. mirabilis (PM13-3). The fourth strain was resistant to tobramycin; its gentamicin/tobramycin resistance was transferable to E. coli K12.
Introduction MANY infections in hospital patients are caused by gram-negative bacilli. In serious and possibly lifethreatening infections, gentamicin, sometimes in combination with other drugs, is often prescribed to provide effective cover against a wide range of
Gentamicin is used either when the causative organism is not known or because it has been shown to be the only effective drug to which the organism is sensitive. Although there have been reports of gentamicin resistance in Pseudomonas a-mginosa, such resistance has so far been uncommon among other aerobic gram-negative bacilli.2,3 Strains of Proteus mirabilis are generally more sensitive to antimicrobial drugs than strains of other Proteus spp. We describe four patients with infection caused by gentamicin-resistant P. mirabilis.
bacterial
Patients Patient 1.-A 62-year-old woman was admitted with head injury and multiple fractures resulting from a road accident. 12 days after admission she was transferred to the intensive-care unit because of renal failure. Septicxmia developed which was almost certainly derived from urinary-tract infection associated with an indwelling catheter. P. mirabilis, resistant to gentamicin as well as to other antimicrobial drugs, was isolated from a catheter specimen of urine and from the patient’s bloodstream (strain A). Treatment with gentamicin was started before the results of cultures were known. Subsequent cultures of blood did not yield bacterial growth. The patient recovered. Patient 2.-A 58-year-old man was admitted for investigation of polyneuritis. During his stay in hospital, flaccid paralysis involving the muscles of respiration
developed and he was transferred to the intensive-care unit. Septicaemia developed which, as in patient 1, was associated with an indwelling catheter. P. mirabilis re-
1356 PROPERTIES OF GENTAMICIN-RESISTANT P. MIRABILIS STRAINS
chloramphenicol and colistin; strain D was sensitive to these two drugs. The four strains were typed in the Cross Infection Reference Laboratory, Central Public Health Laboratory, Colindale, and were found to be of proticine type 2. When tested by Diene’s method, however, strain D was distinguishable from strains A, B, and C. The latter three strains were indistinguishable. Of the four strains, only D transferred gentamicin resistance to Escherichia coli K12 when tested as previously described.5 Gentamicin resistance was not transferable from strains A, B, and C to E. coli K12, but it was transferable to another strain of P. mirabilis PM13-3 (see
accompanying table). In each multiple drug resistance was transferred. Minimum inhibitory concentration (M.i.c.)
was
the lowest concentration
of
drug in diagnostic sensitivity test agar (Oxoid) to prevent visible growth from a surface inoculum of a 4-hour broth culture. Gm = gentamicin; Tb = tobramycin; Cb carbenicillin/ampicillin; Sm = streptomycin; Tc = tetracycline; Km = kanamycin; Cm = chloramphenicol; Su=sulphonamide; Tp=trimethoprim; Ct= colistin; Cp = cephaloridine. =
’PM13-3 is
a
mutant
case
of PM13" resistant
to
nalidixic acid and
rifampicin.
sistant to many antimicrobial drugs, including gentamicin, was isolated from his bloodstream (strain B) and from his urine. The patient was treated with gentamicin and benzyl penicillin. Subsequent blood-cultures proved negative, but the organism persisted in his urine. After antimicrobial treatment had been discontinued, septicaemia again developed and blood-cultures yielded an identical resistant strain of P. mirabilis. Because of the previous response to treatment with gentamicin and the apparent lack of any other effective antimicrobial drug, the patient was then treated with a combination of carbenicillin and gentamicin but he died. Patient 3.-A 69-year-old man was admitted with an abdominal aortic aneurysm, which was excised and replaced by an aorto-femoral graft. However, further aneurysms developed and he was operated upon again. After this he was transferred temporarily to the intensivecare unit before returning to a surgical ward. This patient had an indwelling catheter, and a urinary-tract infection developed which was treated by noxythiolin bladder washouts. P. mirabilis resistant to gentamicin, was isolated from his urine (strain C) and subsequently from his wound. The only antimicrobial therapy given was a short postoperative course of ampicillin and cloxacillin. The patient died. Patient 4.-A 62-year-old woman with severe rheumatoid arthritis was admitted to hospital for total hip replacement. 3 weeks after operation, when the dressing was removed, the wound appeared healthy, but about 10 cm. below the suture line there was excoriation of the skin (7 cm. x 10 cm.) where adhesive plaster had been applied. A strain of P. mirabilis (strain D) with multiple resistance was isolated from the site. Simple dry dressings were the wound healed. and applied superficial
Bacteriological Investigations The organisms isolated from all four patients were identified as typical P. mirabilis by the criteria of Cowan and Steely Disc diffusion tests showed all four strains to be resistant to ampicillin, carbenicillin,
cephaloridine, streptomycin, tetracycline, kanamycin, sulphonamide, and trimethoprim as well as to gentamicin. Strains A, B, and C were also resistant to
Discussion Strains of P. mirabilis (A, B, and C) from the first three patients were indistinguishable. The patients had been in the intensive-care unit at some time during the period of their stay in the hospital but not at the same time. Cross-infection was probable, but an identifiable source in the environment was not found. Strain D, from the fourth patient, was different and was isolated from a superficial lesion in a patient who had not been in the intensive-care unit. Because gentamicin-resistant bacteria are still rare in clinical practice, this drug is commonly used to treat life-threatening infections before the causative organism can be isolated and tested for drug sensitivity. Such routine use of gentamicin in hospitals, however, is likely to increase the frequency of resistant bacteria. Gentamicin resistance in bacteria arises either by mutation or by the acquisition of resistance (R) factors. Gentamicin R factors have been identified in several bacterial genera in various geographical 6-ro areas but have not previously been reported in the U.K. The presence of at least two types of gentamicin R factor in recent isolates of P. mirabilis in one hospital is disquieting. Each of the two types of R factor was harboured by a distinguishable strain of P. mirabilis. The R factor from these strains differed in their host ranges and also in their resistance patterns. Tobramycin is an aminoglycoside antibiotic closely related to gentamicin, having similar degree of toxicity but with greater activity against Ps. ceruginosa. Its activity against enterobacteria and staphylococci, however, is similar to that of gentamicin 11 Gentamicinresistant strains of Ps. ceruginosa and other aerobic gram-negative bacilli are often resistant also to tobramycin 12; laboratory selection using either drug results in resistance to both." Crowe and Sanders 13 reported that most resistant clinical isolates were resistant to both drugs, but some gentamicin-resistant strains were tobramycin sensitive, and a few gentamicin-sensitive strains were resistant to tobramycin. R factors have been identified which determine each of these three patterns of resistance," depending upon which of the aminoglycoside-inactivating enzymes is
produced.15 In the
with septicaemia, treatment with started before the causative organism was isolated and found to be resistant to this drug in vitro. The first patient recovered, but the second two
gentamicin
patients
was
1357
patient, although showing initial progress, eventually died. Only later were the strains tested against tobramycin and found to be susceptible to this drug. The presence of two types of R factor, with different patterns of resistance to gentamicin and tobramycin, indicates that results of in-vitro susceptibility tests against one drug cannot be applied to the other. Clearly, strains of aerobic gram-negative bacilli causing serious illness should be tested against each of these drugs separately before it is decided which is the more appropriate in a given clinical situation. Requests for reprints should be addressed
to
M. S. S.
REFERENCES
E. J. L., Ayliffe, G. A. J. Drug Resistance in Antimicrobial Therapy. No. 938, American Lecture Series, Springfield, Illinois, 1974. 2. Noone, P., Pattison, J. R., Davies, D. G. Postgrad. med. J. 1974, 1.
Lowbury,
3.
50, suppl. p. 9. Anderson, F. M., Datta, N., Shaw, E. J. Br. med. J. 1972, iii,
spective study at this centre has shown that the frequency of post-partum thromboembolism is much lower in Thai womenthan in women studied at the Mayo Clinic.2 We have studied the frequency of thromboembolic complications occurring after major surgery in Thai women. Postoperative thrombosis was determined by the 125I-fibrinogen test and subseThe results were compared quent phlebography. with those obtained by the same technique in women undergoing similar surgery at Oxford. Since identical equipment and the same source of radioactive fibrinogen (Amersham Radiochemical Centre, U.K.) were used in both studies, and the -people performing the test in Bangkok were trained in the methodology at Oxford, the results of the two studies could be directly compared. 169 women undergoing pelvic surgery at the Chulalongkorn Hospital Medical. School,
Bangkok,
were
studied.
82. 4. Cowan, S. T., Steel, K. J. Manual for the Identification of Medical Bacteria. London, 1974. 5. Datta, N. in Recent Advances in Clinical Pathology (edited by S. C. Dyke); p. 43. London, 1968. 6. Witchitz, J. L., Chabbert, Y. A. Annls Inst. Pasteur, Paris, 1972, 132, 367. 7. Lemosquet-Villemon, M., Morel, C., Freymuth, F. Path. Biol. 1972, 21, 227. 8. Martin, C. M., Ikari, N. S., Zimmerman, J., Waitz, A. J. J. infect. Dis. 1971, 124, suppl. p. 24. 9. Bryan, L. E., Semaka, S. D., van den Elzen, H. M., Kinnear, J. E., Whitehouse, R. L. S. Antimicrob. Ag. Chemother. 1973, 3, 625. 10. Jacoby, G. A. ibid. 1974, 6, 239. 11. Waterworth, P. M. J. clin. Path. 1972, 25, 979. 12. Brusch, J. L., Barza, M., Bergeron, M. G., Weinstein, L. Antimicrob. Ag. Chemother. 1972, 1, 280. 13. Crowe, C. C., Sanders, E. ibid. 1972, 2, 415. 14. Jacoby, G. A. ibid. 1974, 6, 807. 15. Benveniste, R., Davies, J. A. Rev. Biochem. 1973, 42, 471. 16. Coetzee, J. N. Ann. Rev. Microbiol. 1972, 26, 23.
POSTOPERATIVE THROMBOSIS IN THAI WOMEN V. POSHYACHINDA T. CHUMNIJARAKIJ Research Team on Clinical World Health Organisation Evaluation of Fertility Regulating Agents, Chulalongkorn Hospital and Medical School, Bangkok, Thailand The 125I-labelled fibrinogen infusion test and phlebography were used to detect evidence of the postoperative development of deep-vein thrombosis (D.V.T.) in the legs of 117 Thai women who had abdominal hysterectomy for benign conditions and of 52 who had major pelvic surgery for malignant disease of the ovary, uterus, and cervix. D.V.T. was demonstrated in 1·7% and 3·8%, respectively. Comparison of these results with an almost identical study in Oxford showed that D.V.T. was significantly more common in women in England— i.e., 12% and 35% in those with benign or malignant
Summary
diseases, respectively. Introduction CLINICIANS have long suspected that there are differences in the frequency of thromboembolism in different geographical regions, with low frequencies in Asian, Arab, and African populations. A retro-
Patients and Methods Patients undergoing either total abdominal hysterectomy for benign conditions or major pelvic surgery for malignant disease were admitted to the study. 117 patients underwent abdominal hysterectomy for benign conditions, while 52 women were operated on for malignant conditions of the ovary, uterus, and cervix.
Diagnosis
of
Leg-vein Thrombosis
Before l2sl_labelled fibrinogen was administered the uptake of radioactive iodine by the thyroid gland was blocked by 100 mg. potassium iodide, and this was continued daily for one week. One hour before the operation 100 ]Lei of 125I-Iabelled fibrinogen was injected intravenously. The level of 125l-labelled fibrinogen activity in the legs was measured using a Pitman 235 isotopelocalisation monitor.3 All measurements were made with the patients in the supine position with the legs elevated by 30° to avoid venous pooling of blood and also to allow The access to the posterior aspect of the calf muscle. limbs were examined four-six hours after operation and Venous thrombosis was on alternate days for seven days. said to have occurred when the count had increased by 20% when compared to the count at the same spot on the previous day, and to the count at the corresponding point on the opposite limb, providing that the activity When persisted and increased in the next few days. thrombosis was detected by 125I-labelled fibrinogen, percutaneous phlebography was carried out, as described elsewhere,4 to determine the exact site and extent of the thrombus.
Results
Postoperative D.v.T. was shown to have developed in the legs of 4 (2-4%) of the 169 women who received the radioactive 1251 fibrinogen. None of the positive cases had any clinical signs or symptoms of pulmonary embolism during the first 7 postoperative days. The accompanying table compares the results obtained in this study with results obtained in a similar study at Oxford.5 D.V.T. was shown to have developed postoperatively in 2 of the 117 patients with benign conditions and 2 of the 52 women with malignant disease. Thrombi were definitely demonstrated in the deep veins of the leg of 1 case by phlebography and not demonstrated in 2 cases. It was not possible to carry out the procedure in the remaining case.
