1403
determinants such as lymph-node involvement, spread through the bowel wall, quality of invasive margin, and lymphocytic infiltrate at advancing margins. Lymphocytic infiltrate was not assessed by Cawthom et al. As the Guildford group comment in their last paragraph, any prognostic system needs to be both reproducible and accurate in the prediction of outcome after surgery. The assessment of mesorectal spread can only be accurate when meticulous technique, such as they describe, is used, and most pathology departments in this country would fall woefully short of such an ideal. Furthermore, the reproducibility of the prognostic importance of mesorectal spread must be regarded as very doubtful in view of the conflicting results from the St Mark’s and Guildford
prognostic
studies. Gloucestershire Royal Hospital, Gloucester GL1 3NN, UK
NEIL A. SHEPHERD
Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Lancet 1986; ii. 996-98. 2. Jass JR, Love SB, Northover JMA. A new prognostic classification of rectal cancer. Lancet 1987; i: 1303-06. 1
Quirke P, Durdey P,
other FVIII:C preparations. J. M. Lusher
(unpublished) tells us that in a multicentre study with monoclate new inhibitors to FVIII:C have developed in seven of thirty-nine patients (predominantly infants and children) who had not previously been exposed to FVIII:C. These inhibitors developed within 50 exposure days. The failure of immune tolerance induction in our patient is disappointing, success having been reported at much higher inhibitor levels.4 B7 Only through the continued close surveillance of patients receiving the new generation of FVIII:C products can we find out whether the development of inhibitors and success or failure in suppressing them are directly related to the use of a specific purified FVIII preparation. This issue will also arise if replacement therapy with genetically engineered recombinant proteins synthesised in mammalian cell lines is introduced.9 Division of Hematology and Oncology, George Washington University Medical Center,
Washington, DC 20037, USA
CRAIG M. KESSLER KAREN SACHSE
GC, Shoemaker CB. Factor VIII gene and hemophilia A. Blood 1989; 73:1-12. Shapiro SS. Genetic predisposition to inhibitor formation. In. Hoyer LW, ed. Factor
1. White
2.
Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate
VIII inhibitors. New York: Alan R Liss, 1984: 45. 3. Moffat EH, Furlong RA, Dannatt AHG, et al. Anti-idiotypes to factor VIII antibodies and their possible role in the pathogenesis and treatment of factor VIII inhibitors.
Br J Haematol 1989; 71: 85-90. IM, Bemtorp B, Zetterall O Induction of immune tolerance m patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII N Engl J Med 1988; 318: 947-50. Schwarzinger I, Pabinger I, Korninger C, et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates Am J Hematol 1987; 24: 241-45. McMillan CW, Shapiro SS, Whitehurst D, et al. The natural history of factor VIII:C inhibitors m patients with hemophilia A. a national cooperative study II: observations on the initial development of factor VIII.C inhibitors. Blood 1988; 71:
4. Nilsson
SIR,-Factor VIII:C inhibitors develop in 5-15% of treated patients with haemophilia A and can complicate the treatment and prevention of bleeding because they rapidly neutralise transfused FVIII:C. The production of these alloantibodies is not clearly understood, although attention has focused on abnormalities of the FVIII:C gene/ a possible association with HLA antigens,2 and failure to produce anti-idiotypic antibodies to neutralise the inhibitor or suppress its development.3 We are probably seeing some sort of abnormal immune response to a "foreign" protein, and the introduction of novel purification and viral attenuation/ elimination techniques into the manufacture of plasma derived concentrates has prompted concern that any subtle denaturation of the native FVIII:C protein might generate a neoantigen. A 38-year-old haemophilic man’s previous course had been uncomplicated except for laboratory evidence of long-standing non-A, non-B hepatitis. He had been managed with fresh frozen plasma, cryoprecipitate, and non-heat-treated FVIII for muscle and joint bleeds and dental surgery until late 1986, when he was switched to a heat-treated concentrate. The patient typically required at least 70 000 units a year to deal with two or three spontaneous bleeds per month. HIV seroconversion was noted in 1987. Monoclonal-antibody-purified, dry-heat-treated FVIII concentrate (’Monoclate’; Armour) was introduced in early 1988. After 62 days of exposure to monoclate a decreased response was noted, together with FVIII:C inhibitor (8-8 Bethesda units). The effects of the inhibitor were easily overcome with infusions of 10 000-15 000 U (150-200 U/kg) of monoclate. In an attempt to suppress the inhibitor the Malin6 procedure for immune tolerance induction was tried.’ This consisted of plasmapheresis followed by intravenous and oral intravenous cyclophosphamide, garnrnaglobulin, and monoclate to raise the FVIII:C level to 25-50%. Over the next 4 months of monoclate therapy, however, the patient’s inhibitor level rose to 53 units and the immune tolerance regimen was withdrawn when venous access and compliance became difficult because of the frequent venepunctures. The patient is now on non-activated heat-treated FIX complex concentrate.
This is the first report of FVIII:C inhibitor developing in an adult receiving monoclonal-antibody-purified FVIII concentrate, and the first adult experience in which this product was tried in an immune tolerance induction regimen. We cannot be certain that monoclate was responsible but several features point in that direction. Development of persistent high titre FVIII:C inhibitor beyond the fourth decade of life is unusual," although McMillan et al6 noted that 26 % of new inhibitors developed after age 30. Most high titre inhibitors first develop within 75 days of exposure to FVIII:C protein,S-7 and this man had had 62 days of exposure to monoclate, having previously had more than 2000 exposure days on
5.
6.
344-48
Ewing NP, Sanders NL, Dietrich SL, Kasper CK. Induction of immune tolerance to factor VIII in hemophiliacs with inhibitors. JAMA 1988; 259: 65-68. 8. Mariani G, Solinas S, Pasqualetti D, et al. Induction of immunotolerance in hemophilia for high titre inhibitor eradication: a long-term follow-up. Thromb Haemostas 1989; 62: 835-39. 9 White GC, McMillan CW, Kindon HS, Shoemaker CB. Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med 1989; 320: 166-70. 7.
Pellagra
in Mozambican
refugees
SiR,—Despite tremendous efforts by the World Food Programme (WFP) rations for refugees are often inadequate, in quantity or quality, and major outbreaks ofxerophthalmia, scurvy, and pellagra have been described. Since late 1986 Mozambican refugees have sought asylum in Malawi. A health information system has been set up by Medecins sans Frontieres (a French non-governmental organisation) in collaboration with the Malawi Ministry of Health and the UN High Commission for Refugees (UNHCR). At the end of May, 1989, medical personnel in the Nsanje district, in south Malawi, started to report an increasing incidence of pellagra dermatitis (in Malawi pellagra is endemic). To assess the magnitude of this we reviewed surveillance data collected from January to December, 1989. From June to December, 1989,1169 cases of clinically diagnosed pellagra were notified, the definition being a roughening and thickening of skin, dryness, scaling, a shiny surface, and brown pigmentation. 984 were from the Tengani camp (attack rate 6-7%) and 198 of these (20%) were less than five years old. No data were available to estimate the case fatality ratio. Despite the low specificity of the case definition used which may have overestimated the attack rate, this increase in incidence constituted a major public health challenge. From January to May, 1989, food rations provided an average of 4-9 mg niacin per person per day (table). World Health Organisation recommendations for daily intake range from 5-4 mg for infants to 20-3mg for adults. This outbreak in Malawi began 5 months after total disruption of groundnuts distribution, a time lapse that fits in with published work on experimental deficiency. This outbreak happened despite the results of a UNHCR mission in February, 1989, which had indicated that inadequate
1404
BASIC FOOD RATION DISTRIBUTEDTOMOZAMBICAN REFUGEES IN MALAWI
same, and to potentially serve as the genetic pool for beta-lactamase negative beta-lactam agent resistance in pathogenic neisseriae. The frequency of such resistance developing in commensal neisseriae after prolonged beta-lactam agent use would be of interest. British Columbia’s Children’s
Vancouver, Canada V6H 3V4
Hospital,
N. CIMOLAI E. BRYCE
C, Salvador C, Rotger, et al. Multiresistance plasmid from commensal strains. Antimicrob Agents Chemother 1985; 27: 120-24. Knapp JS, Johnson SR, Zenilman JM, et al. High-level tetracycline resistance resulting from Tet M in strains of Neisseria spp., Kingella denitrificans, and Eikenella corrodens. Antimicrob Agents Chemother 1988; 32: 765-67. Spratt BG, Zhang Q, Jones DM, et al. Recruitment ofa pencillin-binding protein gene from Neissena flavescens during the emergence of penicillin resistance m Neisseria meningitidis. Proc Natl Acad Sci (USA) 1989; 86: 8988-92.
1. Pintado
Neisseria
2.
3
Sources East Central & Southern Afnca Food and Nutrition Technical Centre for Agricultural and Rural Cooperation
Cooperation and (ACP-EEC Lome
Convention)
rations would certainly lead to outbreaks of pellagra. Furthermore recent data on food distribution among refugees in Malawi indicate that no groundnuts will be available until the end of 1990. This experience indicates the need for better collaboration between the different parties involved in caring for refugees or displaced persons. The attention of donors has to be attracted towards help for refugees, especially in Africa. The tremendous aid needs of Eastern Europe should not divert funds from developing countries. Epicentre, 8 rue Saint-Sabin, 75011 Paris, France Médecins Sans Frontières, Nsanje and Blantyre, Malawi
ALAIN MOREN
DOMINIQUE LEMOULT ALICE BRODEL
Beta-lactam resistance in Neisseria spp SlR,-Dr Turner (March 24, p 732) and Dr Jones (April 7, p 863) and their colleagues’ reports raise questions about the origin of drug resistance in meningococci. Although resistance might emerge in the nasopharyngeal pool of Neisseria meningitidis during exposure to antibiotics, the transfer of resistance genes from other commensal Neisseria spp remains a potentially important mechanism. Betalactamase-producing non-pathogenic Neisseria spp have been reported,’ as have commensal Neisseria spp bearing the tetM determinantSpratt et all have proposed genetic recombination as one mechanism to account for the emergence of beta-lactamasenegative, penicillin-resistant N meningitidis, and have incriminated the commensal Nflavescens in the same. We describe high-level beta-Iactam resistance in another commensal, N mucosa, arising during the use of antibiotics. A 2-year-old girl with achondroplasia and chronic lung disease was admitted with respiratory insufficiency accompanying an acute respiratory syncytial virus infection. Within a few days of mechanical ventilation, she had raised temperatures daily and a white blood cell count of 24x109/1 (polymorphonuclear predominance). No extrapulmonary focus of infection could be identified, and a gram stain of the tracheal aspirate revealed pus and many gram-negative diplococci. Intravenous cefuroxime was given to ensure coverage of beta-lactamase-producing Branhamella catarrhalis. The febrile illness continued, however, despite two weeks of this antibiotic, and at the end of therapy the gram stain appearance of tracheal secretions was unchanged and N mucosa in relative purity was isolated. The organism repeatedly proved beta-lactamase negative (nitrocefin test). Resistance to cefuroxime, penicillin, and ampicillin was seen by disc diffusion assays. Confirmation by microdilution tests with unsupplemented Mueller-Hinton broth revealed minimum inhibitory concentrations (mg/1) of cefuroxime 16, penicillin > 4, and 2. Intravenous and ampicillin chloramphenicol subsequent extubation seem to have cured the febrile illness. Chronic exposure to antibiotics in vivo is well recognised to result in drug-resistant strains for many bacterial species. Our patient demonstrates the ability of some commensal Neisseria spp to do the
Hospital outbreak of Salmonella enteritidis infection treated with ciprofloxacin SIR,--Outbreaks of hospital-acquired salmonellosis can disrupt a hospital and cause substantial morbidity and mortality. There were twenty-eight such outbreaks in Britain during 1988. Although antibiotics are not usually helpful in acute salmonella gastroenteritisl the quinolone agent ciprofloxacin significantly shortens the duration of symptoms and of faecal excretion of salmonellae.2 Ciprofloxacin might therefore be useful in the control of hospital outbreaks. An outbreak of Salmonella enteritidis phage type 4 gastroenterititis affected 41 patients in a psychiatric hospital in October, 1988. 5 patients were discharged home shortly after the outbreak began. Most of the remaining 36 (aged 20-95 years, mean 72) were confused and had poor personal hygiene. The symptoms (diarrhoea, fever, and anorexia) had lasted 7 days on average (range 0-31) before treatment began. 10 severely ill patients were treated initially with intravenous ciprofloxacin 200 mg twice daily and the other 26 were given oral ciprofloxacin 500 mg twice daily. Treatment was for 7 days except in 3 bacteraemic patients who received ciprofloxacin for 14 days. No adverse effects were noted. The ciprofloxacin therapy cost 2100. 32 patients were transferred to the regional infectious diseases unit. 1 patient, who was not severely ill, died unexpectedly of a pulmonary embolus 2 days after starting therapy. The first stool sample for clearance was taken 4 days after the end of the ciprofloxacin treatment. Clearance was defmed as three or more post-treatment negative stool cultures, at least one of which was taken more than a month after completion of therapy. Clearance cultures were completed in 30 of the 35 surviving patients, and in 28 there were no positive stool cultures after initiation of ciprofloxacin treatment. At least one negative and no further positive stool cultures were obtained after treatment from the 5 patients in whom
follow-up was incomplete. Only 1 patient had prolonged diarrhoea after treatment. The other 34 survivors had symptoms for 3 days (range 0-22) after starting ciprofloxacin. The patient with prolonged symptoms had diarrhoea for 73 days. She had received a 14-day course of metronidazole besides ciprofloxacin. Clostridium difficile and S enteritidis were demonstrated in stool cultures 25 days after she completed treatment. After a 21-day course of ciprofloxacin and vancomycin nine further consecutive stool cultures were negative for salmonellae. 1 patient, although symptom-free, had positive stool cultures for S enteritidis at 2 weeks and Iweeks after completing a 14-day course of ciprofloxacin, but three subsequent cultures were negative. Both these patients had been bacteraemic. In patients with salmonella gastroenteritis loose stools usually persist for several days.3 In this outbreak diarrhoea had lasted on average 7 days before treatment but symptoms rapidly resolved after starting ciprofloxacin. Faecal excretion of salmonellae usually persists for more than 4 weeks.l,4 In this outbreak, with two exceptions, no positive cultures were obtained after the start of ciprofloxacin. Ciprofloxacin was well tolerated in these elderly patients. We do not recommend ciprofloxacin for all cases of salmonella gastroenteritis--side-effects and costs must be taken
determinants such as lymph-node involvement, spread through the bowel wall, quality of invasive margin, and lymphocytic infiltrate at advancing margins. Lymphocytic infiltrate was not assessed by Cawthom et al. As the Guildford group comment in their last paragraph, any prognostic system needs to be both reproducible and accurate in the prediction of outcome after surgery. The assessment of mesorectal spread can only be accurate when meticulous technique, such as they describe, is used, and most pathology departments in this country would fall woefully short of such an ideal. Furthermore, the reproducibility of the prognostic importance of mesorectal spread must be regarded as very doubtful in view of the conflicting results from the St Mark’s and Guildford
prognostic
studies. Gloucestershire Royal Hospital, Gloucester GL1 3NN, UK
NEIL A. SHEPHERD
Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Lancet 1986; ii. 996-98. 2. Jass JR, Love SB, Northover JMA. A new prognostic classification of rectal cancer. Lancet 1987; i: 1303-06. 1
Quirke P, Durdey P,
other FVIII:C preparations. J. M. Lusher
(unpublished) tells us that in a multicentre study with monoclate new inhibitors to FVIII:C have developed in seven of thirty-nine patients (predominantly infants and children) who had not previously been exposed to FVIII:C. These inhibitors developed within 50 exposure days. The failure of immune tolerance induction in our patient is disappointing, success having been reported at much higher inhibitor levels.4 B7 Only through the continued close surveillance of patients receiving the new generation of FVIII:C products can we find out whether the development of inhibitors and success or failure in suppressing them are directly related to the use of a specific purified FVIII preparation. This issue will also arise if replacement therapy with genetically engineered recombinant proteins synthesised in mammalian cell lines is introduced.9 Division of Hematology and Oncology, George Washington University Medical Center,
Washington, DC 20037, USA
CRAIG M. KESSLER KAREN SACHSE
GC, Shoemaker CB. Factor VIII gene and hemophilia A. Blood 1989; 73:1-12. Shapiro SS. Genetic predisposition to inhibitor formation. In. Hoyer LW, ed. Factor
1. White
2.
Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate
VIII inhibitors. New York: Alan R Liss, 1984: 45. 3. Moffat EH, Furlong RA, Dannatt AHG, et al. Anti-idiotypes to factor VIII antibodies and their possible role in the pathogenesis and treatment of factor VIII inhibitors.
Br J Haematol 1989; 71: 85-90. IM, Bemtorp B, Zetterall O Induction of immune tolerance m patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII N Engl J Med 1988; 318: 947-50. Schwarzinger I, Pabinger I, Korninger C, et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates Am J Hematol 1987; 24: 241-45. McMillan CW, Shapiro SS, Whitehurst D, et al. The natural history of factor VIII:C inhibitors m patients with hemophilia A. a national cooperative study II: observations on the initial development of factor VIII.C inhibitors. Blood 1988; 71:
4. Nilsson
SIR,-Factor VIII:C inhibitors develop in 5-15% of treated patients with haemophilia A and can complicate the treatment and prevention of bleeding because they rapidly neutralise transfused FVIII:C. The production of these alloantibodies is not clearly understood, although attention has focused on abnormalities of the FVIII:C gene/ a possible association with HLA antigens,2 and failure to produce anti-idiotypic antibodies to neutralise the inhibitor or suppress its development.3 We are probably seeing some sort of abnormal immune response to a "foreign" protein, and the introduction of novel purification and viral attenuation/ elimination techniques into the manufacture of plasma derived concentrates has prompted concern that any subtle denaturation of the native FVIII:C protein might generate a neoantigen. A 38-year-old haemophilic man’s previous course had been uncomplicated except for laboratory evidence of long-standing non-A, non-B hepatitis. He had been managed with fresh frozen plasma, cryoprecipitate, and non-heat-treated FVIII for muscle and joint bleeds and dental surgery until late 1986, when he was switched to a heat-treated concentrate. The patient typically required at least 70 000 units a year to deal with two or three spontaneous bleeds per month. HIV seroconversion was noted in 1987. Monoclonal-antibody-purified, dry-heat-treated FVIII concentrate (’Monoclate’; Armour) was introduced in early 1988. After 62 days of exposure to monoclate a decreased response was noted, together with FVIII:C inhibitor (8-8 Bethesda units). The effects of the inhibitor were easily overcome with infusions of 10 000-15 000 U (150-200 U/kg) of monoclate. In an attempt to suppress the inhibitor the Malin6 procedure for immune tolerance induction was tried.’ This consisted of plasmapheresis followed by intravenous and oral intravenous cyclophosphamide, garnrnaglobulin, and monoclate to raise the FVIII:C level to 25-50%. Over the next 4 months of monoclate therapy, however, the patient’s inhibitor level rose to 53 units and the immune tolerance regimen was withdrawn when venous access and compliance became difficult because of the frequent venepunctures. The patient is now on non-activated heat-treated FIX complex concentrate.
This is the first report of FVIII:C inhibitor developing in an adult receiving monoclonal-antibody-purified FVIII concentrate, and the first adult experience in which this product was tried in an immune tolerance induction regimen. We cannot be certain that monoclate was responsible but several features point in that direction. Development of persistent high titre FVIII:C inhibitor beyond the fourth decade of life is unusual," although McMillan et al6 noted that 26 % of new inhibitors developed after age 30. Most high titre inhibitors first develop within 75 days of exposure to FVIII:C protein,S-7 and this man had had 62 days of exposure to monoclate, having previously had more than 2000 exposure days on
5.
6.
344-48
Ewing NP, Sanders NL, Dietrich SL, Kasper CK. Induction of immune tolerance to factor VIII in hemophiliacs with inhibitors. JAMA 1988; 259: 65-68. 8. Mariani G, Solinas S, Pasqualetti D, et al. Induction of immunotolerance in hemophilia for high titre inhibitor eradication: a long-term follow-up. Thromb Haemostas 1989; 62: 835-39. 9 White GC, McMillan CW, Kindon HS, Shoemaker CB. Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med 1989; 320: 166-70. 7.
Pellagra
in Mozambican
refugees
SiR,—Despite tremendous efforts by the World Food Programme (WFP) rations for refugees are often inadequate, in quantity or quality, and major outbreaks ofxerophthalmia, scurvy, and pellagra have been described. Since late 1986 Mozambican refugees have sought asylum in Malawi. A health information system has been set up by Medecins sans Frontieres (a French non-governmental organisation) in collaboration with the Malawi Ministry of Health and the UN High Commission for Refugees (UNHCR). At the end of May, 1989, medical personnel in the Nsanje district, in south Malawi, started to report an increasing incidence of pellagra dermatitis (in Malawi pellagra is endemic). To assess the magnitude of this we reviewed surveillance data collected from January to December, 1989. From June to December, 1989,1169 cases of clinically diagnosed pellagra were notified, the definition being a roughening and thickening of skin, dryness, scaling, a shiny surface, and brown pigmentation. 984 were from the Tengani camp (attack rate 6-7%) and 198 of these (20%) were less than five years old. No data were available to estimate the case fatality ratio. Despite the low specificity of the case definition used which may have overestimated the attack rate, this increase in incidence constituted a major public health challenge. From January to May, 1989, food rations provided an average of 4-9 mg niacin per person per day (table). World Health Organisation recommendations for daily intake range from 5-4 mg for infants to 20-3mg for adults. This outbreak in Malawi began 5 months after total disruption of groundnuts distribution, a time lapse that fits in with published work on experimental deficiency. This outbreak happened despite the results of a UNHCR mission in February, 1989, which had indicated that inadequate
1404
BASIC FOOD RATION DISTRIBUTEDTOMOZAMBICAN REFUGEES IN MALAWI
same, and to potentially serve as the genetic pool for beta-lactamase negative beta-lactam agent resistance in pathogenic neisseriae. The frequency of such resistance developing in commensal neisseriae after prolonged beta-lactam agent use would be of interest. British Columbia’s Children’s
Vancouver, Canada V6H 3V4
Hospital,
N. CIMOLAI E. BRYCE
C, Salvador C, Rotger, et al. Multiresistance plasmid from commensal strains. Antimicrob Agents Chemother 1985; 27: 120-24. Knapp JS, Johnson SR, Zenilman JM, et al. High-level tetracycline resistance resulting from Tet M in strains of Neisseria spp., Kingella denitrificans, and Eikenella corrodens. Antimicrob Agents Chemother 1988; 32: 765-67. Spratt BG, Zhang Q, Jones DM, et al. Recruitment ofa pencillin-binding protein gene from Neissena flavescens during the emergence of penicillin resistance m Neisseria meningitidis. Proc Natl Acad Sci (USA) 1989; 86: 8988-92.
1. Pintado
Neisseria
2.
3
Sources East Central & Southern Afnca Food and Nutrition Technical Centre for Agricultural and Rural Cooperation
Cooperation and (ACP-EEC Lome
Convention)
rations would certainly lead to outbreaks of pellagra. Furthermore recent data on food distribution among refugees in Malawi indicate that no groundnuts will be available until the end of 1990. This experience indicates the need for better collaboration between the different parties involved in caring for refugees or displaced persons. The attention of donors has to be attracted towards help for refugees, especially in Africa. The tremendous aid needs of Eastern Europe should not divert funds from developing countries. Epicentre, 8 rue Saint-Sabin, 75011 Paris, France Médecins Sans Frontières, Nsanje and Blantyre, Malawi
ALAIN MOREN
DOMINIQUE LEMOULT ALICE BRODEL
Beta-lactam resistance in Neisseria spp SlR,-Dr Turner (March 24, p 732) and Dr Jones (April 7, p 863) and their colleagues’ reports raise questions about the origin of drug resistance in meningococci. Although resistance might emerge in the nasopharyngeal pool of Neisseria meningitidis during exposure to antibiotics, the transfer of resistance genes from other commensal Neisseria spp remains a potentially important mechanism. Betalactamase-producing non-pathogenic Neisseria spp have been reported,’ as have commensal Neisseria spp bearing the tetM determinantSpratt et all have proposed genetic recombination as one mechanism to account for the emergence of beta-lactamasenegative, penicillin-resistant N meningitidis, and have incriminated the commensal Nflavescens in the same. We describe high-level beta-Iactam resistance in another commensal, N mucosa, arising during the use of antibiotics. A 2-year-old girl with achondroplasia and chronic lung disease was admitted with respiratory insufficiency accompanying an acute respiratory syncytial virus infection. Within a few days of mechanical ventilation, she had raised temperatures daily and a white blood cell count of 24x109/1 (polymorphonuclear predominance). No extrapulmonary focus of infection could be identified, and a gram stain of the tracheal aspirate revealed pus and many gram-negative diplococci. Intravenous cefuroxime was given to ensure coverage of beta-lactamase-producing Branhamella catarrhalis. The febrile illness continued, however, despite two weeks of this antibiotic, and at the end of therapy the gram stain appearance of tracheal secretions was unchanged and N mucosa in relative purity was isolated. The organism repeatedly proved beta-lactamase negative (nitrocefin test). Resistance to cefuroxime, penicillin, and ampicillin was seen by disc diffusion assays. Confirmation by microdilution tests with unsupplemented Mueller-Hinton broth revealed minimum inhibitory concentrations (mg/1) of cefuroxime 16, penicillin > 4, and 2. Intravenous and ampicillin chloramphenicol subsequent extubation seem to have cured the febrile illness. Chronic exposure to antibiotics in vivo is well recognised to result in drug-resistant strains for many bacterial species. Our patient demonstrates the ability of some commensal Neisseria spp to do the
Hospital outbreak of Salmonella enteritidis infection treated with ciprofloxacin SIR,--Outbreaks of hospital-acquired salmonellosis can disrupt a hospital and cause substantial morbidity and mortality. There were twenty-eight such outbreaks in Britain during 1988. Although antibiotics are not usually helpful in acute salmonella gastroenteritisl the quinolone agent ciprofloxacin significantly shortens the duration of symptoms and of faecal excretion of salmonellae.2 Ciprofloxacin might therefore be useful in the control of hospital outbreaks. An outbreak of Salmonella enteritidis phage type 4 gastroenterititis affected 41 patients in a psychiatric hospital in October, 1988. 5 patients were discharged home shortly after the outbreak began. Most of the remaining 36 (aged 20-95 years, mean 72) were confused and had poor personal hygiene. The symptoms (diarrhoea, fever, and anorexia) had lasted 7 days on average (range 0-31) before treatment began. 10 severely ill patients were treated initially with intravenous ciprofloxacin 200 mg twice daily and the other 26 were given oral ciprofloxacin 500 mg twice daily. Treatment was for 7 days except in 3 bacteraemic patients who received ciprofloxacin for 14 days. No adverse effects were noted. The ciprofloxacin therapy cost 2100. 32 patients were transferred to the regional infectious diseases unit. 1 patient, who was not severely ill, died unexpectedly of a pulmonary embolus 2 days after starting therapy. The first stool sample for clearance was taken 4 days after the end of the ciprofloxacin treatment. Clearance was defmed as three or more post-treatment negative stool cultures, at least one of which was taken more than a month after completion of therapy. Clearance cultures were completed in 30 of the 35 surviving patients, and in 28 there were no positive stool cultures after initiation of ciprofloxacin treatment. At least one negative and no further positive stool cultures were obtained after treatment from the 5 patients in whom
follow-up was incomplete. Only 1 patient had prolonged diarrhoea after treatment. The other 34 survivors had symptoms for 3 days (range 0-22) after starting ciprofloxacin. The patient with prolonged symptoms had diarrhoea for 73 days. She had received a 14-day course of metronidazole besides ciprofloxacin. Clostridium difficile and S enteritidis were demonstrated in stool cultures 25 days after she completed treatment. After a 21-day course of ciprofloxacin and vancomycin nine further consecutive stool cultures were negative for salmonellae. 1 patient, although symptom-free, had positive stool cultures for S enteritidis at 2 weeks and Iweeks after completing a 14-day course of ciprofloxacin, but three subsequent cultures were negative. Both these patients had been bacteraemic. In patients with salmonella gastroenteritis loose stools usually persist for several days.3 In this outbreak diarrhoea had lasted on average 7 days before treatment but symptoms rapidly resolved after starting ciprofloxacin. Faecal excretion of salmonellae usually persists for more than 4 weeks.l,4 In this outbreak, with two exceptions, no positive cultures were obtained after the start of ciprofloxacin. Ciprofloxacin was well tolerated in these elderly patients. We do not recommend ciprofloxacin for all cases of salmonella gastroenteritis--side-effects and costs must be taken
