Immunosuppressive properties of sera and urine dialysates from kidney-graft recipients treated with azathioprine,prednisolone, and niridazole

Niridazole, an antischistosomal agent, was given to renal transplant recipients in addition to azathioprine and prednisolone, as there is experimental evidence that this combination of drugs is highly immunosuppressive. Sera obtained from kidney-graft recipients during the first two weeks after transplantation were examined for their ability to inhibit the one-way mixed lymphocyte reaction (MLR). Sera from seven patients receiving azathioprine, prednisolone, and niridazole (triple-drug treatment), five patients receiving azathioprine and prednisolone, and two other patients treated with niridazole alone for schistosomiasis produced MLR inhibition by comparison with pretreatment (control) sera.A mean of 78% inhibition was observed with sera taken after one day''s treatment with the three-drug combination, whereas this level of in-vitro immunosuppression occurred only after eight days of treatment with azathioprine and prednisolone. Niridazole alone produced an effect similar to azathioprine and prednisolone. Concentrated dialysate of urine from a patient receiving triple-drug treatment not only inhibited the MLR but also significantly prolonged the survival of heterotopic heart allografts in rats, whereas dialysate from the same patient after niridazole had been stopped gave less MLR inhibition and failed to prolong heart allograft survival.Since niridazole thus increased the in-vitro and in-vivo immunosuppressive action of azathioprine and prednisolone, we suggest that this triple-drug combination might be useful for preventing early acute kidney graft rejection.     

Azathioprine versus Beta Interferons for Relapsing-Remitting Multiple Sclerosis: A Multicentre Randomized Non-Inferiority Trial

For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19–0.37) in the azathioprine and 0.39 (95% CI 0.30–0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RR_AZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61–0.95) in the azathioprine and 0.69 (95% CI 0.54–0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year.The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.

Trial Registration

EudraCT 2006-004937-13     

Factors Associated With the Time to Next Attack in Neuromyelitis Optica: Accelerated Failure Time Models With Random Effects

Background and Objective

Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system with a relapsing and remitting course. We aimed to identify factors associated with the time to next attack, including the effect of the natural disease course and the diverse treatment regimens, by applying a longitudinal statistical analysis to the individual attacks of each patient.

Methods

In total, 184 acute attacks among 58 patients with either NMO or NMO spectrum disorder with anti-aquaporin-4 antibody were assessed retrospectively. Patient demographics, clinical characteristics at each attack, and type of treatment during inter-attack periods were assessed. The dependent variable was defined as the time from each attack to the next attack (inter-attack interval). An exponential accelerated failure time model with shared gamma frailty was adapted for statistical analysis.

Results

A multivariable analysis revealed that the time from each attack to the next attack in NMO increased independently by 1.31 times (95% confidence interval (CI), 1.02–1.67; p = 0.035) with each additional cumulative attack experienced, by 5.34 times (95% CI, 1.57–18.13; p = 0.007) with combined azathioprine treatment and continued oral prednisolone, and by 4.26 times (95% CI, 1.09–16.61; p = 0.037) with rituximab treatment.

Conclusion

The time to next attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Nevertheless, both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were also associated with a longer time to next attack, independently of the natural disease course of NMO.     

Serum IgG and Renal Transplantation

In 57 patients with renal allografts the prolonged administration of prednisolone ≥ 1 mg/kg/day and azathioprine ≥ 3 mg/kg/day caused a significant and persistent fall in serum IgG at all levels of creatinine clearance. The fall in IgG was more striking when creatinine clearance was below 25 ml/min. At lower doses of azathioprine and prednisolone serum IgG fell when the creatinine clearance was less than 35 ml/min, the degree of recovery towards normal being dependent on creatinine clearance and dosage. Post-transplant haemodialysis decreased the depression of IgG, and patients with immediately functioning grafts had minimal IgG depression. An inverse relation between IgG and IgM was observed in some patients. Severe infections and toxicity were associated with the greatest reduction in IgG; leucopenia and thrombocytopenia were not consistently reliable guides to toxicity. The deaths of four patients (7%) were associated with severe infections. Falls in IgG were not related to the rejection process. IgG measurement should be used as a guide to immunosuppression and toxicity in renal allograft patients.     

Renal transplantation in patients treated with haemodialysis and short term and long term continuous ambulatory peritoneal dialysis.

Forty two adult patients who had been treated with continuous ambulatory peritoneal dialysis for one to 142 weeks (mean (SD) 38 (36)) received a total of 44 allografted kidneys. Twenty one had been treated with continuous ambulatory peritoneal dialysis for less than 26 weeks (mean 11 (8)) and the other 21 for longer than 26 weeks (mean 64 (35)). These two groups were compared with 55 patients who had been treated with haemodialysis and received a total of 63 grafts. In the group of patients treated with continuous ambulatory peritoneal dialysis azathioprine and low dose prednisolone were used as the immunosuppressive regimen for 20 transplantations in 18 patients, and 24 patients receiving 24 grafts were treated with cyclosporin A and low dose prednisolone. In the group of patients treated with haemodialysis 38 patients receiving 43 grafts were treated with azathioprine and low dose prednisolone, and 20 patients receiving 20 grafts were treated with cyclosporin A and low dose prednisolone. Actuarial survival of patients and grafts at two years was 95% and 72%, respectively, in the continuous ambulatory peritoneal dialysis group compared with 89% and 58%, respectively, in the haemodialysis group. No difference was found in graft survival between short term treatment with continuous ambulatory peritoneal dialysis (72% graft survival) and long term treatment (65% graft survival). In conclusion, continuous ambulatory peritoneal dialysis is suitable treatment for patients awaiting renal transplantation.     

Controlled trial of azathioprine in chronic ulcerative colitis.

A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed. Among patients who completed the trial the mean dose of prednisolone necessary to control the disease decreased in those treated with azathioprine and those treated with placebo; the reduction was greater among those who took azathioprine (p less than 0.001). Activity of the disease apparently improved in both treatment groups but a significant (p less than 0.001) trend was observed only in those patients treated with azathioprine. No serious side effects from azathioprine occurred during the trial but seven of 24 patients had to stop the drug because of nausea. Azathioprine may have a role in the treatment of a few patients wih troublesome chronic colitis for whom conventional drug treatment is ineffectual, or for whom continuous systemic corticosteroid treatment is needed to control symptoms, and for whom surgical treatment is inappropriate.     

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised,Double Blind,Controlled Pilot Studies in Ethiopia

Background

Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL.

Methods and Results

Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin.

Conclusions

This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients’ assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid–sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale.     

Azathioprine in Treatment of Bullous Pemphigoid

Azathioprine was given to 11 patients with pemphigoid who had been on long-term maintenance therapy with prednisone or prednisolone. In nine of these prednisone therapy was withdrawn and all were maintained symptom-free on azathioprine alone, while in two the dose of prednisone was considerably reduced. One patient who had never received corticosteroids was controlled by azathioprine alone during the initial acute phase of the illness. Since azathioprine acts slowly, it is recommended that corticosteroids should be used together with azathioprine during the acute stage. Thus azathioprine is valuable in long-term management of pemphigoid, particularly in patients showing corticosteroid toxicity or in whom the minimum maintenance dose is dangerously high.     

Hypothalamic–pituitary–adrenal function after subarachnoid haemorrhage

In 18 patients with a ruptured aneurysm of the anterior communicating artery on the circle of Willis hypothalamuc–pituitary–adrenal function has been assessed by the diurnal variation in plasma cortisol levels and by the response to metyrapone, dexamethasone, and pyrogen. Eleven patients had an abnormal diurnal variation, seven had an abnormal response to metyrapone, and eight had an abnormal response to dexamethasone. All who were given pyrogen reacted normally to this stress. Two patients who died had lesions in the anterior hypothalamus, and it is suggested that this localization of lesions was responsible for the pattern of pituitary–adrenal dysfunction which was observed. An improvement in function was seen in many patients after an interval of a month.     

Death Adder Envenoming Causes Neurotoxicity Not Reversed by Antivenom - Australian Snakebite Project (ASP-16)

Background

Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment.

Methodology/Principal Findings

Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom.

Conclusions/Significance

Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The persistent neurological effects despite antivenom, suggests that neurotoxicity is not reversed by antivenom.     

Co-trimoxazole and Azathioprine: A Safe Combination

Ninety-four patients receiving immunosuppressive therapy with azathioprine and prednisone after human cadaver kidney transplantation developed urinary tract infections and were treated with co-trimoxazole or another antibiotic in a controlled randomized prospective trial. The incidence of leucopenia in the group treated with co-trimoxazole (10·6%) was not significantly different from that in the group treated with other antibiotics (23·6%). Leucopenia when it occurred did so soon after transplantation at a time when the function of the renal transplant was poor in relation to the dosage of azathioprine given. In all cases the temporary withdrawal of azathioprine relieved the leucopenia despite continuation of the co-trimoxazole treatment. This study did not provide any evidence that co-trimoxazole plus azathioprine was a more potent cause of leucopenia than azathioprine alone.     

Membranoproliferative Glomerulonephritis and Persistent Hypocomplementaemia

The clinical, laboratory, and histological findings of 50 patients with membranoproliferative glomerulonephritis are described. Three-quarters of the patients, who were mostly older children and young adults, presented clinically with a mixture of “nephritic” and “nephrotic” symptoms; the remaining quarter had no symptoms and were diagnosed after the discovery of proteinuria and microscopic haematuria.Though this clinical picture may occur in other forms of glomerulonephritis, the patients described here were unified as a group by their glomerular morphological appearance—namely, a combination of mesangial proliferation and capillary wall thickening, mainly due to subendothelial accumulations of mesangial matrix.In 68% serum C3 (β10-globulin) levels were reduced initially, while a further 16% subsequently showed a fall to abnormally low levels. All patients had substantial proteinuria, usually of moderately impaired selectivity, and all but one had haematuria in addition. Children frequently presented with an illness resembling acute nephritis, whereas adults usually had a nephrotic syndrome from the start.In 31 patients, followed for periods of one to eight and a half years, serial measurements of glomerular filtration rate were made. Sixteen have experienced no deterioration of renal function, though their proteinuria continues unchanged. Fifteen have shown progressive deterioration; six of them are still well, six are on regular dialysis treatment, and three have died. Treatment with corticosteroids, azathioprine, or cyclophosphamide, alone or in combination, did not seem to influence the course of the disease, and another two patients died from complications of steroid therapy. The disease usually runs a chronic course and appears to be progressive.     

Patient Age and the Prognosis of Idiopathic Membranous Nephropathy

Background

Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients.

Methods

We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65–70 years, and 41 (24.0%) patients ≥71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients.

Results

During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR) = 3.11, 95% confidence interval (CI): 1.45–7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59–242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59–204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51–37.8; P = 0.012).

Conclusions

Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper.     

High versus "low" dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial.

Corticosteroids have the major role in the immunosuppressive treatment of patients who have received renal transplants. Despite their extensive use there is still debate about the appropriate dose that will prevent rejection of the renal allograft with the least morbidity. From March 1979 to November 1981 a randomised controlled trial of high (33 patients) v low oral dose (34 patients) of prednisolone along with azathioprine was conducted in recipients of first cadaveric transplants who had received a blood transfusion within six months of transplantation. The main difference in outcome between the two groups was a high incidence of some infections in the high dose group. Patient mortality, graft survival, transplant function, and number of rejection episodes were indistinguishable in the two groups, but rejection episodes tended to occur later in the high dose group. These findings suggest that the use of lower doses of corticosteroids soon after cadaveric renal transplantation does not jeopardise graft survival and results in lower patient morbidity.     

Predictive Factors for Subjective Improvement in Lumbar Spinal Stenosis Patients with Nonsurgical Treatment: A 3-Year Prospective Cohort Study

Objective

To assess the predictive factors for subjective improvement with nonsurgical treatment in consecutive patients with lumbar spinal stenosis (LSS).

Materials and Methods

Patients with LSS were enrolled from 17 medical centres in Japan. We followed up 274 patients (151 men; mean age, 71 ± 7.4 years) for 3 years. A multivariable logistic regression model was used to assess the predictive factors for subjective symptom improvement with nonsurgical treatment.

Results

In 30% of patients, conservative treatment led to a subjective improvement in the symptoms; in 70% of patients, the symptoms remained unchanged, worsened, or required surgical treatment. The multivariable analysis of predictive factors for subjective improvement with nonsurgical treatment showed that the absence of cauda equina symptoms (only radicular symptoms) had an odds ratio (OR) of 3.31 (95% confidence interval [CI]: 1.50–7.31); absence of degenerative spondylolisthesis/scoliosis had an OR of 2.53 (95% CI: 1.13–5.65); <1-year duration of illness had an OR of 3.81 (95% CI: 1.46–9.98); and hypertension had an OR of 2.09 (95% CI: 0.92–4.78).

Conclusions

The predictive factors for subjective symptom improvement with nonsurgical treatment in LSS patients were the presence of only radicular symptoms, absence of degenerative spondylolisthesis/scoliosis, and an illness duration of <1 year.     

Comparison of Corticotrophin and Prednisolone in Treatment of Idiopathic Facial Paralysis (Bell's Palsy)

In a controlled trial of the effects of intramuscular corticotrophin and oral prednisolone in the treatment of acute Bell''s palsy 186 successive patients with idiopathic facial palsy were grouped for age and duration of palsy. They were then allocated at random to either corticotrophin or prednisolone therapy in pairs. The results were:(1) 94 received corticotrophin and 32 developed some degree of denervation and 92 received prednisolone and 13 developed some degree of denervation (P <0·005); (2) six of the corticotrophin group became severely denervated (less than 50% recovery) compared with none of the prednisolone group (P <0·02); (3) the best results were obtained in the younger patients (less than 45 years old) treated on the first or second day of palsy; and (4) side effects were minimal.It is concluded that oral prednisolone is the treatment of choice for idiopathic facial (Bell''s) palsy.     

Treatment of Psoriasis with Azathioprine

Azathioprine treatment benefited 19 (66%) out of 29 patients suffering from severe psoriasis. Haematological complications were not troublesome and results of biochemical liver function tests remained normal. Minimal cholestasis was seen in two cases and portal fibrosis of a reversible degree in eight. Liver biopsies should be undertaken at regular intervals if azathioprine therapy is continued so that structural liver damage may be detected at an early and reversible stage.     

Azathioprine in Ulcerative Colitis: Final Report on Controlled Therapeutic Trial

Eighty patients, all of whom were suffering from a frank clinical attack of ulcerative colitis, were admitted to the trial. The attack was treated with a standard course of corticosteroids and the patients were immediately placed on treatment with either azathioprine in a dose of 2·5 mg/kg body weight or dummy tablets. The trial tablets were continued for one year while the patients were maintained under regular clinical, sigmoidoscopic, histological, haematological, and biochemical surveillance. If a patient relapsed during such maintenance treatment he or she was treated with a further course of corticosteroids without interrupting maintenance treatment.In the treatment of an actual attack of ulcerative colitis the results in the attacks which brought the 80 patients into the trial show that no benefit came from the addition of azathioprine to a standard course of corticosteroid therapy.Patients admitted in their first attack of ulcerative colitis showed no benefit from the one-year maintenance treatment with azathioprine, the benefits of which were confined to patients admitted in a relapse of established disease. Even in these the difference between the treated group and the control group failed to reach statistical significance, but the difference was big enough to suggest that there is a prima facie case for regarding azathioprine as of some benefit in this group of patients.     

Visceral Leishmaniasis and HIV Co-infection in Bihar,India: Long-term Effectiveness and Treatment Outcomes with Liposomal Amphotericin B (AmBisome)

Background

Visceral Leishmaniasis (VL; also known as kala-azar) is an ultimately fatal disease endemic in the Indian state of Bihar, while HIV/AIDS is an emerging disease in this region. A 2011 observational cohort study conducted in Bihar involving 55 VL/HIV co-infected patients treated with 20–25 mg/kg intravenous liposomal amphotericin B (AmBisome) estimated an 85.5% probability of survival and a 26.5% probability of VL relapse within 2 years. Here we report the long-term field outcomes of a larger cohort of co-infected patients treated with this regimen between 2007 and 2012.

Methods and Principal Findings

Intravenous AmBisome (20–25 mg/kg) was administered to 159 VL/HIV co-infected patients (both primary infections and relapses) in four or five doses of 5 mg/kg over 4–10 days. Initial cure of VL at discharge was defined as improved symptoms, cessation of fever, improvement of appetite and recession of spleen enlargement. Test of cure was not routinely performed. Antiretroviral treatment (ART) was initiated in 23 (14.5%), 39 (24.5%) and 61 (38.4%) before, during and after admission respectively. Initial cure was achieved in all discharged patients. A total of 36 patients died during follow-up, including six who died shortly after admission. Death occurred at a median of 11 weeks (IQR 4–51) after starting VL treatment. Estimated mortality risk was 14.3% at six months, 22.4% at two years and 29.7% at four years after treatment. Among the 153 patients discharged from the hospital, 26 cases of VL relapse were diagnosed during follow-up, occurring at a median of 10 months (IQR 7–14) after discharge. After accounting for competing risks, the estimated risk of relapse was 16.1% at one year, 20.4% at two years and 25.9% at four years. Low hemoglobin level and concurrent infection with tuberculosis were independent risk factors for mortality, while ART initiated shortly after admission for VL treatment was associated with a 64–66% reduced risk of mortality and 75% reduced risk of relapse.

Significance

This is the largest cohort of HIV-VL co-infected patients reported from the Indian subcontinent. Even after initial cure following treatment with AmBisome, these patients appear to have much higher rates of VL relapse and mortality than patients not known to be HIV-positive, although relapse rates appear to stabilize after 2 years. These results extend the earlier findings that co-infected patients are at increased risk of death and require a multidisciplinary approach for long-term management.     

Effects of Treatment on the Mortality Rate in Septicaemia

The results of treatment have been analysed in 173 patients with septicaemia during 1962–8. Between 1962 and 1965 various antibiotics were used, and shock was treated with vasopressor agents. Between 1966 and 1968 kanamycin was given initially, and shock was treated with corticosteroids and with intravenous fluid therapy monitored with a central venous pressure manometer.The mortality rate in 1966–8 fell to half that of the earlier period in patients with Gram-negative infections, and in those with shock. The reduced mortality in the latter was clearly associated with the use of a central venous manometer to control intravenous fluid therapy, though whether the reduction resulted from specific improvement in intravenous therapy or from the necessary closer observation of the patient is not clear. Staphylococcal septicaemia was common during both periods, and its mortality rate did not fall; hence methicillin together with kanamycin is now given initially in all cases.