Dominance of international high-risk clones in carbapenemase-producing Pseudomonas aeruginosa: Multicentric molecular epidemiology report from India

Background: Pseudomonas aeruginosa is one of the most common opportunistic pathogens that cause severe infections in humans. The burden of carbapenem resistance is particularly high and is on the rise. Very little information is available on the molecular mechanisms and its clonal types of carbapenem-resistant P. aeruginosa seen in Indian hospitals. This study was undertaken to monitor the ?-lactamase profile and to investigate the genetic relatedness of the carbapenemase-producing (CP) P. aeruginosa collected across different hospitals from India. Materials and Methods: A total of 507 non-duplicate, carbapenem-resistant P. aeruginosa isolated from various clinical specimens collected during 2014–2017 across seven Indian hospitals were included. Conventional multiplex polymerase chain reaction for the genes encoding beta-lactamases such as extended-spectrum beta-lactamase (ESBL) and carbapenemase were screened. A subset of isolates (n = 133) of CP P. aeruginosa were genotyped by multilocus sequence typing (MLST) scheme. Results: Of the total 507 isolates, 15%, 40% and 20% were positive for genes encoding ESBLs, carbapenemases and ESBLs + carbapenemases, respectively, whilst 25% were negative for the ?-lactamases screened. Amongst the ESBL genes, blaVEB is the most predominant, followed by blaPER and blaTEM, whilst blaVIM and blaNDM were the most predominant carbapenemases seen. However, regional differences were noted in the ?-lactamases profile across the study sites. Genotyping by MLST revealed 54 different sequence types (STs). The most common are ST357, ST235, ST233 and ST244. Six clonal complexes were found (CC357, CC235, CC244, CC1047, CC664 and CC308). About 24% of total STs are of novel types and these were found to emerge from the high-risk clones. Conclusion: This is the first large study from India to report the baseline data on the molecular resistance mechanisms and its association with genetic relatedness of CP P. aeruginosa circulating in Indian hospitals. blaVIM- and blaNDM-producing P. aeruginosa is the most prevalent carbapenemase seen in India. Majority of the isolates belongs to the high-risk international clones ST235, ST357 and ST664 which is a concern.

Randomized controlled trial on the effective dose of anti-snake venom in cases of snake bite with systemic envenomation.

Snake bite is the common cause of morbidity and mortality in India. Snake antivenom, although very effective, is expensive, scarce, and associated with side effects. The conventional dose may not be required in all cases and a smaller dose may be as effective. A randomized double blind controlled trial was conducted to compare the effect of lower versus the conventional (high) dose. Patients presenting within 24 hours of snake bite with hematological or neurological evidence of systemic envenomation were included in the study. Patients were randomized either to receive high dose (2 vials over 1 hour, followed by 2 vials over 4 hours and repeated 4 hourly until clotting parameters normalized and then 2 vials as infusion over 24 hours) or low dose (2 vials over 1 hour, followed by 1 vial over four hours, repeated 4 hourly until clotting parameters were normalized and then 1 vial as an infusion over 24 hours). Thirty one patients received high dose and 29 a low dose. The mean dose of antivenom used was significantly different in the two groups (8.9 and 4.7, respectively). There was no mortality. The duration of stay was 4.94 and 3.48 days, respectively. There was no difference in the transfusion, dialysis or ventilation requirement of the two groups. Low dose regimen is more effective and required 5 vials less than the conventional dose. Each vial costs Rs. 200, so the estimated savings is Rs. 1000 per patient.

A randomised control trial on sequential drug monotherapy versus conventional step care therapy in the treatment of mild to moderate hypertension.

OBJECTIVES: There are many studies in the literature on single drug therapy (monotherapy) for mild to moderate hypertension. These studies show comparable efficacy, side effect profile and compliance. It has not been shown yet, whether the number of patients controlled on monotherapy can be improved by systematically stopping a drug which does not adequately control blood pressure and starting another drug in a sequential manner until blood pressure is well controlled. The aim is to show that sequential drug monotherapy (SDM) is as good as step care therapy (SCT) in controlling mild to moderate hypertension. METHODS: Patients attending three medical outpatient departments of Christian Medical College and Hospital, with mild to moderate hypertension uncontrolled on single drug therapy formed the patient population. They were then randomised to the sequential drug monotherapy or step care therapy. The choice of one of the five antihypertensive drugs was left to the attending physician. RESULTS: Thirty two and 42 patients entered the study and 28 and 35 completed the study in SCT and SDM group, respectively. Follow up was for a period of three months. BP was controlled 100% each in SCT and SDM groups. Efficacy with intention to treat was 85.2% in SCT and 81.8% in SDM group. Percent controlled with second drug was 82 and 71, controlled with third drug was 18 and 14 in SCT and SDM, respectively. Mean duration of treatment for control for BP was 1.7 and 2.3 months in SCT and SDM groups respectively. Average cost in SCT was Rs 66.28 and in SDM was Rs 45.53 per month (p = 0.005). Incidence of ADR was 28.6% and 10.5% in SCT and SDM groups, respectively (p = 0.06). CONCLUSIONS: SDM is as effective as SCT, SDM offers the following advantages: less expensive, better compliance, fewer complications, drug interaction and thus improved quality of life.

Post lumbar puncture headache: is bed rest essential?

Headache following lumbar puncture is a well known and well described complication. Various manoeuvres have been tried to prevent post lumbar puncture headache--the commonest being bed rest for 4 to 24 hours following lumbar puncture, though its value is questionable. Randomised controlled clinical trial was done to evaluate the effect of 24 hours bed rest on the incidence and severity of post lumbar puncture headaches. Two hundred and eight patients were randomly allocated to either the ambulant or the bed rest group. Patients were interviewed by a single investigator on days 0, 1, 2 and 7 about the presence and nature of headache. Other relevant clinical and laboratory data pertaining to the lumbar puncture was collected. The overall incidence of post lumbar puncture headache was 17%; 15% in the ambulant and 18% in the bed rest group. Of the patients who had headaches, severe headache was observed in 57% in the ambulant and 12% in the bed rest group (p = 0.02). Other variables did not alter the outcome of headaches. Bed rest does not appear to alter the incidence of post lumbar puncture headaches, but reduces the severity in those who get headaches, after a lumbar puncture.

A randomized double-blind sham-controlled study of intrathecal human anti-tetanus immunoglobulin in the management of tetanus.

BACKGROUND: Tetanus is a major cause of mortality and morbidity in developing countries. Various modalities of treatment to prevent progression of the disease and alter its outcome have been tried. This study was designed to evaluate the role of intrathecal human anti-tetanus immunoglobulin (TIG) in the management of tetanus. METHODS: Thirty-six adult patients presenting to an university-affiliated teaching hospital were stratified based on the severity of disease into mild and severe disease, and subsequently randomly allocated to receive either 250 i.u. of TIG intrathecally or a sham procedure mimicking the lumbar puncture. RESULTS: In mild tetanus, TIG administration significantly retarded the rate of progression (p = 0.05), reduced the duration of hospital (p = 0.01) and intensive care unit stay (p = 0.05), need for tracheostomies (p = 0.03) and the dose of sedatives required for control of spasms (p = 0.01). In mild tetanus, the mortality rates were 20% and 30% in the treated and control groups, respectively. CONCLUSION: We suggest that TIG is useful in reducing the morbidity, progression of disease and mortality in patients presenting with mild tetanus.

Drug interaction: rifampicin and glibenclamide.

BACKGROUND: Rifampicin is a potent inducer of the hepatic microsomal enzyme system. However, the drug has been shown to cause clinically important interactions with many drugs. This study was designed to test the interaction of rifampicin with the oral hypoglycaemic agent glibenclamide. METHODS: Twenty-nine well-controlled diabetic patients on a combination therapy of diet and glibenclamide, and willing to participate in the trial, received a daily dose of 450 mg (body weight < 50 kg) or 600 mg (body-weight > 50kg) of rifampicin for 10 days. RESULTS: There was a significant (p < 0.001) worsening of fasting and post-prandial blood sugar after administration of rifampicin. Dose modification of glibenclamide was required in 15 of the 17 patients in whom the diabetes became uncontrolled. Blood sugar normalized by day 6 after stopping rifampicin in all patients. CONCLUSION: Rifampicin and glibenclamide interact. Therefore, necessary dose modifications should be made in order to achieve euglycaemia if these two drugs are given together.

Evaluation of two treatment regimens of pralidoxime (1 gm single bolus dose vs 12 gm infusion) in the management of organophosphorus poisoning.

Organophosphorus (OP) poisoning is most frequently encountered among our community. Treatment of poisoning is primarily aimed at reversing the effects of the compound by administration of atropine. Oximes have been shown to be efficacious in case reports. The dose of this drug in these reports varies from 1 gm which is a very low dose and physiologically no dose, to doses upto 16 gm. This is also a very expensive imported drug which causes the nation considerable loss of foreign exchange. We report our experience with the use of two treatment regimens of Pralidoxime (P2AM) in the management of patients with OP poisoning in a prospective trial. Seventy-two adult patients presenting to a large university affiliated teaching institution with a history of consumption of OP compounds and requiring intensive care were entered into the trial. Patients were randomized using a block randomisation to receive either a single bolus dose of 1 gm P2AM at admission (Low dose group) followed by placebo infusion over the next 4 days or a single placebo bolus at admission followed by P2AM 12 gm as a continuous infusion over the next 4 days. Outcome measures analyzed were mortality, duration of ICU stay, need for ventilation and duration of ventilation, time to recovery of consciousness, development of intermediate syndrome and infections. A higher prevalence of intermediate syndrome (p = 0.08) was observed in the high dose group. Ventilatory requirement was also more in the high dose group (p = 0.09). Since this was an equivalence study designed to show that the low dose was as effective as the high dose, these results attain greater significance as the low dose group fared better than the high dose group, even though the pre-test hypothesis was in the reverse direction. Subgroup analysis of patients who received at least 1 gm of P2AM within 12 hours of ingestion of the OP poison with those who received P2AM after 12 hours, showed that there was a significant reduction of intermediate syndrome (p = 0.05) but no significant difference was noted in number ventilated. High dose P2AM infusion has no role in the routine management of patients with OP poisoning. These results also suggest that the time of administration of P2AM after the ingestion of the poison mabe a crucial factor which determines response to therapy. A prospective double blind placebo controlled trial is now justified in the light of the above findings.

Cost-effectiveness of inhaled beta-agonists v. oral salbutamol in asthma: a randomized double-blind cross-over study.

BACKGROUND: Oral beta-stimulants are widely used in the management of chronic asthma in India, in spite of evidence suggesting the superiority of inhaled medication in achieving maximum bronchodilatation. An economic evaluation was performed in a randomized double-blind cross-over trial to evaluate the role of adjuvant oral beta-stimulants in the treatment of asthma. METHODS: Patients who had seasonal or perennial asthma and were using metered dose inhalers for control of symptoms were randomly selected for the study. They received either 4 mg of oral salbutamol or placebo as adjuvant treatment. During the study they controlled their symptoms by adjusting the dose of the inhaler medication. A cost minimization technique was used to assess the economic impact of this intervention in the treatment and control periods. A sensitivity analysis was performed to assess the robustness of the conclusions. RESULTS: The mean cost was significantly greater in the treatment period and a patient lost approximately Rs 20 per month (CI: 13 to 27; p = 0.001) as a result of the adjuvant treatment. There was no significant difference in the quality of life or peak expiratory flow rate during the two periods. The patients also noted mild but significantly increased tremors (p = 0.01) and palpitations (p = 0.001) during the treatment period. There was no treatment-to-period interaction. CONCLUSION: Adjuvant oral beta-agonists do not improve the quality of life or bronchodilatation in asthmatics using an inhaled beta-agonist for control of symptoms.

Hyponatraemia and hiccups.

BACKGROUND. Hiccups are observed in many patients with hypohatraemia. We performed a case-control study to evaluate their association in a referral teaching hospital in South India. METHODS. Fifty consecutive patients who developed hiccups during an 18-month period were studied. They were categorized according to age group and diagnosis and controls matched for age and sex were selected from patients admitted on the same day in the medical wards. Hiccups were graded on a four-point severity scale at recruitment and every day till day 7 or till hiccups subsided. RESULTS. The step-wise logistic regression analysis done to establish independent association showed that for every 10 mEq/L reduction in serum sodium, patients were 17 times (p = 0.001; confidence interval: 4-87) at risk of developing hiccups. The only other significant determinant of the symptom was the diagnostic category of renal failure (odds ratio = 128; confidence interval: 1-1420). The number of patients who had hyponatraemia with varying severity of hiccups showed a dose-response relationship. The crude odds ratios were 7, 58 and 320 for mild, moderate and severe hiccups. CONCLUSION. There is a strong and independent association between hyponatraemia and hiccups in hospitalized patients. A causative association is suggested by the dose-response relationship demonstrated in the study. In many hospitals in developing countries where measurement of serum sodium is difficult and unreliable, it is important to be aware of this association since it can be easily corrected.

Outcomes in the Guillain Barre syndrome: the role of steroids.

Guillain-Barre Syndrome (GBS) is one of the commonest demyelinating diseases of the peripheral nervous system. This retrospective cohort study reports the outcomes of 97 patients in a large teaching hospital in South India. Fifty patients were treated with steroids and 47 had no steroids. Twenty one of the 41 evaluable patients in the steroid group had functional improvement at discharge as compared to 20 of 42 evaluable patients in the non-steroid group. Six patients in each group had worsening of their weakness. Steroids did not show any significant beneficial effect in either improving the disability scores at discharge (steroid-0.42 vs. non-steroid-0.29) or in reducing the duration of ICU stay (4 vs. 8 median days). A higher proportion of patients on steroids developed complications (p = 0.02). The median duration of hospital stay was 16 days in the steroid group as opposed to 14 days in the group not treated with steroids. The mortality was 6 in the steroid treated group and 5 in the non-steroid group. Steroids have no significant benefit on the outcome of GBS.

Study on the effectiveness of enalapril as a monotherapy in mild to moderate hypertension.

This study highlights our experience with 53 patients with mild to moderate hypertension who had monotherapy with Enalapril, one of the newer Angiotensin Converting Enzyme inhibitors. Enalapril was found to be effective in controlling blood pressure in 41 patients (77%). In 12 patients (23%) addition of one more drug was necessary for control of hypertension. Side effects were noted in 9 patients (17%). In two patients the adverse reactions were severe enough to warrant withdrawal of the drug.

Comparison of disease-specific and a generic quality of life measure in patients with bronchial asthma.

BACKGROUND. Quality of life is being increasingly recognized as an important outcome in chronic and terminal illnesses. There are few publications from India on the characteristics of the instrument that measures quality of life in clinical trials. We describe a method for choosing an appropriate instrument in a randomized trial. METHODS. We selected thirty-two patients with bronchial asthma randomly and evaluated them to compare the validity and responsiveness of the disease-specific quality of life instrument in asthma (AQL) and the generic quality of life instrument, 'Sickness impact profile' (SIP), to detect changes in their health status. Validity was determined by a priori constructs (construct validation) and the responsive coefficient was calculated by determining the relationship to the 'minimal significant change in asthma score' and the 'variability' seen in this change in stable patients. RESULTS. The constructs used in validating the scores were that the change in quality of life score would correlate (i) highly with change in self-assessment of the disease (r > 0.7), (ii) moderately with change in physician assessment of the disease (r > 0.5), and (iii) minimally with change in peak flow reading (r > 0.3). We found both instruments to have good construct validity. The responsiveness coefficients noted for AQL and SIP were 1.8 (CI 0.65-3) and 0.7 (CI 0.3-1.2), respectively. CONCLUSIONS. Though both AQL and SIP were valid measures of quality of life, AQL is likely to be more capable of detecting smaller changes in the health status of patients with bronchial asthma and hence was chosen as the instrument in the proposed clinical trial.

Incidence of intermediate syndrome in organophosphorous poisoning.

Seventy two patients admitted to the Intensive Care Unit following ingestion of organophosphorus compounds were studied prospectively with two different doses of pralidoxime (PAM). One group received 1 gm immediately after admission and no further PAM and the other group received infusion of PAM, 1 gm 8 hourly for four days (total 12 gms). The incidence of type II paralysis or intermediate syndrome was 47%. We observed a higher incidence in the 4 days of infusion of PAM group (61%) (20 patients) as compared to the single Bolus dose group (39%) (13 patients). Relative risk 1.48 (confidence interval = 0.9-2.4).

Toxic strep syndrome.

Group A beta-hemolytic streptococci are known to produce infections with protean manifestations. We report here a case of toxic streptococcal syndrome in a patient who presented with a multisystemic disease. Serological and bacteriological evidence strongly suggested an infection by Group A beta hemolytic streptococci.

Betamethasone in tetanus patients: an evaluation of its effect on the mortality and morbidity.

The effect of betamethasone on the outcome in moderate to severe tetanus was studied in a randomised, double blind, placebo controlled study in 22 patients. The mortality rate was reduced by 36.1% with the addition of corticosteroids to the regime of treatment. Betamethasone did not alter the duration of intensive care in those requiring it, but reduced the need for tracheostomy and ventilation. The mean daily dose of diazepam required was not significantly different between the two groups and there was no increase in the incidence of infections in the betamethasone group.

Prevalence & pathogenesis of hypophosphatemia in ventilated patients.

Hypophosphatemia was found in 12 (43%) patients within 24-36 h of mechanical ventilation in a group of 28 patients in an intensive care unit. The hypophosphatemic patients had a significant lowering of renal phosphorus threshold (P = 0.005) and inappropriate phosphaturia. These abnormalities resolved once ventilation was discontinued. Serum parathyroid hormone (PTH) levels were unaltered in this group of patients suggesting that some factor other than PTH was responsible for hypophosphatemia. This study has demonstrated that abnormalities of renal phosphate handling can cause hypophosphatemia in ventilated patients.