Rifampicin Therapy Research Articles

Is there a role for rifampicin, ofloxacin and minocycline (ROM) therapy in the treatment of leprosy? Systematic review and meta‐analysis

A combination of rifampicin, ofloxacin and minocycline (ROM) is one of the newer recommendations for treatment of leprosy. We performed a systematic review and a meta-analysis of studies that had evaluated the efficacy of ROM therapy in treatment of paucibacillary and multibacillary leprosy patients. Studies were identified by searching the PubMed, Embase, LILACS and Cochrane databases. Data were abstracted from all relevant studies, and fixed effects models were used to calculate the summary estimate of effect in paucibacillary and multibacillary leprosy patients. Six studies comparing ROM therapy to multidrug therapy and eight studies that evaluated the effect of ROM therapy alone (no comparison group) were included in the review and meta-analysis. The combined estimate for single dose ROM vs. multidrug therapy in paucibacillary leprosy patients suggested that ROM was less effective than multidrug therapy in these patients [relative risk: 0.91, 95% confidence intervals (CI): 0.86-0.97]. However, the combined estimate for multiple doses of ROM vs. multidrug therapy in multibacillary leprosy patients suggested that ROM was as effective as multidrug therapy in reducing bacillary indices in these patients (proportion change: -4%, 95% CI -31% to 23%). No major side effects were reported in either the ROM or the multidrug treatment groups. Single-dose ROM therapy was less effective than multidrug therapy in paucibacillary patients. However, there are insufficient data to come to a valid conclusion on the efficacy of multidose ROM therapy in multibacillary leprosy, and additional studies with ROM therapy in multibacillary leprosy are needed. Furthermore, multiple doses may be considered as another alternative even for paucibacillary patients, and randomised controlled trials of this therapy may be useful to understand its contribution in the treatment and control of leprosy.

A RARE CAUSE OF INVOLUNTARY WEIGHT LOSS IN AN OLDER WOMAN: ENDOMETRIAL TUBERCULOSIS

To the Editor: Tuberculosis (TB) frequently presents with pulmonary involvement and is one of the oldest and the most fatal infectious disease.1 Genitourinary TB is a rare situation, although it is commonly seen secondary to pulmonary involvement, but the increasing rate of infection with the human immunodeficiency virus worldwide has led to greater clinical use of immunosuppressive therapies, and the development of multidrug resistance in people treated for TB is thought to be the possible reason. People with chronic kidney disease (CKD) also have a greater risk TB infection than the general population.2 A 68-year-old woman was referred to our clinic with complaints of fever, weight loss of 10 kg, and abdominal pain for 3 months. She had been diagnosed with CKD, caused by hypertensive nephropathy, 2 years earlier. She was an ex-smoker. Her physical examination did not reveal any pathological findings. Laboratory analyses indicated leukocytes, 9,000/μL; erythrocyte sedimentation rate, 80 mm/h; blood urea nitrogen, 53 mg/dL; and creatinine, 1.6 mg/dL. Creatinine clearance was 32 mL/min per 1.73m2. Abdominal ultrasonography indicated an increase in wall thickness of the uterus. Probe curettage material of the nulligravid patient demonstrated granulomatous inflammation (Figure 1). She had two scars of Bacillus Calmette-Gurin vaccine; tuberculin skin test was positive and measured 21mm. Her chest X-ray was within the normal range. She was diagnosed with genitourinary TB and initiated antituberculosis therapy of isoniazid (300 mg/d), rifampicin (600 mg/d), ethambutol (1,500 mg/d), and pyrazinamide (2,000 mg/d), which was modulated for renal failure. Her abdominal pain improved after the first 2 weeks of the treatment. Endometrial biopsy showing granulomatous inflammation. The risk of TB is high in individuals with CKD.3 Nutritional status, systemic diseases, and age are the basic features of TB susceptibility. Latent diseases such as TB should be considered in the evaluation of chronic abdominal pain and weight loss. In individuals with chronic renal diseases, endometrial TB is a rare cause of involuntary weight loss, which is associated with mortality.4 Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Alper Azak, Bülent Huddam, and Fatma Kılıç: acquisition of data, preparation of manuscript. Gülay Koçak: acquisition of data, preparation of manuscript, correction of the draft manuscript. Murat Duranay: correction of the draft manuscript and approval for submission. Sponsor's Role: No sponsorship.

Recurrent symptomatic hypocalcemia during rifampicin therapy for brucellosis

Drug-associated hypocalcemia is rare, but may occur during routinely administered drugs. We reported a case of vertebral brucellosis, which developed two hypocalcemic episodes associated with hypokalemic alkalosis with two drug combinations including rifampicin. Possible underlying mechanisms of hypocalcemia were discussed. The patient had carpopedal spasm at both hypocalcemic presentations. Laboratory analysis revealed hypocalcemia, hypokalemia, alkalosis with hypercalciuria, and low-normal parathormone (PTH) at first and elevated PTH at the second admission. The patient improved with cessation of drugs and appropriate management of hypocalcemia and hypokalemia with calcium, vitamin D, magnesium, and potassium replacement. The underlying mechanism of hypocalcemia in this patient seemed to be due to tubular damage resulting with Bartter-like syndrome, which is well defined with aminogylcosides. But the recurrence of hypocalcemia with an aminoglycoside-free antibiotic combination including rifampicin suggests a possible role of rifampicin on hypocalcemia associated Bartter-like syndrome that has never been reported before.

Molecular basis of rifampicin resistance in methicillin-resistant Staphylococcus pseudintermedius isolates from dogs

Methicillin-resistant Staphylococcus pseudintermedius (MRSP) often display resistance to almost all classes of antimicrobial agents used in veterinary medicine. In the present study, we investigated the emergence of rifampicin resistance in MRSP, the persistence of these isolates and identified the corresponding mutations in the rpoB gene. In addition to two rifampicin-resistant MRSP isolates from a multicentre study, consecutive MRSP isolates collected prior to and after rifampicin therapy from nine dogs at five Dutch veterinary hospitals were included in this study. The isolates were tested for resistance to rifampicin and other antimicrobial agents. The rifampicin resistance-determining region (RRDR) within the rpoB gene of the rifampicin-resistant and -susceptible isolates was amplified by PCR and sequenced. PFGE served to determine the genetic relationships of the MRSP isolates. Two MRSP isolates of the multicentre study showed mutations at position 513 or 522 in the RRDR of the rpoB gene. In contrast to the rifampicin-susceptible isolates, all rifampicin-resistant MRSP isolates showed mutations at one or two of the amino acid positions 508, 509, 513, 516, 522, 526 and 531. In most strains, a single amino acid exchange was observed. PFGE analysis confirmed that the rifampicin-resistant MRSP isolates were indistinguishable from or closely related to the rifampicin-susceptible isolate obtained from the same dog prior to rifampicin application. Therapy of MRSP infections with rifampicin results in the rapid emergence of rifampicin resistance and these isolates can persist for months. As a consequence, single therapy with rifampicin is not recommended.

A Case of Brucellosis Presenting with Multiple Hypodense Splenic Lesions and Bilateral Pleural Effusions

Brucellosis is a zoonotic infectious disease, which mainly present with lymphoreticular system invovement. However any organ system can be attacked by the microorganism. In this paper we present a 52-year-old female patient who was admitted to the Infectious Diseases Department with complaints of fatigue, arthralgias, fever, and weight loss. In the medical examination and radiological analysis bilateral pleural effusions and hepatosplenomegaly were detected. Serum transaminase levels were two times higher than the upper limits of normal. Abdominal ultrasound revealed sludge in the gallbladder and multiple hypodense splenic lesions (the largest was 1 cm in diameter). Brucella melitensis was isolated from the blood culture of the patient. Rifampicin (600 mg/day) and doxycycline (200 mg/day) therapy was started. Follow-up chest radiography and ultrasonography revealed the absence of pleural effusion. Splenic lesions and hepatosplenomegaly were totally regressed. The patient has been followed for 3 months after 6 week antibiotic regimen without recurrence. Brucellosis was expected to be the cause of all pathological signs.

Increased intracranial pressure associated with neurobrucellosis: a case report

Neurologic complications of childhood brucellosis are rarely seen. Increased intracranial pressure is a rare presentation of neurobrucellosis. A 15-year-old girl patient was admitted with complaints of blurred vision, diplopia, fatigue, headache, nausea and vomiting. She had a history of systemic brucellosis diagnosed 2 months earlier. Bilateral papilledema was established in neurological assessment. Standard tube agglutination test titer was elevated in serum. We diagnosed increased intracranial pressure and neurobrucellosis on the basis of symptoms and signs of increased intracranial pressure, findings on neuroimaging and cerebrospinal fluid analysis, and substantially increased cerebrospinal fluid pressure. After 8 weeks of treatment with acetazolamide, the headaches and papilledema resolved. The patient was successfully treated using streptomycin, doxycycline and rifampicin therapy for three months. The aim of this case presentation is to draw attention to the importance of neurobrucellosis in the differential diagnosis of papilledema, especially in endemic regions such as in our country.

Safety and efficacy of 4 months rifampicin therapy (4R) for latent TB infection (LTBI) among nursing students in south India

Safety and efficacy of 4 months rifampicin therapy (4R) for latent TB infection (LTBI) among nursing students in south India

A rare case of seronegative neurobrucellosis

Neurobrucellosis is one of the complications of brucellosis. We report a rare case of a 17-year-old girl with seronegative neurobrucellosis and depression and diplopia. Results of agglutination tests for Brucella both in serum and CSF were negative. Diagnosis was made only by positive culture of Brucella mellitensis with inoculation of the patient’s cerebrospinal fluid in a BACTEC 9050 System. The patient was successfully treated using ceftriaxone, doxycycline and rifampicin therapy for six months.

Acute tubulointerstitial nephritis related to antituberculous drug therapy

Acute tubulointerstitial nephritis (ATIN) as a complication of antituberculous therapy has been most commonly reported due to rifampicin therapy. This reaction typically occurs following re-exposure to the drug. This study undertook to investigate the clinicopathological features of ATIN related to antituberculous therapy. We performed a retrospective study of all adult patients with a biopsy-proven diagnosis of ATIN on chemotherapy for tuberculosis. The patients presented with acute renal failure at our institution during 1995 - 2007. The demographic, clinical, biochemical and histopathological features were studied. The patient outcome and management were analyzed. 41 patients had histologically proven ATIN. 23 (56%) were female. The mean age at presentation was 42 years. The most common regimen included rifampicin used intermittently to treat pulmonary tuberculosis. The average duration of antituberculosis therapy was 19 days before presentation and the duration of the acute illness averaged 5 days. The most common clinical manifestation included gastro-intestinal symptoms occurring in 35 (85%) patients with associated hepatitis biochemically in 20 (53%) patients. No skin rashes were observed and eosinophilia was only present in two patients. Hematuria was observed universally without any significant proteinuria. Anemia was present in 37 (90%) patients, with associated thrombocytopenia in 15 (37%). Rifampicin was discontinued in 37 (90%) cases. Nine (22%) patients required dialysis. One patient failed to recover renal function and 4 (10%) patients died. Mortality was related to overwhelming tuberculosis infection. The main factor predicting the need for dialysis was duration of oliguria. ATIN is a rare, but serious complication of repeat antituberculous therapy mainly due to re-exposure to rifampicin. Although the renal prognosis is generally good the disease does carry significant morbidity and mortality risks. A high index of suspicion is needed in re-treatment patients. A suggested screening test is for microhematuria with urine dipstix.

Efavirenz and Rifampicin in the South African Context: Is There a Need to Dose-Increase Efavirenz with Concurrent Rifampicin Therapy?

Increasing efavirenz (EFV) dose from 600 mg to 800 mg daily has been suggested with concomitant rifampicin (RFN), as induction of cytochrome P450 isoenzymes may reduce EFV plasma concentrations. Individuals from the CIPRA-South Africa cohort taking EFV-based antiretroviral therapy with concomitant tuberculosis (TB) were dosed with either increased (800 mg) or standard (600 mg) dose EFV during TB treatment. After TB therapy, all individuals took 600 mg EFV. Two mid-dosing interval EFV concentrations were determined from each individual: after 4 weeks of concomitant EFV and RFN therapy, and ≥4 weeks after TB therapy completion. Mid-dosing interval EFV concentrations were compared within individuals using the Wilcoxon signed-rank test. Paired samples were collected from 72 individuals. Overall, 45 (63%) were women and median weight was 59 kg (IQR 52-67). At antiretroviral therapy start, median CD4(+) T-cell count was 114 cells/mm(3) (IQR 37-165), median viral load was 5.5 log (IQR 5.1-5.9). A total of 38 (53%) individuals took 800 mg EFV during TB treatment and 34 (47%) took 600 mg. EFV concentrations in the 800 mg group were higher with RFN (2.9 mg/l [IQR 1.8-5.6]) than without (2.1 mg/l [IQR 1.4-3.0]; P=0.0003). There was no significant difference in EFV concentrations with RFN (2.4 mg/l [IQR 1.2-5.1]) or without (2.2 mg/l [IQR 1.4-3.7]) in the 600 mg group. There was no increase in EFV-linked adverse effects in either group. The proportion of virologically suppressed individuals at 48 weeks was similar in both groups. EFV concentrations were significantly increased in the EFV 800 mg group on RFN. There was no significant decrease in EFV concentrations when on RFN in the 600 mg group. Dose escalation of EFV 600 mg to 800 mg is not required during concomitant TB therapy in South Africa.

Assessment of in vivo antimalarial activity of rifampicin, isoniazide, and ethambutol combination therapy

The existing armament of drugs for the treatment and prevention of malaria is inadequate due to development of resistance. In addition to this due to lack of economic enticement the rate of new drug development and new drug discovery in the segment of parasitic diseases is very low as compared to the other segments. This has necessitated the better deployment and usage of existing antimalarial drugs as well as discovery of antimalarial activity of drugs which are well characterized for other diseases; these approaches help to reduce the time and cost required for new drug discovery. The present study evaluated the antimalarial activity of antituberculosis drugs rifampicin, isoniazide, and ethambutol in monotherapy and combination in Plasmodium berghei-infected mice. Animals were observed for mortality, parasite progression, and toxicity for a period of 1 month. Rifampicin + isoniazide and rifampicin + isoniazide + ethambutol treatment resulted in an overall survival rate of 60% compared to 0% in vehicle-fed animals by 4 weeks after post-infection without showing any toxicity.

ボリコナゾール薬物動態が投与中止後のリファンピシンに影響を受けた一症例

The purposes of this study were to demonstrate how the interaction between rifampicin and voriconazole can be managed clinically and to characterize the changes in voriconazole concentration levels after discontinuation of rifampicin.The concomitant administration of voriconazole and rifampicin is contraindicated because the interaction between these drugs results in a subtherapeutic concentration of voriconazole.In this regard,voriconazole is known to be metabolized by CYP2C19,2C9,3A4,and rifampicin is a potent inducer of CYP3A4.The interaction between rifampicin and voriconazole was investigated in a 70 year old male patient with severe infection in a prosthetic graft,necessitating simultaneous treatment with vancomycin and rifampicin.Rifampicin therapy was discontinued to start antifungal treatment with voriconazole.Interaction between the 2 drugs was evaluated by measuring voriconazole trough levels 4,7,11,18,and 29 days after starting therapy with it,performing the assays by high-performance liquid chromatography.Four days after starting voriconazole,we observed a significant decrease in its serum concentration,to 0.24μg/mL.After 7 days,it had increased to 0.84μg/mL and to 1.24μg/mL after 11 days,and thereafter,continued to gradually increase.Thus,after discontinuing rifampicin,CYP induction continued to be strong for the first 11 days and then became more moderate over the course of a month.In conclusion,it is essential that patients being treated with both rifampicin and voriconazole have their voriconazole concentrations monitored when rifampicin therapy is discontinued.

Hepatotoxicity due to rifampicin, isoniazid and pyrazinamide in patients with tuberculosis: Is anti-HCV a risk factor?

Background and Rationale. Among the adverse events related to tuberculosis treatment, hepatotoxicity is the most serious, and recognition of risk factors for it is essential to achieve successful therapy. The aim of the study is to evaluate the role of anti-HCV as a risk factor for hepatotoxicity in hospitalized patients under tuberculosis treatment with rifampicin, isoniazid and pyrazinamide (RHZ).Methods. Historical cohort study carried out at Hospital Sanatório Partenon, from 1998 to 2006. Patients aged 18 years or older, tested for anti-HCV, who presented normal pre-treatment aminotransferases (AST, ALT) and bilirrubin and who used RHZ during hospitalization were included in the study. Individuals who used anti-tuberculosis drugs six months prior to hospitalization, had clinical evidence of chronic liver disease or showed previous history of hepatotoxicity to RHZ were excluded.Results. A sample of 534 patients was studied. The incidence of hepatotoxicity was 8.8% (n = 47). After univariate analysis, the following variables were associated to hepatotoxicity: anti-HIV positive, anti-HCV positive, use of antiretroviral therapy and high doses of rifampicin and isoniazid per kg of body weight (p < 0.05). When Cox regression was performed, anti-HIV positive [RR = 2.3 (IC95% 1.2-4.1); p = 0.008] and high doses of isoniazid per kg of body weight [RR = 1.3 (IC95% 1.1-1.7); p = 0.016] remained independently associated to development of hepatotoxicity.Conclusions. In conclusion, the anti-HIV positive and high doses of isoniazid were considered independent risk factors for hepatotoxicity due to RHZ esqueme in the present study. Though univariate analysis showed that anti-HCV was associated to the outcome, it was not identified as an independent risk factor for hepatotoxicity related to the use of RHZ when the analysis was controlled to HIV.

Rifampicin as an Oral Angiogenesis Inhibitor Targeting Hepatic Cancers

Angiogenesis is an important therapeutic target in cancer, and to fully exploit its therapeutic potential, combination chemotherapeutic/antiangiogenic regimens should be optimized and delivered earlier to more patients. Ideally, this could be done by a single potent oral agent with established safety. Rifampicin, a semisynthetic antibiotic derived from the rifamycins, is one of the most commonly used pharmaceutical compounds worldwide in the treatment of tuberculosis. Here, we present the effects of oral rifampicin on human cancer progression and its antiangiogenic properties, which were comparable to the angiogenesis inhibitor endostatin. Clinically, low-dose p.o. administration of rifampicin to six high-risk patients with hepatitis C virus-related liver cirrhosis resulted in a single occurrence of hepatocellular carcinoma during the follow-up period of 97.3 +/- 29.1 (mean +/- SD) months. Experimentally, rifampicin rapidly and markedly down-regulated the expression of a wide spectrum of angiogenesis-associated genes in growing human microvascular endothelial cells, thereby suppressing endothelial cell proliferation and migration. Rifampicin, at higher concentrations, also directly inhibited the growth of a variety of human cancer cells. P.o. administration of rifampicin significantly inhibited in vivo growth and metastases of subcutaneous human cancer xenografts. Thus, the potent antiangiogenic properties of oral rifampicin therapy were effective in suppressing cancer progression. It provides a promising new addition to antiangiogenic strategies for designing human cancer therapies. Considering the clinical pharmacokinetics of rifampicin, which enters the enterohepatic circulation and undergoes subsequent hepatic accumulation, it may be especially beneficial as an antitumor agent targeting hepatobiliary tumors.

Acute interstitial nephritis during rifampicin therapy can be a paradoxical response: a case report

An 18-year-old Ethiopian woman presented with debilitating back pain and high fever. X-ray examinations showed diffuse pulmonary tuberculosis and a psoas abscess. After starting rifampicin, isoniazid, ethambutol and pyrazinamide, acute interstitial nephritis developed that spontaneously recovered. According to Harrison's Online rifampicin should have been causative, but the spontaneous recovery excluded that possibility. The clinical course fit the diagnosis of a paradoxical response, for which recently risk factors have been described. Thus, a paradoxical response should be added to the list of causes of interstitial nephritis in tuberculosis patients and in such cases rifampicin could be continued.

Acute interstitial nephritis during rifampicin therapy can be a paradoxical response: a case report.

An 18-year-old Ethiopian woman presented with debilitating back pain and high fever. X-ray examinations showed diffuse pulmonary tuberculosis and a psoas abscess. After starting rifampicin, isoniazid, ethambutol and pyrazinamide, acute interstitial nephritis developed that spontaneously recovered. According to Harrison's Online rifampicin should have been causative, but the spontaneous recovery excluded that possibility. The clinical course fit the diagnosis of a paradoxical response, for which recently risk factors have been described. Thus, a paradoxical response should be added to the list of causes of interstitial nephritis in tuberculosis patients and in such cases rifampicin could be continued.

CYP2B6 (c.516G→T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV‐infected patients

Interindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G-->T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients. Mid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5'-nuclease assays. Relationships between averaged 4- and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions. CYP2B6 c.516G-->T, CYP2B6 c.983T-->C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P= 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G-->T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively. Our findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.

Acute interstitial nephritis during rifampicin therapy can be a paradoxical response: a case report

Acute interstitial nephritis during rifampicin therapy can be a paradoxical response: a case report

Acute interstitial nephritis during rifampicin therapy can be a paradoxical response: a case report

Acute interstitial nephritis during rifampicin therapy can be a paradoxical response: a case report

Nutritional Support for Acute Diarrhea in Children: Focused on Age-appropriate Diet Therapy after Rehydration

Pseudomembranous colitis (PMC) is known to be associated with the administration of antibiotics which alter normal gastrointestinal flora and allow overgrowth of Clostridium difficile. Most cases of rifampicin-induced PMC are seen in patients with pulmonary tuberculosis, but not with gastrointestinal tuberculosis. We report a case of PMC associated with rifampicin therapy in a patient with gastrointestinal tuberculosis. A 65-year-old female patient with rectal cancer and gastrointestinal tuberculosis was admitted due to abdominal pain and diarrhea. She was treated with anti-tuberculosis agents containing rifampicin. On colonoscopic examination, mucoid exudates and yellowish plaque lesions were observed. Anti-tuberculosis agents were stopped, and the patient was treated with metronidazole. Symptoms were relieved and did not recur when all the anti-tuberculosis agents except rifampicin were started again. When a patient complains of abdominal pain or diarrhea while taking rifampicin, the physician should consider the possibility of rifampicin-associated PMC.