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PubMedDate not supplied

Modeling the use of triple combination therapy in five countries: nevirapine, Zidovudine, and Didanosine.

OBJECTIVE: In this study, we modify previously published models to estimate the short- and long-term consequences of nevirapine triple combination therapy use in five developed countries. Current pharmacoeconomic practice requires the de novo model development for each new therapy comparison. This approach is lengthy and costly, and it may yield models with very different structures. Standardized, detailed disclosure of model assumptions and parameters makes it possible to recycle published models with minor structural modifications to examine the efficiency of therapies based on new trial data. METHODS: Two well-publicized models of HIV therapy are modified to fit new trial data comparing double and triple combination therapy with nevirapine; model parameters are adjusted to represent clinical practice and cost structure in five countries. A short-term model uses trial data from advanced-stage patients to estimate first-year costs and consequences. A long-term model uses data from antiretroviral-naïve patients to estimate long-term cost-effectiveness. RESULTS: During the first year, for each 100 individuals treated with nevirapine triple combination therapy, 2.7 deaths and 30.8-31.4 opportunistic disease events would be averted compared to employing dual therapy. Additionally, 61% to 142% of the first-year costs of nevirapine therapy would be offset by other medical care costs savings [FF19,749, DM3,778, 3334 (x1000) lire, 293 (x1000) ptas, and US $3,569]. Compared to dual combination therapy, nevirapine triple combination therapy is predicted to yield incremental cost-effectiveness ratios (discounted at 3%) of FF101,057, DM30,709, 28,066 (x1000) lire, 1294 (x1000) ptas, and US $14,338. CONCLUSION: Published, well-constructed, and documented cost-effectiveness models can be reused to estimate the economic impact of therapies for HIV disease. Such models can also be used to provide insight into the factors that affect efficiency across countries. Our use of clinical trial data on nevirapine, together with published HIV economic models, provides support for the hypothesis that nevirapine is cost-effective under the cost structures of five developed countries.

AIDS-Related Opportunistic Infections↗
PubMed1997

Hypertension: the rediscovery of combination therapy.

Awareness and treatment of hypertension in the United States has been improving for older patients, but hypertension continues in many cases to be poorly controlled. Three options exist if initial therapy fails to achieve target blood pressure: upward drug titration, substituting another drug, or combination drug therapy. Combination therapy is the attempt to optimize blood pressure control by using two or more agents with additive or synergistic effects. Problems with this approach include noncompliance due to complicated regimens, adverse drug reactions, and the added expense of multiple medications. However, the newer fixed-dose combination products have been shown to offer improved blood pressure control, simplification of drug regimens, decreased adverse reactions, improved compliance, and cost-effectiveness.

Aged↗
PubMed1995

Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group.

BACKGROUND: Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement. METHODS: In a six-month randomized, double-blind trial, we compared combination therapy with cyclosporine (2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals) and methotrexate (at the maximal tolerated dose) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment. The primary outcome measure was the change in the number of tender joints. RESULTS: The mean (+/- SD) dose of cyclosporine at the final treatment was 2.97 +/- 1.02 mg per kilogram per day. As compared with the placebo group, the patients in the treatment group had a net improvement in the tender-joint count of 25 percent, or 4.8 joints (95 percent confidence interval, 0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25 percent, or 3.8 joints (95 percent confidence interval, 1.3 to 6.3; P = 0.005); improvement in overall disease activity as assessed by the physician (19 percent, P < 0.001) and the patient (21 percent, P < 0.001); and improvement in joint pain (23 percent, P = 0.04) and in the degree of disability (26 percent, P < 0.001). The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group (P = 0.006). Thirty-six patients (48 percent) in the cyclosporine group and 12 patients (16 percent) in the placebo group (P < 0.001) met the 1993 criteria for improvement of the American College of Rheumatology (more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables). Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study; 2 patients in the cyclosporine group died, 1 from viral pneumonia and the other in a motor vehicle accident. Serum creatinine concentrations increased by a mean of 0.14 +/- 0.27 mg per deciliter (12 +/- 24 mmol per liter) in the cyclosporine group and by 0.05 +/- 0.19 mg per deciliter (4 +/- 17 mmol per liter) in the placebo group (P = 0.02). CONCLUSIONS: In a six-month study, patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate. Side effects were not substantially increased. Long-term follow-up of patients treated with this combination is needed.

Arthritis, Rheumatoid↗
PubMed2002

Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. OBJECTIVE: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. DESIGN: Double-blind, placebo-controlled discontinuation trial. SETTING: 18 U.S. centers. PATIENTS: 244 postmenopausal, hysterectomized women 44 to 77 years of age. INTERVENTION: 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. MEASUREMENTS: Bone mineral density and biochemical markers of bone turnover. RESULTS: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, -5.0% to -4.0%) and a 2.4% decrease at the trochanter (CI, -2.7% to -2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment. CONCLUSIONS: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.

Adult↗
PubMed2006

Combination therapy of disseminated coccidioidomycosis with caspofungin and fluconazole.

BACKGROUND: The current recommended therapy for diffuse coccidioidal pneumonia involves initial treatment with amphotericin B deoxycholate or high-dose fluconazole, followed by an azole after clinical improvement. Amphotericin B is more frequently used as initial therapy if the patient's deterioration is rapid. CASE PRESENTATION: A 31-year-old Korean male with coccidioidomycosis presented to the hospital with miliary infiltrates on chest X-ray (CXR) and skin rash on the face and trunk. Initially, the patient did not respond to amphotericin B deoxycholate therapy. However, following caspofungin and fluconazole combination therapy, the patient showed favourable radiological, serological, and clinical response. CONCLUSION: This appears to be the first case of diffuse coccidioidal pneumonia with skin involvement in an immunocompetent patient who was treated successfully with caspofungin and fluconazole. Combination therapy with caspofungin and fluconazole may, therefore, be an alternative treatment for diffuse coccidioidal pneumonia that does not respond to amphotericin B deoxycholate therapy.

Adult↗
PubMed2004

Combination therapy with ribavirin and interferon in a cohort of children with hepatitis C and haemophilia followed at a pediatric haemophilia treatment center.

Nearly all children with bleeding disorders who received factor concentrates prior to the late 1980s were infected with hepatitis C. Treatment of adults infected with hepatitis C with combination therapy consisting of ribavirin and interferon has shown sustained response rates of 30-60%. Little data is available on the response of children infected with hepatitis C treated with combination therapy, especially those with bleeding disorders. We wish to report a single paediatric haemophilia treatment center's results of treatment of adolescents with haemophilia and hepatitis C infection with combination therapy. All patients followed at the haemophilia treatment center with hepatitis C, who were human immunodeficiency virus (HIV) negative and had a measurable hepatitis C viral load were eligible. Study patients received at least 6 months of 3 MU interferon-alpha via subcutaneous injection three times per week and 1000 mg day(-1) of ribavirin. Eleven patients agreed to participate in the study. Three patients had an un measurable viral load after 6 months of combination therapy. All three completed 12 months of medication and continued to remain free of hepatitis C for 12 months after discontinuation of therapy. Side-effects of combination therapy were significant but tolerable. The sustained response rate in this study is similar to the historical response rate seen in adults but less than the other reported response rates seen in children treated with combination therapy. Given the toxicity of combination therapy, and natural history of hepatitis C infection in children, consideration of a liver biopsy to evaluate disease progression prior to considering antiviral medications is warranted.

Antiviral Agents↗
PubMed1982

Combination therapy for osteoporosis with estrogen, fluoride, and calcium.

Nine women with postmenopausal spinal osteoporosis were treated with combination therapy consisting of estrogen, fluoride, and calcium. Their data were compared with those of a control group treated with fluoride, and calcium without estrogen. Bone mass was measured about every six months by photon absorptiometry (bone mineral content/bone width (BMC/BW)] and total-body neutron activation analysis [total-body calcium (TB Ca)]. Time-trend analysis revealed positive slopes for TB Ca (P = 0.002) and BMC/BW (P = N.S.) for the combination therapy group. The change in BMC/BW in the combination therapy group was significantly different from the response in the fluoride - calcium group. These data suggest that combination therapy may be successful in increasing bone mass in postmenopausal osteoporosis. A clinical trial to establish efficacy and examine risk/benefit ratios should be performed.

Adult↗
PubMed2006

Monotherapy versus Combination Therapy in Patients Hospitalized with Community-Acquired Pneumonia.

Current international guidelines for the management of community acquired pneumonia (CAP) recommend therapy with a beta-lactam plus a macrolide or a 'respiratory' fluoroquinolone alone in patients hospitalized in a medical ward, and combination therapy with a beta-lactam plus a macrolide or a fluoroquinolone in patients hospitalized in the intensive care unit. However, which of the available options should be preferred remains a matter of debate, and there are surprisingly few prospective randomized trials strictly comparing mono- versus dual therapy strategies in CAP patients. Thus, the recommendation of combining a macrolide with a beta-lactam rather than using a beta-lactam alone in hospitalized patients is derived mainly from observational data, and the suggested combination of a beta-lactam with a fluoroquinolone in severe CAP has been rarely examined in a clinical trial.As there have been sound theoretical arguments for and against combination therapy regimens, the rationale for the different options is discussed and available clinical trial data are reviewed in this article. A final conclusion about the superiority of one antibacterial regimen over another in hospitalized patients with CAP cannot be drawn on the basis of the limited data available. So far, combination therapy probably should be preferred in all patients presenting with severe pneumonia, whereas in general, combination therapy is not necessary in patients in a medical ward, and combination therapy with a beta-lactam plus a macrolide or monotherapy with a respiratory fluoroquinolone should be considered equivalent in this latter patient group. On the other hand, the available data demonstrate that empirical coverage of atypical bacteria in all patients with mild-to-moderate CAP seems unnecessary, and beta-lactam monotherapy might perform equally well when compared with respiratory fluoroquinolones in patients with non-severe CAP. Thus, the alternative use of a beta-lactam alone at adequate dosage in clinically stable patients seems justified, if CAP due to Legionella pneumophila is unlikely.

Anti-Bacterial Agents↗
PubMed1987

Effects of nicorandil on rest and effort angina unresponsive to combination therapy with a calcium antagonist and oral nitrate.

The efficacy of nicorandil, a new anti-anginal agent, was evaluated in 11 patients with rest and effort angina not inhibited by combination therapy with a calcium antagonist and an oral nitrate. Electrocardiographic findings during an attack demonstrated ST depression in seven patients, ST elevation in three, and either elevation or depression in two. Coronary angiography in nine patients revealed significant stenosis (greater than or equal to 75%) in eight. Angina persisted in all 11 patients in spite of treatment with 120 to 360 mg/day of diltiazem or 80 mg/day of nifedipine plus 20 to 160 mg/day of isosorbide dinitrate. Three patients were receiving beta-blocker as well; seven were receiving antiplatelet therapy. During combination therapy, patients had between 3.7 and 25 anginal attacks per week (mean +/- SD, 12.2 +/- 6.9). When nicorandil in a dosage of 20 to 40 mg/day was added to the regimen, the mean number of attacks dropped significantly (P less than 0.01) to 1.4 +/- 1.8 times/week. Two patients did not respond to nicorandil. When placebo was substituted for nicorandil in eight of nine responders, the frequency of attacks increased significantly (P less than 0.05) from 0.6 +/- 0.7 to 6.7 +/- 4.8 times/week. Nicorandil did not affect heart rate or blood pressure. These results suggest that nicorandil inhibits rest and effort angina unresponsive to usual doses of calcium antagonist and oral nitrate.

Aged↗
PubMed1986

Effects of combination therapy with captopril and nifedipine in severe or resistant hypertension.

To assess the effect of potent vasodilator therapy in patients with severe or resistant hypertension, 10 patients underwent therapy with captopril and nifedipine alone and in combination. Blood pressure (BP), heart rate, and blood chemistry values were monitored for 4 weeks during captopril monotherapy and after 8 weeks during combination therapy with captopril and nifedipine. Compared with baseline, the BP decreased during captopril monotherapy (180 +/- 11/98 +/- 7 vs. 209 +/- 16/118 +/- 12 mm Hg; P less than 0.005). After the addition of nifedipine, the BP was further reduced (148 +/- 23/85 +/- 16 mm Hg), but there was no change in heart rate. In three patients not achieving the diastolic BP goal during combination therapy with dosing every 8 hours, automatic 24-hour ambulatory BP monitoring demonstrated lack of antihypertensive control for only the last 2 to 3 hours of the dosing interval. These data demonstrate that combination therapy with captopril and nifedipine is effective in patients with severe hypertension, but frequent dosing intervals are necessary for adequate antihypertensive control.

Adult↗
PubMed1999

Ritonavir combination therapy restores intestinal function in children with advanced HIV disease.

OBJECTIVES: To investigate the intestinal absorptive processes in children with HIV infection before and after treatment with combination therapy that includes ritonavir. To test the hypothesis that combination therapy improves intestinal function. DESIGN: Intestinal function tests were performed in 10 children with advanced HIV disease at the enrollment and after 3 and 6 months of therapy with ritonavir combined with two HIV reverse transcriptase inhibitors. HIV viral load and CD4 cell counts were also determined; body weight was monitored. METHODS: The D-xylose absorption test, the steatocrit and the determination of fecal alpha1-antitrypsin concentration were used to evaluate carbohydrate and fat absorption, as well as fecal protein loss. Serum iron levels were measured to indirectly evaluate iron absorption. HIV-1 RNA-polymerase chain reaction (PCR) and immunofluorescence imaging were used to evaluate virologic and immunologic responses. RESULTS: In all, 9 children had carbohydrate malabsorption, 3 steatorrhea, 2 protein loss, and 7 iron deficiency. Most tests produced normal results after 3 months of therapy, and all abnormalities were abolished 6 months after institution of combination therapy. Mean results of each of four absorption tests were significantly changed on combination therapy. Viral load was progressively reduced and CD4 count was increased, with an inverse relationship. An evident shift of body weight pattern toward catch-up growth was observed in all children. CONCLUSIONS: Ritonavir combination therapy results in prompt and sustained restoration of intestinal function, which is associated with reduction in viral load, increase in CD4 counts, and gain in body weight.

Adolescent↗
PubMedDate not supplied

Burning Mouth Syndrome: open trial of psychotherapy alone, medication with alpha-lipoic acid (thioctic acid), and combination therapy.

OBJECTIVE AND STUDY DESIGN: This open study of 192 otherwise healthy persons with burning mouth syndrome, examined the efficacy on control of symptoms of psychotherapy alone with two hour sessions weekly for two months; alpha lipoic acid (ALA, tioctic acid; Tiobec) 600 mg/day alone for two months; or combination therapy of psychoanalysis and 600 mg/day ALA for two months. Controls received placebo alone. RESULTS: Most benefit was obtained with combination therapy. Combination therapy of psychoanalysis and alpha lipoic acid (ALA, tioctic acid; Tiobec. 600 mg/day) for two months gave most benefit and significantly more than psychoanalysis alone for two 1 hour sessions weekly for two months (p<0.0005), or ALA 600 mg/day alone for two months (p<0.0005). CONCLUSION: The present results suggest that alpha lipoic acid may complement psychotherapy and can be an acceptable alternative to psychoactive agents, but trials to compare the two approaches are now warranted.

Adult↗
PubMed2001

Effects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats.

Previous studies have demonstrated that growth hormone (GH) has a marked anabolic effect on cortical bone, and parathyroid hormone (PTH) has been shown to increase cancellous bone markedly and cortical bone to some extent in ovariectomized (ovx) rats. Combined therapies mostly focused on combining a bone anabolic agent with an antiresorptive agent. The following study was carried out to examine the efficacy of combined therapy with GH and PTH, two bone anabolic agents in rebuilding bone after loss due to ovariectomy in lumbar vertebrae, which contain both cortical and cancellous bones. Twelve-month-old female F344 rats were divided into five groups: sham + solvent vehicle, ovx + solvent vehicle, ovx + GH (2.5 mg/kg/day), ovx + PTH (80 microg/kg/day), and ovx + GH (2.5 mg/kg/day) + PTH (80 microg/kg/day). After surgery, animals were left for 4 months to become osteopenic before the beginning of therapy. Hormone administrations were given 5 days per week for 2 months and the animals were killed. The L3 vertebra was removed and examined by pQCT densitometry and by histomorphometry. Compared with age-matched, sham-operated controls, there was a 21% decrease in total bone mineral content (BMC) (p < 0.0001), 17.0% decrease in total bone mineral density (BMD) (p < 0.0001), 25.4% decrease in cortical BMC (p < 0.001), 3.1% decrease in cortical BMD (p < 0.05), 50.5% decrease in cancellous BMC (p < 0.01), 47.3% decrease in cancellous BMD (p < 0.01), and 14.5% decrease in cancellous bone volume (BV/TV) (p < 0.05) in the vehicle-treated ovx rats. Compared with age-matched, vehicle-treated ovx controls, GH, PTH, and GH + PTH increased total BMC by 22.8% (p < 0.001), 32.4% (p < 0.0001), and 72.7% (p < 0.0001), respectively; total BMD by 9.7% (p > 0.05), 22.6% (p < 0.001), and 38.8% (p < 0.0001), respectively; cortical BMC by 28.8% (p < 0.01), 50.8% (p < 0.0001), and 98.4% (p < 0.0001), respectively; and cortical BMD by 4.5% (p < 0.01), 2.9% (p < 0.05), and 6.3% (p < 0.0001), respectively. PTH and GH + PTH significantly increased cancellous BMC by 95.3% (p < 0.01) and 255.8% (p < 0.0001), respectively; cancellous BMD by 77.6% (p < 0.05) and 181% (p < 0.0001), respectively; cancellous BV/TV by 38.6% (p < 0.0001) and 55.9% (p < 0.0001), respectively; and trabecular thickness by 48% (p < 0.0001) and 68.3% (p < 0.0001), respectively. Note that GH by itself had no significant effect on vertebral cancellous BMC, cancellous BMD, and cancellous BV/TV. In conclusion, the effect of PTH was mostly more marked than that of GH. GH acted mainly by increasing cortical bone with less effect on cancellous bone, while PTH acted by increasing both cortical and cancellous bones. Combined therapy with GH and PTH was more effective in rebuilding bone after ovariectomy than either therapy alone. The effects of combined therapy with GH and PTH were additive in vertebral bone in the aged osteopenic rats.

Aging↗
PubMedDate not supplied

[Schizophrenia combination therapy with neuroleptics and benzodiazepines].

The literature review of combination therapy of schizophrenia with neuroleptics and benzodiazepines is presented. Early trials from the 60s are difficult to evaluate because of the heterogeneity of the patients' groups selected, non-standardized evaluation methods and different diagnostic criteria. The more recent trials, methodologically more correct, were aimed at the allevation by the benzodiazepines of anxiety and agitation symptoms often observed in schizophrenia. The trials aimed at the efficacy of co-therapy with neuroleptics and benzodiazepines, (mainly alprazolam) in schizophrenia were less frequent. As the result, not univocally positive effect of such a therapy was found. The differences in clinical effect might be caused by the individual susceptibility to the anxiolytics. The attempts to correlate various clinical effects of combination therapy with neuroleptics and benzodiazepines and the biological changes in central nervous system in schizophrenia, are also discussed.

Antipsychotic Agents↗
PubMed2004

Posaconazole and amphotericin B combination therapy against Cryptococcus neoformans infection.

To investigate the effects of posaconazole (POS) and amphotericin B (AMB) combination therapy in cryptococcal infection, we established an experimental model of systemic cryptococcosis in CD1 mice by intravenous injection of three distinct clinical isolates of Cryptococcus neoformans. Therapy was started 24 h after the infection and continued for 10 consecutive days. POS was given at 3 and 10 mg/kg of body weight/day, while AMB was given at 0.3 mg/kg/day. Combination therapy consisted of POS given at a low (combo 3) or at a high (combo 10) dose plus AMB. Survival studies showed that combo 3 was significantly more effective than POS at 3 mg/kg for two isolates tested (P value, < or = 0.001), while combo 10 was significantly more effective than POS at 10 mg/kg for all three isolates (P values ranging from <0.001 to 0.005). However, neither combination regimen was more effective than AMB alone. For two isolates, combination therapy was significantly more effective than each single drug at reducing the fungal burden in the brain (P values ranging from 0.001 to 0.015) but not in the lungs. This study demonstrates that the major impact of POS and AMB combination therapy is on brain fungal burden rather than on survival.

AIDS-Related Opportunistic Infections↗
PubMed1979

Combination therapy for psoriasis. Psoralens plus long-wave ultraviolet radiation with betamethasone valerate.

In the treatment of psoriatic patients with psoralens plus long-wave ultraviolet radiation (PUVA), clearing of psoriatic lesions was obtained more quickly and with smaller doses of ultraviolet light when topically applied corticosteroid therapy was added. Twelve patients with symmetrical plaque-type psoriasis were given PUVA on one side of the body and PUVA plus betamethasone valerate on the other side in a paired comparison study. Ten of the patients had faster clearing of lesions on the side that was treated with PUVA and betamethasone than on the side treated with PUVA alone. The other two patients had equal clearing on both sides. All patients remained clear of lesions during maintenance with PUVA alone for at least five months after steroid therapy was discontinued. Combination therapy may save the patient time, expense, and unnecessary exposure to radiant energy.

Adult↗
PubMed2004

Considerations in combination therapy: fibrinolytics plus glycoprotein IIb/IIIa receptor inhibitors in acute myocardial infarction.

The combined use of a fibrinolytic and a platelet glycoprotein (GP) IIb/IIIa receptor inhibitor to target the fibrin and platelet components of occlusive thrombi offers the potential for more rapid and complete reperfusion in patients with acute myocardial infarction (MI), although there have been concerns about the safety of this combination therapy. Data from the recent GUSTO-V and the ASSENT-3 trials support the use of this regimen in that the 30-day death or nonfatal reinfarction rate (7 days) in GUSTO-V and death or in-hospital reinfarction or in-hospital refractory ischemia rate in ASSENT-3 were reduced (p = 0.001 and p = 0.0001, respectively). The need for revascularization in both these trials was also reduced significantly. There was no increased risk of intracranial hemorrhage or stroke with the combination therapy, but an increased rate of nonintracranial severe or major bleeding was observed. At present, patients aged > 75 years should not receive combination therapy. Further studies in subgroup patient populations are warranted.

Angioplasty, Balloon, Coronary↗
PubMed2006

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.

BACKGROUND: Optimal antibiotic treatment for sepsis is imperative. Combining a beta-lactam antibiotic with an aminoglycoside antibiotic may have certain advantages over beta-lactam monotherapy. OBJECTIVES: We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004); MEDLINE (1966 to July 2004); EMBASE (1980 to March 2003); LILACS (1982 to July 2004); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2003). We scanned citations of all identified studies and contacted all corresponding authors. SELECTION CRITERIA: We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam and one aminoglycoside for sepsis. DATA COLLECTION AND ANALYSIS: The primary outcome was all-cause fatality. Secondary outcomes included treatment failure, superinfections, colonization, and adverse events. Two authors independently collected data. We pooled relative risks (RR) with their 95% confidence intervals (CI) using the fixed effect model. We extracted outcomes by intention-to-treat analysis whenever possible. MAIN RESULTS: We included 64 trials, randomizing 7586 patients. Twenty trials compared the same beta-lactam in both study arms, while the remaining compared different beta-lactams using a broader spectrum beta-lactam in the monotherapy arm. In studies comparing the same beta-lactam, we observed no difference between study groups with regard to all-cause fatality, RR 1.01 (95% CI 0.75-1.35) and clinical failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all cause fatality RR 0.85 (95% CI 0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). No significant disparities emerged from subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and Pseudomonas aeruginosa infections. We detected no differences in the rate of resistance development. Adverse events rates did not differ significantly between the study groups overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95% CI 0.23-0.39). We found no heterogeneity for all comparisons. We included a small subset of studies addressing patients with Gram-positive infections, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies. AUTHORS' CONCLUSIONS: The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.

Aminoglycosides↗