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Certain combinations improve outcomes

Drug combinations can be used to treat multidrug-resistant bacteria, but little data are available on the benefits and drawbacks of specific pairings. In a large-scale screening study, researchers profiled almost 3,000 drug combinations on six strains of three different disease-causing bacteria: Escherichia coli, Salmonella enterica serovar Typhimurium, and Pseudomonas aeruginosa. They systematically studied the effect of antibiotics when paired with each other, with other drugs, and with food additives.


They found that although many pairings impaired antibiotic effectiveness, over 500 combinations improved antibiotic performance. One of the most promising was the combination of the compound vanillin with spectinomycin, an older antibiotic rarely used today because of antibiotic resistance. When paired with vanillin, spectinomycin was able to enter bacterial cells and inhibit their growth. Surprisingly, however, vanillin diminished the effectiveness of other antibiotics.


These discoveries have several clinical implications. Besides revitalizing older antibiotics, they could help prevent adverse drug reactions by protecting beneficial bacteria in the body from antibiotic effects. According to research group leader Nassos Typas, "this would also decrease antibiotic resistance development, as healthy bacteria would not be put under pressure to evolve antibiotic resistance, which can later be transferred to dangerous bacteria."


Sources: Brochado AR, Telzerow A, Bobonis J, et al. Species-specific activity of antibacterial drug combinations. Nature. 2018;559(7713):259-263. Combining antibiotics changes their effectiveness. European Molecular Biology Laboratory. July 4, 2018.



Triple drug combination gets results

To assess whether a low-dose triple combination antihypertensive medication would achieve better BP control than usual care, researchers conducted a randomized trial for adults with mild-to-moderate hypertension requiring initiation or escalation of antihypertensive therapy. Patients enrolled from 11 urban hospital clinics were randomized to a once-daily fixed-dose triple combination pill (20 mg telmisartan, 2.5 mg amlodipine, and 12.5 mg chlorthalidone; 349 patients) or usual care (351 patients). The primary outcome was the proportion achieving target systolic/diastolic BP (less than 140/90 mm Hg or less than 130/80 mm Hg in patients with diabetes or chronic kidney disease) at 6 months. Secondary outcomes included mean systolic/diastolic BP difference during follow-up and withdrawal of BP medications due to an adverse event.


The results showed that the proportion of patients achieving the target BP was higher with the triple combination pill versus usual care at 6 months (70% versus 55%). At 6 months, the mean systolic/diastolic BP was 125/76 mm Hg for participants in the study group versus 134/81 mm Hg for those in the usual-care group. About 38% of patients in the study group experienced adverse reactions compared with 35% of patients in the usual-care group. The most common were musculoskeletal pain, dizziness, presyncope, or syncope.


The authors concluded that the triple-pill combination may be an effective way to manage hypertension as either initial therapy or as a replacement for monotherapy.


Source: Webster R, Salam A, de Silva HA, et al. Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial. JAMA. 2018;320(6):566-579.



Hope for patients with limited options

Current treatment regimens allow many patients with HIV type 1 (HIV-1) infection to maintain durable viral suppression, but highly drug-resistant HIV-1 infection is an issue for some patients and increases the risk of multidrug-resistant (MDR) HIV transmission. In a search for new therapies, researchers enrolled 40 adults with MDR HIV-1 infection in whom multiple antiretroviral therapies had failed. This single-group, open-label, phase 3 study focused on ibalizumab, a humanized IgG4 monoclonal antibody that blocks the entry of HIV-1 by noncompetitive binding to CD4. All enrolled patients had a viral load of more than 1,000 copies of HIV-1 RNA per milliliter.


In a 7-day control period, patients continued to receive their current therapy. They then received a loading dose of ibalizumab (2,000 mg) via I.V. infusion. The viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. Thirty-one patients completed the study.


The study showed that "ibalizumab combined with an optimized background regimen had antiviral and immunologic activity. Our findings also showed the feasibility and acceptability of twice-monthly I.V. administration of an antiretroviral therapy," the authors write. The most common adverse reaction, diarrhea, was mild to moderate in all patients.


Study participants who continued to receive therapy were invited to enroll in an extension study to follow the effects of ibalizumab plus an optimized background regimen during a 48-week period. All eligible patients opted to continue in the follow-up study.


Source: Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379(7):645-654.



FDA approves drug to treat smallpox

Tecovirimat (TPOXX) is the first drug indicated to treat smallpox to be approved by the FDA. Although smallpox is considered eradicated throughout the world, concern that the disease could be weaponized for bioterrorism spurred development of the new drug.


Caused by the variola virus, smallpox is often fatal and spread by person-to-person contact. Signs and symptoms include fever, exhaustion, headache, and backache. The characteristic rash progresses to pus-filled lesions that lead to permanent scarring. Complications include encephalitis and corneal ulcerations leading to blindness.


The new drug's effectiveness was established by studies conducted in animals infected with viruses that are closely related to the smallpox virus. Its safety was tested in 359 healthy human volunteers. The most frequently reported adverse reactions were headache, nausea, vomiting, and abdominal pain.


Tecovirimat is the first drug to be awarded a Material Threat Medical Countermeasure priority review by the FDA. This program provides incentives for development of medical products intended to treat or prevent harm from chemical, biological, radiologic, and nuclear threats.


Source: FDA approves the first drug with an indication for treatment of smallpox. U.S. Food & Drug Administration. News release. July 13, 2018.