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Tag: Respiratory Tract Infections

  • Antibiotics ineffective for cough treatment in lower respiratory tract infections

    Antibiotics ineffective for cough treatment in lower respiratory tract infections

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    Use of antibiotics provided no measurable impact on the severity or duration of coughs even if a bacterial infection was present, finds a large, prospective study of people who sought treatment in U.S. primary or urgent care settings for lower-respiratory tract infections.

    The study by researchers at Georgetown University Medical Center and colleagues appeared April 15, 2024, in the Journal of General Internal Medicine.

    Upper respiratory tract infections usually include the common cold, sore throat, sinus infections and ear infections and have well established ways to determine if antibiotics should be given. Lower respiratory tract infections tend to have the potential to be more dangerous, since about 3% to 5% of these patients have pneumonia. But not everyone has easy access at an initial visit to an X-ray, which may be the reason clinicians still give antibiotics without any other evidence of a bacterial infection. Plus, patients have come to expect antibiotics for a cough, even if it doesn’t help. Basic symptom-relieving medications plus time brings a resolution to most people’s infections.”


    Dan Merenstein, MD, professor of family medicine at Georgetown University School of Medicine

    The antibiotics prescribed in this study for lower tract infections were all appropriate, commonly used antibiotics to treat bacterial infections. But the researchers’ analysis showed that of the 29% of people given an antibiotic during their initial medical visit, there was no effect on the duration or overall severity of cough compared to those who didn’t receive an antibiotic.

    “Physicians know, but probably overestimate, the percentage of lower tract infections that are bacterial; they also likely overestimate their ability to distinguish viral from bacterial infections,” says Mark H. Ebell, MD, MS, a study author and professor in the College of Public Health at the University of Georgia. “In our analysis, 29% of people were prescribed an antibiotic while only 7% were given an antiviral. But most patients do not need antivirals as there exist only two respiratory viruses where we have medications to treat them: influenza and SARS-COV-2. There are none for all of the other viruses.”

    To determine if there was an actual bacterial or viral infection present, beyond the self-reported symptoms of a cough, the investigators confirmed the presence of pathogens with advanced lab tests to look for microbiologic results classified as only bacteria, only viruses, both virus and bacteria, or no organism detected. Very importantly, for those with a confirmed bacterial infection, the length of time until illness resolution was the same for those receiving an antibiotic versus those not receiving one – about 17 days.

    Overuse of antibiotics can result in dizziness, nausea, diarrhea, and rash along with about a 4% chance of serious adverse effects including anaphylaxis, which is a severe, life-threatening allergic reaction; Stevens-Johnson syndrome, a rare, serious disorder of the skin and mucous membranes; and Clostridioides difficile-associated diarrhea. Another significant concern of the overuse of antibiotics is resistance. The World Health Organization released a statement on April 4, 2024, stating: “Uncontrolled antimicrobial resistance [due to the overuse of antibiotics] is expected to lower life expectancy and lead to unprecedented health expenditure and economic losses.”

    “We know that cough can be an indicator of a serious problem. It is the most common illness-related reason for an ambulatory care visit, accounting for nearly 3 million outpatient visits and more than 4 million emergency department visits annually,” says Merenstein. “Serious cough symptoms and how to treat them properly needs to be studied more, perhaps in a randomized clinical trial as this study was observational and there haven’t been any randomized trials looking at this issue since about 2012.”

    In addition to Merenstein and Ebell, the other co-author is Bruce Barrett MD, PhD at the University of Wisconsin, Madison,

    This work was supported by an AHRQ grant R01HS025584.

    Source:

    Georgetown University Medical Center

    Journal reference:

    Merenstein, D.J., et al. (2024) Antibiotics Not Associated with Shorter Duration or Reduced Severity of Acute Lower Respiratory Tract Infection. Journal of General Internal Medicine. doi.org/10.1007/s11606-024-08758-y.

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  • Drug repurposing study finds lonafarnib effective against RSV

    Drug repurposing study finds lonafarnib effective against RSV

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    In a study published in the journal Nature Communications, researchers screened ReFRAME (short for repurposing, focused rescue, and accelerated Medchem), a drug-repurposing library, for drugs against respiratory syncytial virus (RSV). They identified lonafarnib as a potent inhibitor of RSV fusion protein and investigated its therapeutic potential against an RSV infection.

    Study: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / ShutterstockStudy: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / Shutterstock

    Background

    RSV causes severe lower respiratory tract infections in young children, immunosuppressed individuals, and older adults, with millions of annual hospital admissions and deaths. The recent coronavirus disease 2019 (COVID-19) pandemic and associated interventions have led to altered RSV epidemiology, with a transient suppression and resurgence of RSV circulation, raising concerns about increased infections.

    RSV infection treatment is currently symptomatic. While ribavirin shows in vitro efficacy, it is not very efficacious in patients. Palivizumab provides prophylaxis but is costly, offers only a partial reduction in hospitalization rates, and faces challenges like rapid resistance development. Although nirsevimab was recently approved for RSV prevention in newborns, there remains a dearth of therapeutic options.

    Various antiviral strategies against RSV, including immunoglobulins, are being developed. Repurposing libraries containing licensed drugs or compounds in clinical development serve as repositories with potential for accelerated therapeutic applications. Researchers in the present study screened the ReFRAME library and identified lonafarnib as an RSV fusion protein inhibitor while demonstrating its therapeutic ability.

    About the study

    The library (of 12,000 molecules) was screened using a recombinant RSV subtype A strain GFP (short for green fluorescent protein) reporter virus. Cell viability was determined using an MTT (short for 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The primary hit criteria were RSV infection ≤ 16% and cell viability ≥ 80%. Fourteen molecules met the primary criteria, and 16 additional molecules were selected. Two farnesyl-S-transferase inhibitors, lonafarnib, and tipifarnib, were evaluated and compared for their inhibitory effects on RSV infection. To identify the potential viral target of lonafarnib, passages of the RSV reporter virus were conducted with increasing doses of lonafarnib. The resulting virus populations were sequenced, and mutations were analyzed. The study additionally involved orthogonal infection assays, plaque reduction assays, RSV lentiviral pseudotype assays, and RSV F protein cell-to-cell membrane fusion assays. Surface plasmon resonance and crystallization experiments were conducted to investigate the interaction of lonafarnib with a recombinant RSV subtype A pre-fusion F protein.

    Therapeutic effects of lonafarnib were evaluated by inoculating A549 cells with HRSV-A-GFP, treating with lonafarnib or ribavirin 24 hours post-inoculation, and monitoring virus spread over time. The drug’s effect in a more natural model of RSV infection and cell entry was investigated using the immortalized human basal cell line BCi-NS1.1, which was further differentiated into the pseudostratified ciliated epithelium.

    Six mice were treated with oral lonafarnib or solvent control and infected with an RSV reporter virus. The animals’ weight was monitored, and on day 4, tissues were extracted, and lung RSV copy number was measured.

    A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.

    Results and discussion

    Twenty-one molecules, including lonafarnib, demonstrated antiviral activity against RSV. Lonafarnib is approved for Hutchinson-Gilford progeria syndrome and is in phase III clinical trials for hepatitis delta virus infections. Lonafarnib, but not tipifarnib, demonstrated inhibition of RSV infection, as evidenced by reduced reporter virus activity, plaque reduction, and suppressed syncytia formation in infected cells. Further, lonafarnib, not tipifarnib, was found to interact with the pre-fusion F protein in a binding site that has been previously observed for other fusion inhibitors.

    Lonafarnib-exposed virus populations accumulated two coding mutations (T335I and T400A) within the RSV fusion protein, leading to phenotypic resistance to lonafarnib. Further, lonafarnib was found to inhibit RSV’s entry into the cells by binding to the fusion protein and inhibiting membrane fusion. This inhibition was found to be overcome by resistance mutations in the fusion protein.

    In vitro, combinations of lonafarnib and ribavirin showed minor inhibitory or slightly synergistic activity at selected doses. Lonafarnib treatment post-inoculation in A549 cells restricted the spread of the HRSV GFP virus by 30% as compared to controls. In the BCi-NS1.1 cell culture model, prophylactic lonafarnib treatment from both the apical and basolateral sides dose-dependently inhibited RSV infection, resulting in a 10- to 15-fold reduction in virus load. Therapeutic application of lonafarnib only from the basolateral side also reduced virus load by approximately 50% in a clinical RSV isolate infection.

    In vivo, lonafarnib-treated animals showed a significantly reduced reporter virus signal in the lung and nose compared to controls. On day 4, a dose-dependent decline was observed in viral ribonucleic acid in the lungs of treated mice, and there was a lesser weight loss compared to controls. However, cellular infiltrates were observed in the lungs of lonafarnib-treated mice.

    Conclusion

    In conclusion, the study identified lonafarnib as a potential therapeutic candidate for RSV treatment, highlighting the utility of drug-repurposing studies. The findings demonstrate the promising antiviral activity of lonafarnib in cell culture as well as mice models of RSV infection. Further research is warranted to confirm the findings.

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  • Treatment modalities shape infection profiles in advanced lung cancer patients

    Treatment modalities shape infection profiles in advanced lung cancer patients

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    Pulmonary malignancy is one of the most frequent and fatal cancers in older patients. Studies have shown that lung cancer patients have a high incidence of lower respiratory tract infections. This is due to the fact that these patients usually have airway obstruction, sticky sputum that is not easy to cough up, destruction of mucosal surfaces, and treatment with radiotherapy and chemotherapy. When most patients are found to have lung cancer, they have already developed distal metastasis and lost the chance of surgery, therefore, they usually choose to be treated with radiotherapy, chemotherapy, and targeted drugs. Radiotherapy and chemotherapy may cause lung injury. Patients who develop pneumonia will delay radiotherapy, which is not conducive to the patient’s prognosis and long-term survival.

    Some patients may only require chemotherapy or may not be able to tolerate radiotherapy, while some patients may be treated with a combination of therapies. Such studies are necessary to clarify the severity and pathogenetic distribution of lower respiratory tract infections in both types of patients and to better focus on treatment. Recently, the researchers from China analyzed the clinical characteristics and pathogenic data of lower respiratory tract infections in advanced lung cancer patients with different treatment modalities, which were published in Malignancy Spectrum.

    The researchers found that compared to patients treated with just chemotherapy, those treated with combination therapy had more elevated inflammatory markers (calcitonin, blood sedimentation, and ultrasensitive C-reactive protein) and were more likely to have mixed infections after developing lower respiratory tract infections. Whereas patients treated with simple chemotherapy were more likely to have infections with viruses, those treated with combination therapy were more likely to have infections with gram-negative bacilli. Therefore, it is best to focus on the use of antibiotics and ensure the coverage of pathogens in patients with advanced lung cancer in two different treatment modalities. Since infections are more severe in combination therapy patients, it is even more important to complete drug sensitivity testing as soon as possible for early intervention.

    Source:

    Journal reference:

    Guo, R., et al. (2023). Clinical characteristics and pathogenic analysis of lower respiratory tract infections in advanced lung cancer patients with different treatment modalities. Malignancy Spectrum. doi.org/10.1002/msp2.17.

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