In addition to the fact that the incidence of coronavirus is growing, doctors - as well as places in hospitals - are becoming less and less, test results are waiting for a long time, those doctors who remain in service make a number of mistakes when prescribing a treatment regimen.
An infectious disease doctor and researcher at PSPbSMU named after A.V. helped to understand the situation Academician I.P. Pavlova Oksana Stanevich together with the “Not in vain” foundation.
We will talk about what mistakes doctors make, what examinations, in addition to the COVID-19 test, show the presence of coronavirus, why you should not immediately take antibiotics, and what medications you should have at home.
Playing blind
Most outpatient doctors immediately prescribe medications without properly examining the patient. The worst thing is that the doctor, in the absence of information, cannot adequately formulate his own indications for hospitalization.
“It often happens that people come to the hospital, literally breaking all the laws, doing tests on their own in a commercial laboratory, deceiving their doctor, deceiving the laboratory, saying that he is not sick with Covid, and self-propelled - on foot, in personal transport, in a taxi - arrives to the hospital in serious or moderate condition.”
What additional examination is needed?
When infected with coronavirus, it is necessary to constantly monitor saturation indicators, which are measured with a pulse oximeter. This device looks like a clothespin that is attached to your finger. It shows how saturated the blood is with oxygen, i.e. saturation. It is measured as a percentage, and the norm for a healthy person without diseases of the lungs and cardiovascular system is 98−99%.
During coronavirus infection, saturation should be measured at least 4 times a day and for at least 30 seconds.
Photo: Vladimir Gerdo/TASS
Additional examination, which should be prescribed by the attending physician, may include a chest examination on a computed tomography (CT) scanner, a complete blood count, a blood test for c-reactive protein* and d-dimer*.
Based on these indicators, it is possible to timely determine the criteria for hospitalization, even if saturation indicators do not deviate greatly from the norm.
Example: a 49-year-old woman had a temperature above 38.5 for five days, a terrible cough, and shortness of breath. At the same time, saturation did not fall below 95%. She took tests, and the value for c-reactive protein was 126. The norm for this indicator is up to 5. Such a pronounced increase can be considered the start of a cytokine storm*, which is considered a complication of coronavirus infection. The woman called an ambulance, the doctor listened to her and did not hear anything in the lungs, which happens very often with covid pneumonia. The doctor told her that the blood tests meant nothing at all and left. She, breaking quarantine, came to the hospital through an acquaintance, where she underwent a CT scan, which showed that 65% of her lungs were affected. This corresponds to the third degree of lung damage out of four.
*Cytokine storm is an excessive immune response of the body to an infection that affects organs without the participation of a pathogen.
*C-reactive protein (CRP) is a highly sensitive indicator of inflammation and infection and responds to significant tissue damage.
*D-dimer - intensity and nature of thrombus formation processes.
A significant increase in c-reactive protein begins with a reading above 50.
In the photo: a patient undergoing examination on a computed tomography machine (Photo: Sergey Savostyanov/TASS)
Azithromycin
Antacids
Antacids do not affect the bioavailability of azithromycin, but reduce the maximum concentration in the blood by 30%, so the drug should be taken at least 1 hour before or 2 hours after taking these drugs and food.
Cetirizine
Concomitant use of azithromycin with cetirizine (20 mg) for 5 days in healthy volunteers did not lead to pharmacokinetic interaction or a significant change in the QT interval.
Didanosine (didezokeyinosine)
The simultaneous use of azithromycin (1200 mg/day) and didanosine (400 mg/day) in 6 HIV-infected patients did not reveal changes in the pharmacokinetic indications of didanosine compared to the placebo group.
Digoxin (P-glycoprotein substrates)
Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates, such as digoxin, leads to increased concentrations of P-glycoprotein substrate in the blood serum. Thus, with the simultaneous use of digoxin and azithromycin, it is necessary to take into account the possibility of increasing the concentration of digoxin in the blood serum.
Zidovudine
Concomitant use of azithromycin (single dose of 1000 mg and multiple doses of 1200 mg or 600 mg) has a minor effect on the pharmacokinetics, including renal excretion of zidovudine or its glucuronide metabolite. However, the use of azithromycin caused an increase in the concentration of phosphorylated zidovudine, a clinically active metabolite in peripheral blood mononuclear cells. The clinical significance of this fact is unclear.
Azithromycin interacts weakly with isoenzymes of the cytochrome P450 system. Azithromycin has not been shown to participate in pharmacokinetic interactions similar to erythromycin and other macrolides. Azithromycin is not an inhibitor or inducer of cytochrome P450 isoenzymes.
Ergot alkaloids
Given the theoretical possibility of ergotism, the simultaneous use of azithromycin with ergot alkaloid derivatives is contraindicated.
Pharmacokinetic studies were conducted on the simultaneous use of azithromycin and drugs whose metabolism occurs with the participation of isoenzymes of the cytochrome P450 system.
Atorvastatin
Concomitant use of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not cause changes in atorvastatin plasma concentrations (based on an HMC-CoA reductase inhibition assay). However, in the post-marketing period, isolated case reports of rhabdomyolysis have been received in patients receiving concomitant azithromycin and statins.
Carbamazepine
Pharmacokinetic studies involving healthy volunteers did not reveal a significant effect on the plasma concentrations of carbamazepine and its active metabolite in patients receiving concomitant azithromycin.
Cimetidine
In pharmacokinetic studies of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were detected when cimetidine was used 2 hours before azithromycin.
Indirect anticoagulants (coumarin derivatives)
In pharmacokinetic studies, azithromycin did not affect the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. Potentiation of the anticoagulant effect has been reported after simultaneous use of azithromycin and indirect anticoagulants (coumarin derivatives). Although a causal relationship has not been established, the need for frequent monitoring of prothrombin time should be considered when using azithromycin in patients receiving indirect oral anticoagulants (coumarin derivatives).
Cyclosporine
In a pharmacokinetic study involving healthy volunteers who took azithromycin (500 mg/day once) orally for 3 days and then cyclosporine (10 mg/kg/day once), a significant increase in maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-5) of cyclosporine. Caution is advised when using these drugs together. If simultaneous use of these drugs is necessary, it is necessary to monitor the concentration of cyclosporine in the blood plasma and adjust the dose accordingly.
Efavirenz
Concomitant use of azithromycin (600 mg/day once) and efavirenz (400 mg/day) daily for 7 days did not cause any clinically significant pharmacokinetic interaction.
Fluconazole
Concomitant use of azithromycin (1200 mg once) did not change the pharmacokinetics of fluconazole (800 mg once). The total exposure and half-life of azithromycin did not change with simultaneous use of fluconazole, however, a decrease in Cmax of azithromycin was noted (by 18%), which had no clinical significance.
Indinavir
Concomitant use of azithromycin (1200 mg once) did not cause a statistically significant effect on the pharmacokinetics of indinavir (800 mg three times a day for 5 days).
Methylprednisolone
Azithromycin does not have a significant effect on the pharmacokinetics of methylprednisolone.
Nelfinavir
The simultaneous use of azithromycin (1200 mg) and nelfinavir (750 mg 3 times a day) causes an increase in the equilibrium concentration of azithromycin in the blood serum. No clinically significant side effects were observed and no dose adjustment of azithromycin was required when used concomitantly with nelfinavir.
Rifabutin
The simultaneous use of azithromycin and rifabutin does not affect the concentration of each drug in the blood serum. Neutropenia has sometimes been observed with simultaneous use of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship between the use of the combination of azithromycin and rifabutin and neutropenia has not been established.
Sildenafil
When used in healthy volunteers, there was no evidence of the effect of azithromycin (500 mg/day daily for 3 days) on the AUC and Cmax of sildenafil and its main circulating metabolite.
Terfenadine
In pharmacokinetic studies, there was no evidence of interaction between azithromycin and terfenadine. There have been isolated cases reported where the possibility of such an interaction could not be completely excluded, but there was no concrete evidence that such an interaction occurred.
It has been found that the simultaneous use of terfenadine and macrolide antibiotics can cause arrhythmia and prolongation of the QT interval.
Theophylline
No interaction has been detected between azithromycin and theophylline.
Triazolam/midazolam
No significant changes in pharmacokinetic parameters were detected with simultaneous use of azithromycin with triazolam or midazolam in therapeutic doses.
Trimethoprim/sulfamethoxazole
Concomitant use of trimethoprim/sulfamethoxazole with azithromycin did not show a significant effect on the total exposure or renal excretion of trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those found in other studies.
Useless antibiotics
One of the common mistakes is prescribing antibiotics. But antibiotics have no effect on the coronavirus itself.
Back in the spring, research was carried out “in a hurry” and a regimen was developed - a combination of azithromycin and hydroxychloroquine. In laboratory conditions, hydroxychloroquine showed a positive effect, and the antibiotic azithromycin was used as a “courier” of hydroxychloroquine inside the cell.
In practice, this combination did not work. It did not improve the outcome of the disease, and people died just as often as those who did not receive these drugs. Moreover, this combination does not shorten the length of hospitalization and does not shorten the stay of the virus in the body.
Azithromycin
Azithromycin is one of the most commonly used broad-spectrum antibiotics today. It exhibits a bacteriostatic effect by binding to the 50S ribosomal subunit of bacteria and inhibiting the action of the peptide translocase enzyme at the key stage of protein synthesis - translation, which, for obvious reasons, does not have the most favorable effect on the processes of growth and reproduction of microorganisms. At high concentrations, the drug can be not only a development inhibitor, but also a killer, having a bactericidal effect. The effectiveness of any antibiotic is determined by the number of bacterial strains sensitive to it. Azithromycin looks very presentable against this background. Its optical sight captures both gram-positive and gram-negative specimens: Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus viridans, Haemophilus influenzae, Gardnerella vaginalis, Moraxella catarrhalis, Neisseria gonorrhoeae, Bordetella pertussis, Legionella pneumophila, Campylobacter jejuni, Bordetella parapertussis, as well as anaerobic bacteria Bacteroides bivius, Peptococcus, Clostridium perfringens, Peptostreptococcus spp., chlamydia (Chlamydia pneumoniae, Chlamydia trachomatis) and their closest “companions”, breaking records in the frequency of detection of ureaplasma (Ureaplasma urealyticum) by venereologists, mi coplasma ( Mycoplasma pneumoniae) and mycobacteria (Mycobacteria avium complex), spirochetes (Borrelia burgdorferi, Treponema pallidum).
Speaking about the “technical and tactical” characteristics of azithromycin, what is striking is the ease of its passage through histohematic barriers, due to which it quite quickly enters organs and tissues, as well as cell membranes (in this regard, it is effective against infections potentiated by intracellular pathogens such as chlamydia ). A stable level of the drug in the blood plasma is achieved 5-7 days after the start of antibacterial therapy. High concentrations of azithromycin, which can have a therapeutic effect, remain in the body for another 5-7 days after discontinuation of the drug.
The drug under the name azithromycin can be found in Russian pharmacies in two dosage forms: domestic tablets and domestic capsules. The drug should be taken, like almost any oral antibiotic, with reference to a meal: either 1 hour before or 2 hours after it. The frequency of administration is 1 time per day. The single and daily dose, as well as the duration of taking the drug, are determined by the specific disease and its severity.
Disservice
Azithromycin itself did not initially work and was simply a conduit for hydroxychloroquine. Even without reference to the coronavirus, Russian people are accustomed to treating any infection with antibiotics. And, what is absurd, outpatient doctors continue to use the azithromycin monotherapy regimen in the treatment of coronavirus infection.
Pneumonia caused by different causes (viruses or bacteria) affects the lung tissue in different ways, and for this reason, treatment tactics will differ.
There are 4 lines of antibacterial drugs on the World Health Organization (WHO) list that should be used in certain situations. The notorious azithromycin is included in the second line and is used for specific indications.
In addition, there is a list of antibiotics that are not recommended for use in certain combinations, because they have very pronounced side effects.
Now the most common combination of coronavirus treatment at the prehospital stage is a combination of azithromycin and levofloxacin. This particular combination is not recommended by WHO. It is prohibited by clinical pharmacologists, including in Russia.
Photo: Anton Vergun/TASS
Drug interactions
Antacids do not affect the bioavailability of azithromycin. but reduce the maximum concentration in the blood by 30%, so the drug should be taken one hour before or two hours after taking these drugs and eating.
Azithromycin does not affect the concentration of carbamazepine, didanosine, rifabutin and methylprednisolone in the blood when used together.
In pharmacokinetic studies of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were detected when cimetidine was used 2 hours before azithromycin.
Concomitant use of azithromycin (600 mg/day once) and efavirenz (400 mg/day) daily for 7 days did not cause any clinically significant pharmacokinetic interaction.
Concomitant use of azithromycin (1200 mg once) did not change the pharmacokinetics of fluconazole (800 mg once). The total exposure and half-life of azithromycin were not affected by concomitant use of fluconazole. however, a decrease in Cmax of azithromycin was observed (by 18%). which had no clinical significance.
Concomitant use of azithromycin (1200 mg once) did not cause a statistically significant effect on the pharmacokinetics of indinavir (800 mg three times a day for 5 days).
Concomitant use of azithromycin with cetirizine (20 mg) for 5 days in healthy volunteers did not lead to pharmacokinetic interaction or a significant change in the QT interval.
When used in healthy volunteers, there was no evidence of the effect of azithromycin (500 mg/day daily for 3 days) on the AUC and Cmax of sildenafil or its main circulating metabolite.
Azithromycin does not affect the bioavailability of co-trimoxazole.
No significant changes in pharmacokinetic parameters were detected with simultaneous use of azithromycin with triazolam or midazolam in therapeutic doses.
Neutropenia has occasionally been observed with concomitant use of azithromycin and rifabutin, although neutropenia has been associated with the use of rifabutin; a causal relationship between the use of the combination of azithromycin and rifabutin and neutropenia has not been established.
Azithromycin does not affect the pharmacokinetics of theophylline; however, when taken together with other macrolides, the concentration of theophylline in the blood plasma may increase.
If combined use with cyclosporine is necessary, it is recommended to monitor the concentration of cyclosporine in the blood plasma and adjust the dose accordingly.
When taking digoxin and azithromycin together, it is necessary to monitor the concentration of digoxin in the blood, because simultaneous use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates, such as digoxin. leads to an increase in the concentration of the substrate P-glycoprotein in the blood plasma.
If co-administration with warfarin is necessary, careful monitoring of prothrombin time is recommended.
It was found that the simultaneous use of terfenadine and macrolide antibiotics causes arrhythmia and prolongation of the QT interval. Based on this, the above complications cannot be excluded when terfenadine and azithromycin are used together.
Since there is a possibility of inhibition of the CYP3A4 isoenzyme by azithromycin in parenteral form when used together with cyclosporine, terfenadine, ergot alkaloids, cisapride, pimozide, quinidine, astemizole and other drugs whose metabolism occurs with the participation of this enzyme, the possibility of such interaction should be taken into account when prescribing azithromycin for administration inside.
Given the theoretical possibility of ergotism, the simultaneous use of azithromycin with ergot alkaloid derivatives (ergotamine and dihydroergotamine) is not recommended.
When used concomitantly with zidovudine, azithromycin has little effect on the pharmacokinetics, including renal excretion, of zidovudine or its glucuronide metabolite.
Azithromycin weakly interacts with cytochrome P450 isoenzymes. It has not been revealed that azithromycin is involved in pharmacokinetic interactions similar to erythromycin and other macrolides; azithromycin is not an inducer or inhibitor of cytochrome P450 isoenzymes.
The simultaneous use of azithromycin (1200 mg) and nelfinavir (750 mg 3 times a day) causes an increase in the equilibrium concentration of azithromycin in the blood plasma; no clinically significant side effects were observed and no dose adjustment of azithromycin is required when used simultaneously with nelfinavir.
There have been isolated case reports of rhabdomyolysis in patients taking azithromycin and statins concomitantly.
Spectacular side effect
The regimen of hydroxychloroquine and azithromycin that was initially recommended has significant side effects. Hydroxychloroquine damages the heart tissue, which can lead to heart rhythm disturbances, including paroxysmal atrial fibrillation. A rhythm disturbance can cause cardiac arrest or provoke the formation of blood clots.
The fact that hydroxychloroquine not only does not work, but is also harmful, became clear back in the summer. However, outpatient and sometimes inpatient doctors continue to prescribe it.
Moreover, it is included in clinical recommendations and, for example, in St. Petersburg is given free of charge to people who are being treated for Covid at home.
The azithromycin and levofloxacin regimen is also toxic to the heart and also disrupts the heart rhythm.
***
When taking antibiotics as an outpatient, antibiotic-associated diarrhea often occurs. This may hide a more serious complication - pseudomembranous colitis. Simply put, it is an inflammation of the large intestine where plaque-like, membrane-like formations appear on its walls. This manifests itself as an increase in bowel movements up to 5-10 times a day, but can reach up to 20 times.
When bacteria multiply, many toxins are released into the blood, which can lead to fever, intoxication, dehydration and septic condition. In extreme cases of dehydration, the kidneys, heart and brain begin to suffer.
The intestines may not work until intestinal paresis occurs. This condition can only be treated with surgery and is potentially life-threatening.
“We have had several cases where we have proven the occurrence of colitis due to pre-hospital antibiotic use. There is an analysis that allows us to determine that this is pseudomembranous colitis. This is a stool test for toxins A and B. Even if one toxin is detected, it is already colitis.”
Unfortunately, coronavirus infection simply does not have an application point for the use of antibiotics. It is impossible to cure Covid with antibiotics.
“A fatal complication of coronavirus infection—acute respiratory distress syndrome, when suddenly all the lungs shut down, the affected area expands, respiratory failure develops, and the person dies—antibiotics do not help.”
VS - sudden death
SCD - sudden death from heart disease
TBVT - bidirectional fusiform ventricular tachycardia
CVD - cardiovascular disease
Prerequisites for the study
Azithromycin is a macrolide antibiotic with a broad spectrum of antimicrobial action, the use of which, according to previously published data, relatively rarely leads to toxic effects on the heart [1]. At the same time, it is known that the use of drugs similar to azithromycin, such as erythromycin and clarithromycin, can cause the development of severe ventricular arrhythmias [2–7] and are accompanied by an increased risk of sudden death (SD) [8–10]. Moreover, there is increasing evidence that azithromycin may also have a proarrhythmic effect. There are at least 7 published reports of patients with an initially normal QT interval in whom taking azithromycin was accompanied by side effects associated with the development of arrhythmias, including a pronounced prolongation of the QT interval [11-13], the occurrence of bidirectional fusiform ventricular tachycardia - DVVT ( torsades de pointes) [14-16] and polymorphic ventricular tachycardia without prolongation of the QT interval [17]. The US Food and Drug Administration's Adverse Event Reporting System includes at least 20 case reports of DVT associated with azithromycin [18].
Given that ventricular arrhythmias associated with azithromycin are often rapidly fatal, a retrospective cohort study was performed to evaluate mortality associated with the use of this antibiotic.
Purpose of the study
To test the hypothesis that there is an increased risk of death from complications of cardiovascular disease (CVD), and especially the risk of sudden death from heart disease (SCD), in patients taking azithromycin compared with people not using antibiotics and patients using other specific antibiotics. antibiotics.
Research structure
Retrospective observational study.
Material and research methods
The study cohort was drawn from individuals enrolled in the Tennessee Medicaid program. The use of an electronic Medicaid database that has access to death certificates and a national hospital discharge database provided information on Medicaid enrollment and health care claims, as well as date and cause of death. Information on antibiotics and other medications used was obtained from Medicaid medical assistance program records that contain drug therapy data.
The study cohort included patients prescribed azithromycin between 1992 (when azithromycin was introduced into clinical practice in the United States) and 2006 if their characteristics met the inclusion criteria at the time of prescription of this antibiotic.
The study included individuals aged 30 to 74 years who did not have a life-threatening disease not related to the cardiovascular system, as well as a history of drug abuse or stay in a nursing home during the previous year or hospitalization during the previous year. 30 days. To ensure the validity of the data collected for analysis, studies required that the participant had been at least 365 days post-enrollment in Medicaid and had been a regular user of health care. The analysis also included data from matched control periods (similar in length to antibiotic courses) during which participants did not use the antibiotics assessed in the study. For each specific azithromycin prescription, 4 control periods were established and frequency-matched based on the treatment preference bias score using 153 covariates. On the day of the start of the control period, participants in the control group had to meet the inclusion criteria and could not have taken any of the study antibiotics in the 30 days preceding inclusion. To account for confounding factors associated with certain indications for azithromycin use, the analysis included additional control groups of patients who used one of three other antibiotics: amoxicillin (including amoxicillin with potassium clavulanate), ciprofloxacin, and levofloxacin.
Amoxicillin is the main comparison antibiotic and is used for indications similar to those of azithromycin; There were no side effects on the heart when using amoxicillin [8]. Azithromycin has a number of common indications for use with ciprofloxacin and levofloxacin. Ciprofloxacin is believed to have a minimal effect on electrophysiological parameters, despite reports of cases of development of DVT during therapy with this antibiotic [1, 19]. Evidence of an association with levofloxacin (which is considered to have greater proarrhythmic effects than ciprofloxacin [1, 19]) has been included in several case reports of DVT [18]. One patient may have been prescribed multiple antibiotics under evaluation; in addition, such patients may have had a control period during which they did not use the antibiotics being evaluated. However, there was no crossover of this period for each participant, and the adverse outcome (death) was considered only for one specific period. Thus, the assumption of statistical independence was not violated.
The main indicators assessed were mortality from CVD complications and overall mortality. The analysis tested the hypothesis that mortality from CVD complications would be increased if azithromycin had a proarrhythmic effect, especially in a cohort of patients that was selected to reduce the likelihood of death from severe disease outside the hospital. Overall mortality was analyzed to eliminate misclassification of causes of death associated with the use of the study antibiotic. Taking into account the hypothesis being tested, the frequency of VS was also analyzed, the cause of which was established using a formalized definition based on many data sources. The validity of this definition was independently established, and the predictive value of the assessment performed with its help reached 88%.
The unit of analysis in this study was the course of antibiotic therapy, which was defined as a fixed period, starting from the date of prescription, during which patients were advised to use the antibiotic. This period should have corresponded to the greatest risk of developing side effects of the antibiotic on the heart, given that descriptions of cases of death while taking azithromycin suggested an acute mechanism for the development of an unfavorable outcome [11–17]. Because the usual length of the treatment period varies among different antibiotics, 2 periods were analyzed: a 5-day period typically recommended for azithromycin treatment and a 10-day period most commonly used for the other antibiotics evaluated; The 10-day period analyzed for azithromycin also included an interval during which the likelihood of taking the drug was low (between days 6 and 10); such days were considered separately in several analyses. Although these periods were usually of a fixed duration (5 or 10 days), data from participants who were subsequently prescribed an antibiotic, as well as participants who no longer met the inclusion criteria, were included in the analysis as incomplete (censored) observations.
The analysis assessed the cumulative incidence, or risk, of death during a course of antibiotic therapy. Standardized rates were calculated using the Kaplan–Meier method. To estimate the RR of death between treatment groups for specific antibiotics studied, hazard ratios were calculated using Cox regression models, adjusting for participant characteristics.
Each comparison across the study was standardized for an expanded set of covariates (reflecting the participant's status on the day the antibiotic was prescribed) that were potentially associated with both the use of a particular antibiotic and the risk of death. This standardization was performed using a scale to assess the presence of treatment bias [20] (the conditional probability of prescribing the study antibiotics that is conditional on covariates). Specific scales to assess the presence of treatment bias were established for each pairwise comparison. The scales for comparison between the studied antibiotics took into account the indications for the use of antibiotics.
To test for possible misspecification of regression models used to calculate scales to assess the presence of treatment bias, the distribution of covariates across study groups was checked for evenness. For the azithromycin group and the control group, which included participants who did not use antibiotics, this distribution was unstandardized because selection of groups based on treatment preference would ensure an even distribution of covariates. For amoxicillin, the distribution was standardized to the appropriate scale score using a modified weighting method by determining the inverse probability of receiving a given treatment, which was used to standardize the distribution for azithromycin. The distribution of scale scores was also checked for overlap to assess the presence of treatment bias. To summarize the risk of death from CVD complications, the risk of developing CVD complications was calculated using the appropriate scale [21]. Assessment on this scale made it possible to determine the risk of death from CVD complications (without the use of the study antibiotic) as a function of indicators of the presence of concomitant diseases.
Differences were established between the cumulative incidence of death during a 5-day period of taking azithromycin and the incidence of such an outcome during a similar duration of taking amoxicillin. The additional risk of developing such an outcome for each course of azithromycin use was determined as (HRa-1) ´ I0, where HRa is the risk ratio for the use of azithromycin compared with amoxicillin, and I0 is the unstandardized cumulative incidence of CVD complications in patients using amoxicillin. The difference in risk was also calculated in accordance with the deciles of the risk of developing CVD complications, which was calculated using the risk scale for developing such diseases.
In addition, alternative analyzes were performed to test the validity of several study assumptions. These analyzes included repeated measures analyzes that tested the validity of designating treatment periods as independent observations, as well as analyzes using stratification according to deciles corresponding to a particular treatment bias score. All types of statistical analyzes were performed using the SAS software package version 9.3 (SAS Institute). All p values reported were two-sided.
results
The study cohort included participants who had 347,795 azithromycin prescriptions, as well as 1,391,180 study antibiotic-free periods, 1,348,672 amoxicillin prescriptions, 264,626 ciprofloxacin prescriptions, and 193,906 levofloxacin prescriptions. Azithromycin was used predominantly by women, who made up 77.5% of patients taking this antibiotic; the average age of patients in this group reached 49 years; It noted frequent use of medications for the treatment of CVD or respiratory diseases, as well as emergency department visits and indications of previous use of antibiotics. The characteristics of patients taking azithromycin were similar to those of control groups, who were matched to the azithromycin group on a scale reflecting the presence of treatment bias. In contrast, patients prescribed ciprofloxacin or levofloxacin were generally more likely to have complications of diabetes mellitus, urinary or fecal incontinence, and more frequent use of a wheelchair or walker. Average total scores on the CVD risk scale were higher in patients who used amoxicillin, ciprofloxacin and levofloxacin, reaching 9.5, 10.3 and 10.6 points, respectively; for comparison, in the azithromycin group this figure was 9.3 points. In both the azithromycin and amoxicillin groups, the most common indications for antibiotic use were ear, nose, or throat infections in general and bronchitis; the number of cases in which the indications for antibiotics were known were 62 and 63%, respectively. (43 and 40% of all prescriptions, respectively). The most common indication for the use of ciprofloxacin was gastrointestinal tract infections. Levofloxacin was commonly prescribed for ear, nose, or throat infections and other indications related to other respiratory or genitourinary diseases.
Within 5 days of taking azithromycin, 29 patients died from CVD complications (85.2 deaths from CVD complications per 1 million courses); including 22 patients who died suddenly (64.6 cases of VS per 1 million courses). During the 5-day control period, during which study participants did not use antibiotics, 41 patients died from CVD complications (29.8 deaths from CVD complications per 1 million periods); including 33 patients who died suddenly (24.0 cases of VS per 1 million periods). During the first 5 days of taking amoxicillin, 42 patients died from CVD complications (31.5 deaths from CVD complications per 1 million courses); including 29 patients who died suddenly (21.8 cases of VS per 1 million courses).
When comparing the incidence of adverse outcomes occurring during 5 days of azithromycin use versus a corresponding 5-day period without antibiotic use, azithromycin was associated with an increased risk of death from both CVD complications and all causes. For death from CVD complications, the risk ratio reached 2.8 (95% CI 1.79 to 4.63; p<0.001); Moreover, the risk of both VS and death from other CVD complications increased. Although there was no increase in the risk of death from non-CVD causes, the risk of death from any cause increased (hazard ratio 1.85, 95% CI 1.25 to 2.75; p=0.002). For the 10-day period after antibiotic initiation, azithromycin use was associated with an increased risk of death from CVD complications (hazard ratio 1.86, 95% CI 1.27 to 2.73; p=0.002), but the risk of death from any cause during this period period increased statistically insignificantly (risk ratio 1.27 with 95% CI from 0.92 to 1.75; p=0.20). In contrast, amoxicillin use was not associated with a statistically significant increase in the risk of death from CVD complications or non-CVD causes, or death from any cause, either during the first 5 days of therapy or over the entire 10-day treatment period.
Against the background of a 5-day course of taking azithromycin, compared with the first 5 days of using amoxicillin, there was a statistically significant increase in the risk of death from complications of CVD (hazard ratio 2.49 with 95% CI from 1.38 to 4.50; p = 0.002), and from any cause (risk ratio 2.02 with 95% CI from 1.24 to 3.30; p=0.005). Based on the data obtained, it was calculated that while taking azithromycin, 47 additional deaths due to complications of CVD develop per 1 million 5-day courses of therapy. The results were similar for alternative analyses, including a repeated measures analysis, an analysis using stratification by deciles corresponding to a particular treatment bias score, and an analysis using a model in which the data were included about the use of other proarrhythmic drugs. The risk of death from CVD complications was statistically significantly higher overall for the 10-day period (hazard ratio 1.87, 95% CI 1.16 to 3.01; p=0.01), despite the fact that between 6 On the 10th and 10th days after starting azithromycin, the risk did not increase. Over a 10-day period, the risk of death from any cause was not statistically significantly increased with azithromycin use.
Ciprofloxacin compared with amoxicillin did not increase the risk of death from CVD complications or from any cause during a 10-day course of therapy, but there was a trend towards an increased risk of death from CVD complications with levofloxacin (risk ratio 1.50 with 95% CI from 0.82 to 2.72; p=0.18). Taking azithromycin for 5 days compared with the first 5 days of using ciprofloxacin was associated with an increased risk of death from CVD complications (hazard ratio 3.49 with 95% CI 1.32 to 9.26; p = 0.01) and a trend to increase risk of death from any cause (hazard ratio 1.75, 95% CI 0.91 to 3.37; p=0.09). However, there were no statistically significant differences between azithromycin and levofloxacin (hazard ratio for death from CVD complications 1.27, 95% CI 0.66 to 2.47; p=0.48; hazard ratio for death from any cause 1.07 with 95% CI from 0.61 to 1.85; p=0.82).
The absolute risk increase (AR) for death from CVD complications in patients who took azithromycin compared with patients who used amoxicillin varied depending on the baseline CVD risk score. In the subgroup of patients whose risk of developing CVD corresponded to the highest deciles of this risk, 59% of all deaths from CVD complications that developed during azithromycin therapy were observed; It was calculated that in this subgroup of azithromycin there would be 245 additional deaths due to CVD complications per 1 million 5-day courses of therapy.
Conclusion
Within 5 days of taking azithromycin, there is a small risk of death from CVD complications, which is most pronounced in patients with an initially high risk of developing CVD complications.
A comment
The results of the study indicated that a 5-day course of azithromycin was associated with a small risk of developing CVD complications, which was greatest in patients with CVD risk corresponding to the highest deciles of baseline CVD risk. In patients taking azithromycin, there was no increase in mortality from causes not related to CVD, but a statistically significant increase in overall mortality. The risk of death from CVD complications was statistically significantly higher with the use of azithromycin compared with the use of amoxicillin or ciprofloxacin, but was not statistically significantly different from the risk with the use of levofloxacin.
During the study, special attention was paid to confounding factors associated with both the use of azithromycin and the increased risk of death from CVD complications. These factors included the presence of CVD and other comorbidities, as well as behavioral risk factors associated with CVD (eg, smoking, high body mass index, poor diet and low physical activity) and indications for antibiotic use.
To minimize the effect of confounding factors, two different control groups were formed. One group included control periods, which were selected according to scores on a scale reflecting the presence of systematic error associated with the preferred assignment of a particular treatment. The use of such a control group provided a more even distribution of the prevalence of CVD and other comorbidities, and also may have allowed for the influence of behavioral risk factors to be taken into account, since it may have been mediated in part by factors that are more easily identified in database analysis (particularly hyperlipidemia, hypertension , diabetes mellitus, heart failure, angina pectoris or previous myocardial infarction). To minimize the impact on the results of such a confounding factor as infection, a second control group was formed, which made it possible to compare the incidence of adverse outcomes when using amoxicillin, prescribed for indications similar to azithromycin, and when using azithromycin. Patients who used amoxicillin did not experience an increased risk of death from CVD complications or overall mortality during the study period, which is consistent with previously obtained data [8]. A head-to-head comparison of azithromycin and amoxicillin in an analysis that included antibiotic indications suggested that azithromycin continued to have an increased risk of death.
The reason for this study was data on the proarrhythmic effect of azithromycin [11-17]; This led to the assumption that taking azithromycin leads to an increased risk of VS. In an analysis based on a previously developed formal definition of SIDS, patients taking azithromycin had an increased risk of SIDS [22]. It should be noted that while taking azithromycin, there was a similar increase in the risk not only of SCAD, but also of other deaths from CVD complications that were observed outside the hospital, although the number of such deaths was small. These findings may have been due to misclassification of causes of death due to the fact that this study used a definition of SCD that was developed to increase the specificity of identifying SCD. A previous study suggested that at least 25% of deaths may be misclassified as deaths from CVD complications, in which another mechanism was suspected [22]. In addition, it must be taken into account that the proarrhythmic effect of azithromycin could lead to an increased risk of death from other CVD complications. Thus, although the study provided evidence of a cardiac side effect of azithromycin, it cannot be used to accurately determine the mechanism by which the use of such an antibiotic led to an increased risk of death.
The increased risk of death from CVD complications during a standard 5-day course of azithromycin therapy did not persist after discontinuation of the drug. Although tissue concentrations of azithromycin remain elevated for several days after discontinuation of azithromycin, blood levels of the drug decrease more rapidly, reaching a minimum after 24 hours [23]. It should be noted that for other drugs with proarrhythmic action, an increased concentration of the drug in the blood remains a factor determining the increased risk of developing arrhythmia [24]; This is precisely the basis for the recommendation to avoid rapid infusion of erythromycin [19].
Due to the fact that the study included patients who took ciprofloxacin and levofloxacin, it became possible to obtain data on the relative safety of the use of such fluoroquinol antibiotics with a wide spectrum of antimicrobial action. For ciprofloxacin, the risk of death from both CVD complications and from any cause during the treatment period was similar to that for amoxicillin, which confirms the existing opinion about the weak proarrhythmic effect of ciprofloxacin [1, 19]. In contrast, levofloxacin, for which there is evidence of a proarrhythmic effect [1, 19], was associated with a trend towards an increased risk of death from CVD complications, although this increase did not reach the level of statistical significance. In a direct comparison of azithromycin and levofloxacin, there were no statistically significant differences in the risk of death from either CVD complications or from any cause.
Thus, taking azithromycin for 5 days was associated with a small PAR of death from CVD complications. When taking azithromycin, compared to taking amoxicillin, 47 additional deaths due to CVD complications occur per 1 million 5-day courses of therapy. In the subgroup of patients in the highest deciles of CVD risk, azithromycin compared with amoxicillin resulted in 245 additional CVD-related deaths per 1 million 5-day courses of treatment.
The deficit we create ourselves
Since spring, people in panic began to buy everything they thought they needed. At first it was buckwheat and toilet paper, then lemons, garlic and ginger, then medical masks, and gradually the turn came to basic mercury thermometers and medicines.
Those who have encountered coronavirus infection more closely may know about the drug dexamethasone, its analogue is prednisolone. Now it is almost impossible to find dexamethasone in pharmacies. There have been rumors that it can supposedly cure cytokine storm, is effective in preventing coronavirus, or can stop the more complex, fatal course of covid.
In the photo: oxygen concentrator (Photo: Sergey Malgavko/TASS)
“Back in the summer, a study was conducted in the UK, which showed that the administration of dexamethasone actually improved the outcome of the disease and made it possible not to develop more severe respiratory failure. However, there was one “but”, which for some reason is again not taken into account anywhere. The benefit of dexamethasone has been shown only in combination with oxygen support (prescribed when saturation decreases below 95%). In the absence of oxygen support, outcomes did not improve and there was even a trend towards worse outcomes.”
In outpatient treatment, dexamethasone cannot help. And if you decide to buy it “just in case,” then do not forget to buy an oxygen concentrator, the cost of which varies around 60-70 thousand rubles.
Time for antibiotics: when needed
In the early stages - up to the 8th-9th day - there can be no talk of antibiotics at all. During this period, coronavirus pneumonia develops, which cannot be stopped by prescribing antibiotics.
Some may develop secondary bacterial pneumonia. This occurs more often in people with an initially suppressed immune status. For example, with decompensated diabetes mellitus.
“When there is a lot of glucose in the blood, bacterial microflora has a greater chance of superimposing viral pneumonia and stimulating the proliferation of bacteria in the lungs. It has certain laboratory signs. We cannot prescribe antibiotics for diabetes and Covid for prevention. Because it won’t work for prevention, antibiotics don’t prevent secondary bacterial pneumonia, they only treat it.”
To prevent the development of bacterial pneumonia, it is necessary to reduce glucose levels with the help of glucose-lowering drugs or insulin under the supervision of a doctor.
Photo: Vladimir Gerdo/TASS
Why was the antibiotic Azithromycin removed from the list of drugs recommended for the treatment of COVID-19?
Doctors have long urged people not to take antibiotics without a diagnosis of bacterial pneumonia. At the same time, the drugs remaining on the Ministry of Health list continue to cause controversy. How is Covid treated almost a year after the start of the pandemic, and will specialized medications be expected soon?
Photo: Evgeny Sofiychuk/TASS
Favipiravir, remdesivir, umifenovir, hydroxychloroquine, and interferon-alpha remain on the Ministry of Health list. They are used to make the expensive “Coronavir” and “Areplivir”, as well as the more familiar “Arbidol”, “Grippferon” and other drugs. The Ministry of Health registered two drugs containing remdesivir only in October, and there is almost no drug available for public sale.
Free antiviral drugs from the list began to be provided to those receiving treatment at home in September. But, as practice has shown, few received them; antibiotics were more often given. Here's what Business FM employees who have already recovered from coronavirus said.
Elena Marchukova Deputy Editor-in-Chief of Business FM “The doctor prescribed us the antibiotic Flemoklav.” When the doctor came to us, he diagnosed that there was no longer Covid. There is pneumonia, with minor damage to the lungs. We had a CT scan. We were not offered any medications to be given. But not against Covid, but against the possible consequences of pneumonia, so that the bacterial component does not join.”
Business FM presenter Igor Lomakin comments.
Igor Lomakin, Business FM presenter “Before this, it was believed that I had ARVI, so I was prescribed only ingavirin. On the day when it finally became clear that I had a real coronavirus, no one came for a long time, and all this time I continued to finish ingavirin. Actually, when I started taking azithromycin, I took a weekly course. There were no side effects, nothing happened, but you have to understand that by the time I was diagnosed, in general I already felt almost healthy.”
This is what Business FM producer Ekaterina Rodionova said.
Ekaterina Rodionova producer, Business FM “The doctor took a smear, gave me Arbidol and went off into the sunset. Then, when the test was confirmed, another doctor came and gave me a sheet with all the treatment regimens with options: if you have a cough, do this, if you have a runny nose, take this. They really only gave me one medicine, and in the end I didn’t even take it, because they told me that if the temperature persists, then start taking it, otherwise it will kill your liver.”
Previously, the already small list of recommended medications by the Ministry of Health included the antibiotic Azithromycin. Often they offered other antibacterial drugs to replace it, sometimes several at once.
In the fall, the consumption of antibiotics increased sharply in the country. The Ministry of Health called for stopping thoughtlessly buying them for two reasons. Firstly, there was a shortage of drugs in pharmacies due to the introduction of new labeling. Secondly, they are useful only for the treatment of bacterial pneumonia, and with coronavirus such a diagnosis is not always made.
But doctors continued to prescribe them just in case, says Ilya Yasny, head of scientific expertise at the pharmaceutical venture fund Inbio Ventures.
Ilya Yasny, head of scientific expertise of the pharmaceutical venture fund Inbio Ventures “Indeed, the whole world has long abandoned the prophylactic use of antibiotics, because it has been shown that it does not improve the outcome, and at the same time there are risks of using antibiotics - this is both their direct toxicity and possible development of resistant forms in the body. The more antibiotics are used, the more bacteria become resistant to them, and this could become a problem in the future.”
The effectiveness of the remaining drugs on the list in treating coronavirus has also not been proven. All experts have been talking about this since spring, and the Ministry of Health recognizes this. “Information about the results of therapy does not allow us to draw an unambiguous conclusion about their effectiveness or ineffectiveness; use is permissible by decision of the medical commission if the potential benefit to the patient outweighs the risk of their use,” the recommendations say.
All these medicines were created before the pandemic and are prescribed to patients with COVID-19, as they say, off-label, that is, not according to the instructions. Favipiravir is the most effective and safest among them, the Ministry of Health says. At the same time, among the recommendations only interferon-alpha is suitable for pregnant women.
Nikolay Bespalov, development director of the analytical company RNC-Pharma, comments.
Nikolay Bespalov Director of Analytical Development.
Previously, The Lancet published a study about one of the first effective drugs for treating COVID-19. An international group of scientists tested the drug Peginterferon Lambda on 60 subjects. In 80% of cases, when taking the medicine, treatment was accelerated by an average of three days. But the drug is still far from being registered. By this point, we may already have gotten over everything.
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Signs of secondary bacterial pneumonia
With secondary bacterial pneumonia, a clinical blood test will show an increase in the level of leukocytes, neutrophils, including their immature forms.
The patient may develop purulent sputum, colored - green, rusty, streaked with blood. Sputum may become more abundant.
Another sign of the development of secondary bacterial pneumonia is an increase in body temperature to 38.5 degrees or higher in the later stages - 12-14 days of Covid disease.
After 2 weeks of coronavirus infection in the body and the development of covid pneumonia, changes occur in the lung tissues that are most convenient for the addition of bacteria and the development of bacterial pneumonia.
“Changes in the lungs after covid pneumonia persist for about 8 weeks after recovery. This does not mean that post-Covid pneumonia needs to be treated somehow. Saturation should be restored to your normal by the end of the infection.”
Therapy of despair
The new virus has misled the entire global medical community, researchers and experts. What can we say about the paramedics and doctors who come to our home when called. Patients with Covid are prescribed azithromycin, arbidol, hydroxychloroquine, and other useless, unnecessary or dangerous drugs.
Indeed, it happens that doctors do not know what to prescribe, and they prescribe at least something for the sake of prescribing, to reassure the patient and give him hope that he will recover. Do not forget that they follow the guidelines approved by the Ministry of Health, the schemes of which are used only in Russia.
Photo: Alexander Demyanchuk/TASS
“I started to get the impression that outpatient doctors weren’t just doing this to prescribe. They want to reassure not only the patient, but also to overcome their fear of this infection and their fear of complications that may arise suddenly. It feels like they are trying to use everything, but as a therapy for despair. Thus, they delay the moment of what they believe are complications, and they also gain time for themselves, giving themselves the opportunity to reduce their vigilance towards this patient. So the doctor shifts responsibility to those who created these clinical recommendations.”
There are also those who have not read clinical studies or studied the opinions of the world medical community. Prescriptions by such doctors occur out of ignorance.
Coronavirus therapy now [RECOMMENDATIONS] First aid kit for Covid
These recommendations from our expert should only be used after consultation with your doctor.
- If possible, buy a pulse oximeter and monitor your saturation readings.
- Of the medications, first of all, it is necessary to have any antipyretics. The WHO warning that some antipyretics worsen the course of the new coronavirus infection has now been completely debunked. This warning was withdrawn back in March.
- You can also use any usual painkillers (in the absence of individual contraindications).
- For those taking birth control pills or who have a tendency to clot, it is necessary to have anticoagulants. These are drugs that thin the blood and prevent the formation of blood clots.
- When taking anticoagulants and antipyretics, you need to remember to protect the stomach (omeprazole, famotidine, etc.) to avoid gastrointestinal bleeding.
- If you have a new coronavirus infection, you should drink more fluids to prevent dehydration and kidney problems.
Do not forget that the doctor must explain to the patient what he is prescribing and why.
*Based on materials from Oksana Stanevich’s broadcast for the “Not in vain” foundation and personal consultation for the “SP” publication.
