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Repurposed Drugs for Long-Haul

Please be aware that I am not a proponent of antibiotics. However, they are among the few classes of pharmaceuticals that sometimes provide more benefits than their risks. Ivermectin and hydroxychloroquine should also be considered antibiotics. They may have their place in long-haul sufferers who are not responding to functional/integrative approaches.



I don't suggest you read the entire article because the authors shed a positive light on Remdesivir, although this is their conclusion regarding this killer.


"Moreover, a few more studies are going on to determine the safety, antiviral efficacy, pharmacokinetic property, and tolerability of remdesivir alone and in combination with other agents like tocilizumab, merimepodib, and convalescent plasma therapy in cases of severe and moderate COVID-19 patients in the United States, Bangladesh, Nepal, China, and Canada (Anonymous, 2020a). However, with a lack of adequate evidence supporting remdesivir use in COVID-19, WHO recently deprecated its use regardless of hospitalized patients’ severity of illness (WHO, 2020)."


Doxycycline

Doxycycline (1967) is a semisynthetic second-generation class of tetracyclines with a broad spectrum of antimicrobial activity. It was developed by chemical modification of basic chlortetracycline structure and identified and named by mycologist B. M. Duggar in 1944 (Joshi and Miller, 1997). Having antiviral, immunomodulatory, and anti-inflammatory properties, doxycycline and other tetracycline antibiotics could be potential options for treating COVID-19 patients. An in vitro antiviral activity study of doxycycline involving VERO E6 cell line showed positive results against SARS-CoV-2 with median effective concentration (EC50) of 5.6 ± 0.4 µM. For prophylaxis, doxycycline could be used in combination with hydroxychloroquine or chloroquine (Gendrot et al., 2020).


Several mechanisms have been proposed for the actions of doxycycline against SARS-CoV-2. Effectiveness of tetracyclines (e.g., tetracycline, doxycycline, and minocycline) against COVID-19 infection can be attributed to their higher lipophilicity with higher lung tissue penetration ability facilitating their role in viral replication inhibition in the lungs. Again, tetracyclines can form chelate with zinc compounds on matrix metalloproteinases (MMPs) of the host while coronaviruses rely heavily on MMPs of the host for cell adhesion, infiltration, survival, and replication, thus inhibiting the virus’ ability to replicate within the host. They might also act by inhibiting positive-sense single-stranded RNA replication of COVID-19. Again, due to their anti-inflammatory mechanism, tetracyclines are used to treat different inflammatory conditions. They can decrease the levels of inflammatory cytokines, such as tumor necrosis factor-a, interleukin (IL)-1b, and IL-6, which are elevated when lung tissue is infected with severe acute respiratory syndrome–associated coronavirus (SARS-CoV) deteriorating the infection itself (Sodhi and Etminan, 2020). The anti-COVID-19 action of doxycycline is displayed in Figure 2.



Doxycycline (a tetracycline antibiotic), being a non-toxic mitochondrial biogenesis and cellular respiration inhibitor and having various pleiotropic features, can attenuate the replication of most viruses which need the energy of aerobic glycolysis to replicate and use mitochondria as cellular powerhouses. It is suggested that doxycycline in combination with Vitamin C shows more effectiveness against COVID-19 (Szolnoky, 2020).


Again, Sargiacomo et al. suggested that senolytic drugs such as doxycycline can be used for SARS-CoV-2 infection to prevent fibrotic transformation. SARS-CoV-2 can cause stormy inflammation and subsequent fibrosis after binding and replicating, preferably with senescent and chronologically aged lung cells (Sargiacomo et al., 2020).

In New York, 89 high-risk COVID-19 patients (diagnosed from March 18 to May 13, 2020) received early treatment with doxycycline in long-term care facilities and demonstrated early clinical recovery, reduced hospitalization, and reduced mortality. Among 89 patients, 76 (85%) were clinically recovered, three patients (3%) showed deterioration of clinical condition requiring transfer to hospital, and 10 patients (11%) died (Alam et al., 2020). A prospective case-series study involving 21 COVID-19 patients from Iran from September 14, 2020 to September 28, 2020 suggested the potential effectiveness of doxycycline in COVID-19 treatment (Meybody et al., 2021). Recovery of four high-risk COVID-19 patients with comorbid pulmonary diseases who were treated with doxycycline was reported (Narendrakumar et al., 2021).


Doxycycline shows more effectiveness against SARS-CoV-2 when used in combination with other drugs like hydroxychloroquine, ivermectin, and dapsone. More studies are required to establish its effectiveness in proposed combination therapies for COVID-19 (Farouk and Salman, 2020; Malek et al., 2020). At present, various clinical trials are being conducted with doxycycline alone or in combination with other drugs for COVID-19 treatment. An experimental trial with a combination of hydroxychloroquine and doxycycline involving 54 high-risk COVID-19 patients demonstrated higher clinical recovery, decreased hospital stay, and reduced mortality (Narendrakumar et al., 2021). A recent double-blind and randomized interventional trial of doxycycline in combination with ivermectin was conducted with 400 participants. Early clinical improvement was reported in 60.7% of patients (111 out of 183 patients) with doxycycline and ivermectin combination compared to 44.4% (80 out of 180) with placebo (NCT04523831, 2020). More studies are still in progress in Iraq, Egypt, and Bangladesh to assess the efficacy and safety of this combination for COVID-19 treatment (Anonymous, 2020b).


Azithromycin

Azithromycin, a macrolide derivative and the first of the fifteen-membered ring azalide class of antimicrobials, shows a broad spectrum of activity against various gram-positive and gram-negative bacteria and other atypical pathogens (Ballow and Amsden, 1992). They act by inhibiting bacterial growth through interference with their protein synthesis. Azithromycin showed in-vitro activity against Ebola and Zika viruses and prevented severe viral infections of the respiratory tract. Previously they have been used as an adjunctive therapy to treat viral respiratory tract infections due to their anti-inflammatory and immunomodulatory activities in addition to extended antibacterial coverage (Wu et al., 2020). With no available definite treatment option for COVID-19, azithromycin has undergone several studies recently to find its effectiveness against SARS-CoV-2. An in-vitro screening with VeroE6 (ATCC CRL-1586) and Caco-2 (ATCC HTB-37) cells reveals Azithromycin to be a potential inhibitor of SARS-CoV-2 replication with EC50 (50% effective concentration) = 2.12 µM and EC90 (90% effective concentration) = 8.65 µM. (Touret et al., 2020).


There is no known specific mechanism; instead, several mechanisms have been proposed for the probable antiviral activity of Azithromycin. Any of these mechanisms could be responsible for its activity against SARS-CoV-2. For example, being a weak base, azithromycin can inhibit the uncoating of coronaviruses as the uncoating of enveloped viruses requires an acidic environment. Again, preferential accumulation of this drug in lysosomes and endosomal vesicles can elevate pH and limit replication of the virus by blocking endocytosis. Another possible mechanism can be the amplification of host’s interferon (IFN) pathway-mediated antiviral responses, resulting in a reduction of viral replication. A quantum mechanical model proposes that azithromycin’s interference in the binding interaction of SARS-CoV-2 spike protein and host receptor ACE2 (angiotensin converting enzyme-2) protein can be responsible for limited viral entry (Damle et al., 2020). Azithromycin has also been suggested to have senolytic activity used to inhibit viral replication and IL-6 production (Sargiacomo et al., 2020). The anti-COVID-19 action of Azithromycin is displayed in Figure 3.




Currently, various clinical trials are being conducted to evaluate the efficacy of Azithromycin in combination with hydroxychloroquine for COVID-19 treatment. According to a study, azithromycin and hydroxychloroquine combination therapy was encouraged in the treatment of early symptomatic and high-risk outpatients (Esper et al., 2020). Several other preliminary trials also reported positive results like the one performed by Pfizer in France and another reported by Gautret et al. (2021) which previously suggested the use of combination treatment of azithromycin and hydroxychloroquine for COVID-19 (Gautret et al., 2021; Wu et al., 2020). According to another retrospective observational study, azithromycin (introduced after 6–8 h from being diagnosed) could notably improve the hospital stay duration and requirement of respiratory support in hospital days (Ishaqui et al., 2020). Despite having no clear idea about the optimal dose of azithromycin against SARS-CoV-2, in accordance with IDSA guidelines and RECOVERY trial, 500 mg azithromycin once daily (OD) for 5 days is recommended in the case of severe patients. Again, based on previous studies, azithromycin was only suggested to early phase patients with COVID-19 infection as in later phases it failed to deliver any beneficial impacts on clinical status (Echeverría-Esnal et al., 2021).


On the contrary, one of the biggest randomized controlled clinical trials conducted on hospitalized patients with mild to moderate COVID-19 infection involved the administration of hydroxychloroquine monotherapy azithromycin and hydroxychloroquine cotherapy, which did not alleviate patient status at 15 days compared to standard care (Arshad et al., 2020; Echeverría-Esnal et al., 2021).


Another experiment also failed to demonstrate any evidence of rapid antiviral activity in severe COVID-19 patients with hydroxychloroquine and azithromycin combination therapy (Molina et al., 2020). Moreover, this combination is reported to prolong QT and lacks safety data for patients with arrhythmia or renal or hepatic impairment. So, robust clinical data are required to support the efficacy and safety of this combined therapy (Machiels et al., 2020). Recently an open-label and randomized phase-3 clinical trial of hydroxychloroquine and azithromycin for COVID-19 treatment in pregnant women has been withdrawn.


In another UK-based, open label, multi arm, and randomized clinical trial, the routine use of azithromycin failed to display promising activities to shorten the recovery time or risk of hospitalization of COVID-19 infected individuals. The trial also reported inappropriate and excessive use of azithromycin during the COVID-19 pandemic which ultimately leads to antimicrobial resistance (Butler et al., 2021). A few other clinical studies also suggested the same inefficacy of azithromycin or combination of azithromycin with hydroxychloroquine in terms of virologic clearance and other poor clinical outcomes (Molina et al., 2020; Echeverría-Esnal et al., 2021). Besides, the administration of hydroxychloroquine and azithromycin in hospitalized patients has been linked to an increased risk of cardiac adverse events. More specifically, such a combination has been associated with an increased risk of QTc prolongation, ventricular arrhythmia, TdP (0.4%), atrial fibrillation, atrioventricular block, and cardiac failure (Echeverría-Esnal et al., 2021).


Interestingly, some very recent studies revealed that in combination therapy, hydroxychloroquine might cause cardiac toxicity not azithromycin (Echeverría-Esnal et al., 2021). In addition, in the only randomized-controlled clinical trial conducted to date in hospitalized patients, azithromycin monotherapy did not confer a higher risk of adverse effects like hydroxychloroquine or combination therapy with hydroxychloroquine (Arshad et al., 2020; Echeverría-Esnal et al., 2021). Thus, though a cautious risk-benefit ratio and follow up of ADRs should be monitored, from a safety perspective azithromycin could be being studied for its use against SARS-CoV-2 infection (Echeverría-Esnal et al., 2021).


 

Previous blog on how antibiotic use helped explain the mechanism of COVID / Spike protein.


I published a couple of blogs during COVID-19 highlighting some experts who discussed bacterial pathways during COVID-19 and how antibiotics helped.


Lewis Note: I now confidently suggest a natural antibiotic regimen that has been proven to work very well. However, it's important to note that in very late-stage cases, regardless of the condition, pharmaceuticals may still be beneficial. Remember, ivermectin IS a pharmaceutical!


Here are those blogs.




 

Now comes a very interesting article documenting positive outcomes in COVID by several doctors using antibiotic therapy as part of their regiment.




I suggest you read the article. Below, I am reproducing just part of the article. The part I am not including is how governments recommended against antibiotic use. That tells a lot. You should know by now that doing just the opposite of these types of recommendations is often the right path!


 

Physicians defying public health authorities


When physicians chose to use antibiotics to treat patients in defiance of public health authorities, they reported some startling results.


Physicians in Toledo, Spain, empirically administered antibiotics to covid-19 patients during spring 2020, contrary to official guidance. This resulted in zero hospitalizations or deaths in their care homes after they started routine administration. Their resulting mortality over spring 2020 was approx. 7% versus 28% in other comparable care homes (and the 7% died before they started routine antibiotic use).


Likewise in Romania a physician, Flavia Groșan, was reported in the media as approaching covid-19 as “atypical pneumonia”, saying there were huge mistakes with excessive oxygen therapy and intubation:

“Too much oxygen for too lengthy periods at a time, says Groșan, can lead to cerebral edema which in turn can cause death.”

She gave her patients ‘enough’ oxygen for their needs, antibiotics and other cheap medicines. On the choice of antibiotics, she said:

“There are only three antibiotics in the macrolide class, erythromycin, which everyone knows, azithromycin and clarithromycin. I don’t like azithromycin because it’s a weaker copy of clarithromycin. I worked in some very interesting clinical studies on pneumonia and there I learned about the viral tropism of clarithromycin, as well as the anti-inflammatory role of clarithromycin, which no antibiotic has.
I have been working with this antibiotic in viral and atypical pneumonias for 10 years. When the pandemic hit I went for an etiological treatment, clarithromycin. Of course, in addition to this antibiotic, there are several adjuvant treatments, because it can’t cope alone. It is a treatment scheme that is my own.”

Lewis Comment: These drugs may not treat virals, but there is almost always comorbid bacterial infections. If we can reduce your bacterial burden, maybe your immune system can begin to overcome the (weaker?) virals.


She reported healing 100% of some 1,000 patients using this approach.

At St Paul’s hospital in Vancouver, Canada, Russell and Walley learned that Covid-19 is not deadly in itself, but it is sepsis that causes the organ failure leading to death. In this article they say:

“The pandemic we’ve all been living through is actually a pandemic of sepsis due to COVID-related pneumonia.  Everybody who dies of COVID actually dies of sepsis and pneumonia. Everybody.”

Sepsis is the number one cause of death worldwide. They go on to emphasise the importance of antibiotics and other measures in treating Covid-19:

It’s a complex syndrome that can require antibiotics, oxygen, drugs to stabilize blood pressure, and dialysis to support failing kidneys. In addition to this, there’s also no diagnostic test available to detect sepsis, making the diagnosis a challenge. 

Ivermectin protocols as antibiotic treatments

The various protocols for use of ivermectin as an early treatment and prophylactic for covid-19 also include the administration of antibiotics, such as doxycycline and azithromycin, as documented in the Zelenko protocol:


And of course, ivermectin is reported to have antimicrobial policies, in itself, as documented here.

Finally, there is this evidence that chloroquine is a potent treatment for SARS.

Note that these protocols recommend antibiotics for high-risk patients. Those are the same patients who may be likely suffering from bacterial pneumonia.

It is worth pointing out that ivermectin and many antibiotics often have antioxidant or anti-inflammatory properties that will also help when treating viral and bacterial infections. This is the case with azithromycin and a cursory search of pubMed results in 58 papers on the topic.

Antibiotics and the common cold

A fascinating letter appeared in the Proceedings of the Royal Society of Medicine in 1958 written by a Dr J. Morrison Ritchie in response to an article on the common cold by Hope Simpson3. In it he describes a study carried out at the Birkenhead Public Health Laboratory on 1,000 volunteers in the winter of 1955/56 where they applied antibiotics for patients suffering cold symptoms. They reported that:

There were 22/581 colds among those receiving antibiotic tablets on the first day, as against 87/338 among those receiving inert control tablets: 3.8 % as against 25.7%, a drop to one-seventh. In the adult industrial population, the proportion was one to nine, and this drop was evident in all the units of the investigation.

Clearly many colds were not viral infections at all but bacterial infections, but such is the overlap in observed respiratory symptoms for these broad classes of pathogen, that absent the administration of antibiotics, this would have escaped attention.

If physicians can easily confuse common cold infections with bacterial infections what is to say they will be able to differentiate between SARS-CoV-2 and bacterial pneumonia?


The use of face coverings may have magnified the harms

The possibility must be raised that the widespread use of face coverings was synergistically harmful when combined with a deliberate policy of restricting antibiotic use.


It has long been recognised that bacterial pneumonia frequently caused by so-called “commensal” bacteria - i.e., those which normally colonise the nose and mouth.

Hence it was not at all surprising that colonies of such bacteria (as well as fungi) were found on nearly all the face coverings used by the volunteers in this study performed in Japan, published in Nature.


The less effective immune system of the elderly is yet another factor which could have acted synergistically with the above to increase the likelihood of them developing bacterial pneumonia under the policies imposed.


 

Azithromycin

Azithromycin is a commonly used macrolide antibiotic that has antiviral properties mainly attributed to reduced endosomal transfer of virions as well as established anti-inflammatory effects.


It has been commonly used in COVID-19 studies initially based on French reports demonstrating markedly reduced durations of viral shedding, fewer hospitalizations, and reduced mortality combination with HCQ as compared to those untreated.


In the large inpatient study (n = 2451) discussed previously, those who received azithromycin alone had an adjusted HR for mortality of 1.05, 95% CI 0.68-1.62, and P = 0.83.


The combination of HCQ and azithromycin has been used as standard of care in other contexts as a standard of care in more than 300,000 older adults with multiple comorbidities.


This agent is well-tolerated and like HCQ can prolong the QTc in <1% of patients. The same safety precautions for HCQ listed previously could be extended to azithromycin with or without HCQ. Azithromycin provides additional coverage of bacterial upper respiratory pathogens that could potentially play a role in concurrent or secondary infection. Thus, this agent can serve as a safety net for patients with COVID-19 against clinical failure of the bacterial component of community-acquired pneumonia.


The same safety precautions for HCQ could be extended to azithromycin with or without HCQ. Because both HCQ and azithromycin have small but potentially additive risks of QTc prolongation, patients with known or suspected arrhythmias or taking contraindicated medications or should have more thorough workup (eg, review of baseline electrocardiogram, imaging studies, etc.) before receiving these 2 together. One of many dosing schemes is 250 mg po bid for 5 days and may extend to 30 days for persistent symptoms or evidence of bacterial superinfection.


Doxycycline

Doxycycline is another common antibiotic with multiple intracellular effects that may reduce viral replication, cellular damage, and expression of inflammatory factors.


This drug has no effect on cardiac conduction and has the main caveat of gastrointestinal upset and esophagitis. As with azithromycin, doxycycline has the advantage of offering antibacterial coverage for superimposed bacterial infection in the upper respiratory tract. Doxycycline has a high degree of activity against many common respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, anaerobes such as Bacteroides and anaerobic/microaerophilic streptococci and atypical agents like Legionella, Mycoplasma pneumoniae, and Chlamydia pneumoniae.


One of many dosing schemes is 200 mg po followed by 100 mg po bid for 5 days and may extend to 30 days for persistent symptoms or evidence of bacterial superinfection. Doxycycline may be useful with HCQ for patients in whom the HCQ-azithromycin combination is not desired.


 

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