Vancomycin, Linezolid and Daptomycin

Infections with multidrug-resistant pathogens are a challenging reality and a threat to public health. Therefore, knowing and knowing how to indicate the treatment with the appropriate antimicrobials is essential.

While Polymyxins, Aminoglycosides and Carbapenems are the main names that come to mind when it comes to multidrug-resistant Gram-negatives, none of these are effective against resistant Gram-positives, such as the famous and feared Oxacillin-resistant Staphylococcus aureus (MRSA).

It is in this scenario that antibiotics such as Vancomycin, Linezolid and Daptomycin, among others, come into play, which are the drugs of choice, in most cases, against resistant Gram-positive strains. Do you want to know how these drugs work? How about learning about its spectrum of action and its adverse effects? So get smart and come with Jaleko.

But, who are we fighting against?

Before we start talking about antibiotics, we need to know the bacteria we are dealing with well. When speaking of resistant Gram-positive, most likely the name that comes to your mind is MRSA , that is, methicillin- resistant Staphylococcus aureus . MRSA is a strain of S. aureus with a mutation of the antibiotic action site, that is, the penicillin-binding protein (PBP). With this, the action of oxacillin, the main drug of choice against S. aureus , and of practically all β-lactams, on the bacteria is inhibited.

Hey, but is it methicillin or oxacillin? In fact, strains with this resistance profile were initially identified as resistant to methicillin, an old drug that is no longer used, but this resistance mechanism also encompasses oxacillin. So, technically, it would be an oxacillin  resistant S. aureus , but the term remained as it was coined.

Initially, MRSA was isolated from hospitalized patients, as were the vast majority of multidrug-resistant bacteria. However, we currently have strains of MRSA circulating and infecting patients in the community. That is, the patient already arrives at the hospital infected with S. aureus resistant to the main drugs, which would be used to treat community infections. These strains acquired in the community, however, tend to be more sensitive to some classes of antibiotics, such as clindamycin, sulfamethoxazole-trimethoprim and some quinolones, being called CA-MRSA , while those acquired in the hospital are more resistant, called HA-MRSA .

In view of the isolation of MRSA, the main drug used is Vancomycin. Going a step further, there are already reports in some centers of strains of S. aureus with intermediate resistance to Vancomycin (MIC 4-8ug / mL), called VISA , or, more rarely, complete resistance to this drug (MIC> 8ug / mL), the VRSA . These strains are not common in Brazil, and the drugs of choice are Linezolid or Daptomycin.

Similar to MRSA, there are multidrug- resistant strains of Staphylococcus epidermidis , including oxacillin, the so-called MRSE , which require treatment in a similar way to MRSA. Reports of S. epidermidis resistant intermediate to Vancomycin exist, so, theoretically, we also have VISE , but these are not frequent.

It is also worth remembering that S. epidermidis is the main negative staphylococcus coagulase and is closely related to infection of prostheses and catheters, but it can also be contaminating samples, as it is found on the skin.

Other Gram-positives worth mentioning are Enterococcus spp. The main species are E. faecalis and E. faecium , the latter being naturally more resistant than the former and more likely to become multi-resistant. If sensitive, the drug of choice is penicillin or ampicillin, but if they become resistant, Vancomycin comes on the scene. Unlike S. aureus , the strains of Enterococcus sp. resistant to Vancomycin are not uncommon and present a major challenge to intensive care centers. Thus, the VRE , that is, enterococci resistant to Vancomycin, are the great challenge and require the use of Linezolid or Daptomycin, too.

How do antibiotics work?

Now that we know the main multidrug-resistant Gram-positive bacteria, let’s get to know the drugs we have to fight them and how they work.

Vancomycin

Class and mechanism of action

The Vancomycin belongs to the class of glycopeptides , which also belongs to Teicoplanina . Its mechanism of action is based on the interruption of cell wall synthesis, by interfering in the formation of bridges between peptidoglycan chains, which would form the wall, which kills the bacteria. For this reason, they are considered bactericidal. Although they also influence cell wall synthesis, glycopeptides do not have a β-lactam ring in their composition and do not bind to PBPs (penicillin-binding proteins). Therefore, they cannot be classified as β-lactams.

Action spectrum

Vancomycin, as we have already said, is the drug of choice for the treatment of MRSA or MRSE, and is also used to treat sensitive enterococci and anaerobic Gram positive, such as Peptostreptococcus spp. and Clostridium difficile itself , which causes pseudomembranous colitis, in its oral use. The spectrum of action of Teicoplanin is practically identical to that of Vancomycin, with the exception of C. difficile , a bacterium against which it is not effective.

Strains of S. aureus resistant to Vancomycin (VISA and VRSA) have emerged in different parts of the world, and the mechanism proposed for this is the formation of a thicker and disorganized cell wall, which prevents the drug from reaching its target site. Vancomycin-resistant enterococcal strains (VRE) are even more common.

Pharmacokinetics

The main route of administration of glycopeptides is intravenous and its oral absorption is practically zero. Even so, there are still oral presentations in capsules or powder for Vancomycin solution used to treat pseudomembranous colitis , an infection caused by Clostridium difficile,which usually appears in the context of prolonged use of antimicrobials by hospitalized patients and manifests itself as diarrhea refractory to conventional treatment. The desired effect, in this case, is not the action on the bacteria in a systemic way, but on the intestinal mucosa, often being combined with another drug for systemic effect, such as Metronidazole. These special oral presentations are not available in Brazil, but it is possible to use the preparation of the intravenous drug and administer it orally, in the same dose that would be used via the IV route.

The initial dose of Vancomycin is usually 1g every 12 hours , but adjustment should be made for patients with kidney disease, according to kidney function. The goal is to achieve a serum concentration between 15 and 20 mg / L. The half-life is 4 to 6 hours and elimination is renal after glomerular filtration. The penetration into the central nervous system is not so high (7-14%), requiring high doses to reach therapeutic levels. There is also the possibility of intrathecal administration, that is, directly into the subarachnoid space through the spinal canal, to treat infections of the central nervous system, avoiding such high doses via IV, since the passage through the blood-brain barrier is no longer necessary.

Vancomycin and Teicoplanin are very similar in terms of spectrum of action and clinical application, but the big difference between them is that Teicoplanin does not penetrate the central nervous system , being an option to treat infections outside that site.

There is also the possibility of performing a continuous infusion of Vancomycin, aiming to reach therapeutic concentrations more quickly and in a sustained manner, increasing the bactericidal action. It is important to monitor the serum levels of the drug, as higher concentrations increase the chance of adverse effects. For this, you can request the dosage of Vankokinaemia , that is, the concentration of the drug in the blood.

Adverse effects

The most classic adverse effect resulting from the use of Vancomycin is the Red Man Syndrome (or red neck), which occurs when the drug is infused very quickly, based on the release of histamine. This syndrome is characterized by redness in several parts of the body, pruritus and periorbital edema, which can cause dyspnea, chest pain and shock. Discontinuation of the drug is required immediately and treatment is supportive, and may involve antihistamines or even vasoactive drugs, in more severe cases.

DRESS syndrome , which means “drug-induced rash with eosinophilia and systemic symptoms”, is a hypersensitivity reaction, which is also related to vancomycin and is characterized by fever, skin rash and itching, lymphadenopathy, hepatitis, pericarditis, interstitial nephritis and pneumonitis, in addition to eosinophilia, thrombocytopenia and abnormal white blood cell count on the blood count. This syndrome can manifest itself in a similar way to the Stevens-Johnson syndrome, and this progresses with involvement of mucous membranes. Treatment also involves withdrawal of the causative drug, use of systemic corticosteroids and support.

Even if Vancomycin does not get to characterize one of these syndromes, it can cause rash , fever , thrombocytopenia and neutropenia as isolated adverse effects.

There are reports of high dose Vancomycin-induced ototoxicity . This adverse effect is more frequent in older patients and manifests itself as hearing loss for high frequencies.

Vancomycin-induced nephrotoxicity has been described in patients receiving high doses of the drug for a prolonged period. This kidney injury, however, appears to be reversible and the risk is increased if combined with Piperacillin-Tazobactam, but not with Meropenem or Cefepime. The causal relationship between vancomycin and kidney injury, however, remains unproven, due to the bias generated by confounding factors, such as the fact that most patients receiving the drug in high doses are in shock, or using vasopressors. , other nephrotoxic drugs, radioactive contrast, among others.

New glycopeptides

More modern representatives of the glycopeptide class are Dalbavancina,  the telavancin and Oritavancina. The Dalbavancina was more effective than vancomycin against MRSA and MRSE, i.e. was able to contain these infections with lower doses (i.e., lower MIC), besides presenting activity in vitro against VISA and VRSA, which still lacks proof practice.

Dalbavancina, however, has no activity against VRE strains, which differentiates it from Telavancina and Oritavancina , which have activity against this bacterium in vitro . The hypothesis is that these two drugs have this spectrum expanded due to a second mechanism of action, which consists of the rupture of the bacterial cell membrane barrier, in addition to the inhibition of its synthesis. More information about these new glycopeptides here and here.

It is worth mentioning that none of these new drugs has any action against any Gram-negative bacteria.

Linezolid

Class and mechanism of action

Linezolid was the first drug in the oxazolidinone class to be launched. Its mechanism of action is based on blocking the beginning of protein synthesis, by interfering with the formation of the initiation complex, which consists of carrier RNA + messenger RNA + ribosome. This drug binds to the 50S ribosomal subunit, which distorts the binding site of the transporter RNA, thereby inhibiting the formation of the 70S initiation complex.

As it acts in protein synthesis, it is able to inhibit the production of toxins by toxigenic strains of Staphylococcus aureus or Streptococcus pyogenes , in patients with toxic shock syndrome by either of these two pathogens.

Action spectrum

Linezolid is effective against all Gram-positive coconuts, including MRSA, MRSE and the dreaded VRE, being the first line for the latter. It is also effective against VISA, VRSA and strains of Streptococcus pneumoniae resistant to Vancomycin. Basically, it becomes the drug of choice in the face of resistance to Vancomycin. In addition to these bacteria, it is also effective against some Gram-positive and Gram-positive anaerobic rods, but it has no action against any Gram-negative.

Pharmacokinetics

Unlike the other drugs mentioned here, Linezolid is completely absorbed by the oral route, existing in both intravenous and oral preparation, the doses being identical for both presentations.

This fact makes it a very useful resource when you want to perform outpatient treatment or discharge a patient colonized by MRSA, as Vancomycin does not allow oral use in this way (remembering that in pseudomembranous colitis, Vancomycin is not absorbed, acting only on the mucosa intestinal), while Linezolid allows.

The usual dose for adults is 600mg IV or VO every 12 hours and, differently from other drugs mentioned in the article, does not require dose adjustment for patients with kidney disease or on hemodialysis.

The drug easily passes through the blood-brain barrier and penetration into cerebrospinal fluid is excellent (60-70%), reaching therapeutic levels in the central nervous system.

A possible disadvantage in relation to the other antibiotics presented is its variable concentration in body fluids, such as blood or urine, and is not the most recommended option for treating infections of the bloodstream or urinary tract. In these cases, the use of Vancomycin or Daptomycin is preferable.

On the other hand, its concentration in tissues is excellent, having even shown advantages in the treatment of hospital-acquired pneumonia or associated with mechanical ventilation by MRSA over Vancomycin, with less adverse effects.

Adverse effects

The main non-specific adverse effects of Linezolid, described with its short-term use, are rash, nausea and vomiting, diarrhea and pseudomembranous colitis.

With prolonged exposure, that is, more than 2 weeks, there is a risk of bone marrow suppression , manifested by thrombocytopenia, anemia and neutropenia. This risk is especially important in patients with end- stage renal disease and hemodialysis. The proposed mechanism would be the accumulation of the drug in the bone marrow. Although there is no recommendation for dose adjustment for renal patients, it is recommended to evaluate the serum levels of the drug in dialysis patients.

With more prolonged use, over 4 weeks, cases of lactic acidosis, peripheral neuropathy and optic neuropathy have been described. There is evidence of dose-dependent mitochondrial toxicity , that is, Linezolid inhibits intramitochondrial protein synthesis, in addition to inhibition of bacterial ribosomes. And that would be the proposed mechanism for late hematological and neurological effects. This action only seems to occur, however, in individuals with some mitochondrial RNA polymorphism patterns, genetically determined, which are more susceptible.

Linezolid, by inhibiting MAO, can cause HYPERTENSION if administered together with foods rich in thiamine. Some drugs, especially selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, need to be avoided due to the risk of serotonin syndrome , manifested by fever, agitation, changes in mental status and tremors, if administered concomitantly with Linezolid.

New oxazolidinones

The Tedizolida (shown as Tedizolida phosphate) is the second drug of the class of oxazolidinones to be approved by the FDA. Its spectrum and mechanism of action are basically identical to those of Linezolid, covering even some strains resistant to Linezolid, but there is no data to prove its effectiveness against rods and Gram positive anaerobes.

The usual dose for adults is 200 mg IV or VO every 24 hours. Although the adverse effects are practically the same as those of Linezolid, Tedizolid appears to be safer, especially with regard to myelotoxicity. The proposed reason for this is the fact that it reaches therapeutic levels with a single daily dose, compared to the dose every 12 hours of Linezolid.

Daptomycin

Class and mechanism of action

Daptomycin is the main representative of the lipopeptide class, whose mechanism of action is the irreversible binding to the bacterium’s cytoplasmic membrane, depolarizing it and causing loss of ionic gradients, which leads to the rapid death of the cell. The bactericidal action of this drug is considered extremely effective, being much more lethal than Vancomycin against sensitive and resistant Gram-positive strains.

It is worth mentioning that, although very similar, the mechanisms of action of glycopeptides (Vancomycin) and lipopeptides (Daptomycin) have different target sites. While glycopeptides act on cell wall synthesis, lipopeptides act on the cell membrane.

Action spectrum

The Daptomycin is capable of containing infections by Staphylococcus aureus , multidrug-(MSSA) and MRSA, reaching to cover, including vancomycin intermediately resistant strains (VISA) and to demonstrate activity in vitro against VRSA. It is also effective against coagulase-negative staphylococci, including MRSE, streptococci and enterococci, including VRE, and is a drug of choice against these strains. It is also effective against some anaerobic Gram positive, but no activity against any gram negative. It is also not used for C. difficile infection .

Resistance to Daptomycin is very rare, and the mechanism for adding a lysine to the cell surface has been proposed, which increases the positive charges that repel the drug, which is positively charged. The combination with another drug capable of decreasing positivity, such as trimethoprim-sulfamethoxazole or Nafcilin, has been a proposed strategy to reverse this situation. In practice, you are unlikely to encounter Daptomycin resistant strains.

Pharmacokinetics

Daptomycin is not absorbed orally, the route of administration being intravenous. The usual dose for adults is 4 to 6 mg / kg every 24 hours . Single daily administration has been shown to be effective and safer. Its penetration into the blood-brain barrier is minimal and excretion is renal, so the dose should be adjusted for patients with renal failure.

An extremely important fact, which should always be taken into account when prescribing Daptomycin, is the fact that the drug is inactivated by the pulmonary surfactant , so that it cannot be used to treat infections of the lower airways . This is a major limiter for the use of Daptomycin, which loses its effectiveness against germs that infect the lungs, even if sensitive in vitro , such as Streptococcus pneumoniae .

On the other hand, Daptomycin has a very good concentration in the blood, demonstrating non-inferiority to Vancomycin in the treatment of infectious endocarditis , once its etiology has been confirmed by Gram-positive cocci, especially S. aureus .

Adverse effects

The main adverse effect described related to the use of Daptomycin is myopathy , which is very associated with its concomitant use with statins. The recommendation is weekly dosage of creatinophosphokinase (CPK) and discontinuation of the antibiotic if its values ​​increase more than 10x or symptoms of myopathy with CPK> 1000. It is also recommended to stop the use of statins during therapy with Daptomycin.

Other less common and less specific adverse effects include phlebitis at the infusion site, fever, rash, nausea and vomiting, diarrhea, headache, increased nitrogen slag and pseudomembranous colitis (remembering that this is an infectious diarrhea that occurs in the context of antibiotic therapy ).

Honorable Mentions

The Ceftaroline is a 5th generation cephalosporin that, unlike other cephalosporins advanced generations (Ceftriaxone, Ceftazidime and Cefepime), no action so focused on Gram-negative, but has expanded spectrum for Gram-positive multiresistant, especially MRSA and MRSE . It has in vitro activity against VISA and VRSA, but has no action against VRE, which maintains the resistance pattern of cephalosporins with respect to enterococci.

A synergistic effect between Ceftaroline and Vancomycin or Daptomycin has already been demonstrated , increasing the effectiveness against resistant strains, including Daptomycin. The Ceftobiprole is another 5th generation cephalosporin with basically the same spectrum Ceftaroline. These two drugs are the only cephalosporins effective against resistant Gram positive.

The action of these 5th generation cephalosporins against Gram-negative is similar to Ceftriaxone and has no activity against Pseudomonas aeruginosa  or Acinetobacter baumannii , being inhibited by Gram-negative producers of extended spectrum β-lactamase (ESBL).

The Tigecycline has one of the greatest action spectra of all the antibiotics and is effective against most bacteria multi – resistant Gram-negative and some Gram-positive multiresistant, too. This would be a potential option against MRSA or MRSE infections, but not against VRE or VRSA. In practice, Tigecycline is not one of the first options, both because of its extremely broad spectrum. as for its lesser effectiveness against these germs, compared to the drugs of choice, mentioned above.

New tetracyclines, such as Eravacycline and Omadacycline, have a spectrum of action very similar to Tigecycline, but with lower minimum inhibitory concentrations (MIC) in general. They are effective against MRSA and MRSE, but not VRE. On the Gram-negative side, they cover enterobacteria producing carbapenemases (ERC) , ESBL and metallo-β-lactamases (MBL), anaerobes, Acinetobacter baumannii and Stenotrophomonas maltophilia , but do not cover Pseudomonas aeruginosa or Proteus sp., As well as to Tigecycline.

Good old sulfamethoxazole-trimethoprim may also be effective against some strains of MRSE and MRSA, especially those purchased in the community (CA-MRSA), but not against Gram-positive strains resistant to Vancomycin.

Conclusion

Gram-positive bacteria can develop multiple resistance mechanisms and pose a great challenge for the infectious management of patients. In order to combat them and, above all, to avoid the selection of these multi-resistant strains, it is necessary to know the antibiotics that we have and to know how to apply them in a coherent and well-founded way.

When the most common options become ineffective, Vancomycin, Linezolid, Daptomycin, Ceftaroline and other antibiotics come into play that need to be handled with caution, knowing their adverse effects and indications.

It is to help you on this journey that we are here. Certainly, you are now much better prepared to reason over your patients’ cases and, more importantly, offer them the best care.

 

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