Gram Positive Bacteria Staphylococcus Aureus Biology Essay

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Staphylococcus aureus is a gram-positive bacterium that colonises the skin and can be found in the anterior nares in about 25-30% of healthy individuals. Meticillin-resistant of Staphylococcus aureu was isolated in the year 1961 in UK, half a year after the introduction of meticillin into the community. It became one of the most prevalent bacteria globally that causes an infection and it also resists other members in the beta-lactam antibiotic class, including penicillins, cephalosporins and carbapenems. Vancomycin has been used as the standard treatment of MRSA infection in the past 50 years. However, MICs are generally rising as a result of resistance development which led to a decline in successful treatment rate. New potential alternatives to vancomycin are therefore required. Daptomycin and linezolid are two new antibacterial agents discussed in this review. The pharmacokinetics, pharmacodynamic, side effects, resistance and indications are mentioned in this review and comparisons between vancomycin and linezolid are made. Treatment option is based on patient's acceptability, resistance, side-effects, route of administration, site of infection and cost.

1. Introduction

Staphylococcus aureus is a gram-positive bacterium that colonises the skin and is present in the anterior nares in about 25-30% of healthy people. S. aureus can cause different diseases in man depending on its intrinsic virulence or the ability of the host with its opportunistic behavior. [1] Resistance of antibiotics of the bacteria can be acquired by the mutation of an existing bacterial gene or horizontal transfer of a resistant gene from another bacterial cell. Among the resistance strain that have been isolated, meticillin resistance is clinically the most important because S.aureus with this gene resist the most commonly prescribed class of antibiotics which is the beta-lactam antibiotics, including penicillins, cephalosporins and carbapenems. It is named meticillin-resistance staphylococcus aureus (MRSA). It can infect human from outside to inside, from skin, ear, nose, reproductive tract, blood, bone, joint, and the central nervous system. It particularly affects children, elderly and people who are immunocompromised such as HIV and patients on immunosupressive drug after organ transplant. [2]

MRSA was first discovered in the UK in 1961, half a year after the introduction of meticillin into the community and became one of the most prevalent bacteriua globally that cause an infection, ranging from 2% in the Netherlands and Switzerland, to 70% in Japan and Hong Kong. [2, 3]The prevalence rate in the UK was 1.28% in the year 2006, with skin and soft-tissue infection (49.1%) which is the commonest infection type among all MRSA infections followed by eyes, ENT and mouth infections(29.3%), bone and joint infections(28.1%) and surgical site infections (27.6%). Others include urinary tract infections, bacteraemia, endocarditis and respiratory tract infections. [4]

Vancomycin has been used long and still is the standard treatment for MRSA infections. However, due to its weak bactericidal effect, poor penetration into tissues, especially in the lung, toxicity and growing of resistance, discovery of new therapeutic agents that are active against MRSA is important. Linezold and daptomycin are newer antibacterial agents developed and are used as alternatives to vancomycin. Linezolid can be administrated orally so earlier switch to oral dosing is enabled. On the other hand, daptomycin has no CYP450 related-drug interaction so it is safer when used in patients on multi-drug therapies. They can be considered as the first-line treatment choice and used if vancomycin treatment is failed or contraindicated, for example patients with previous hearing loss. Nevertheless, they have similar clinical outcomes when compared with vancomycin with certain conditions. They are also more expensive and toxicity profile is not improved but only different. The pharmacokinetic properties, pharmacodynamic properties, side effects, resistance, efficacy and cost are discussed in this review and comparison is made between linezolid and vancomycin. [5-10]

2.Vancomycin

Vancomycin belongs to an antibiotic class called glycopeptid produced by Amycolatopsis orientalis, a species in the actinobacteria class by fermentation and it was isolated in the year 1953. [10] From the past 50 years until nowadays, vancomycin is still the standard treatment for MRSA infections.[5]

2.1 Pharmacokinetic

It is a large hydrophilic molecule which does not cross through the gastro-intestinal lining. Its oral use is only indicated for Clostridium difficile infection which oral administration is necessary for the drug to reach the colon.

As vancomycin is not orally absorbed, it is administered intravenously for the treatment of MRSA infection. However, vancomycin is not suitable for IV bolus injection and rapid infusion. It is very irritating to body tissue and it can cause injection site necrosis, severe pain and thrombophlebitis if it is administered by IV injection. Rapid IV infusion may cause occasional hypotenion, histamine like response and erythematous rash, also known as 'red man syndrome' which may last for twenty minutes to several hours. Slow intermittent infusion is more preferable than continuous infusion which should only be used if intermittent infusion is not suitable. Rate of infusion of vancomycin is suggested at a maximum rate of 10mg/min over 1 hour to avoid these anaphylactic reactions and trough serum concentration can be maintained above the MIC. [11] Longer infusion time is required for a stronger doses and slow infusion over at least an hour is recommended for infant and children. Moreover, the risk of overdosing and developing toxicity result from high peak concentration is reduced. [10, 11]

Vancomycin undergoes no metabolism and is excreted unchanged in the urine. Clearance of vancomycin from the body is highly dependent on the renal function of the patient. Increased blood concentration can be a result of decreased renal function and may lead to toxicity, include further renal damage and ototoxicity. Therefore, modification of the dosing regime is essential, based on the creatinine clearance of each individual and the optimum dosages and dosing intervals can be deduced. [12].

2.2 Toxicity

Nephrotoxicity is one of the significant side effects followed by high dose, prolonged or combined vancomycin therapy with aminoglycoside. Serum creatinine level of all patients receiving vancomycin should be closely monitored, especially if the patient is renally impaired. Aminoglycoside itself is a nephrotoxic drug. Risk of renal damage is increased notably when vancomycin and aminoglycoside are used in combined therapy. [7, 10, 13] Several studies has been carried out to investigate the risk of renal damage result from vancomycin monotherapy, aminoglycoside monotherapy and combined therapy of both drugs.

Seven studies have been meta-analyzed and the risk of nephrotoxicity with combination therapy was 13.3+ 3.1% (7.3 - 19.4%) greater than therapy with vancomycin alone (P < 0.01), and 4.3+ 1.4% (1.6 - 7.0%) greater than aminoglycoside alone (P < 0.05). The results indicated that other than combined therapy of vancomycin and an aminoglycoside which is one of the main factor of increased risk of nephrotoxicity, prolonged treatment with vancomycin ( >21days) and vancomycin trough serum concentration (>10mg/L) could also be a key factor leading to renal damage. Therefore, vancomycin alone or in combination with an aminoglycosides should be used with caution and close monitor on the renal function is essential.[14] Long term vancomycin/aminoglycoside combine therapy is also discouraged.

Ototoxicity is another side effect resulted from vancomycin therapy and is dose related. Although it is less likely to occur than renal damage, it is still significant. Unlike renal toxicity, result obtained from study investigating auditory damage is more reliable as it is unlikely to be caused by other clinical factors that occur in the hospital environment. A study investigated 89 patients who had audiogram before and after 27days of vancomycin therapy. 11/89 patients (12%) result in worsening in audiogram after the course, with 0/89 (0%) patients aged below 53 years and 11/89 patients (12%) aged 53 or above. These data suggested that middle-aged and elderly patients are under a greater risk of developing ototoxicity if they are treated with high-dose, long-term vancomycin therapy. Use of vancomycin should hence be avoided, if possible for middle-aged, elderly and patients with previous hearing loss.

[10, 15]

2.3 Pharmacodynamic

Vancomycin is an antibiotic that exhibits various different pharmcokinetics of bacterial killing and the most accepted model is MIC/AUC. MIC value should be <1mg/L when it is used as monotherapy against fully susceptible S. aureus (VSSA). Its mode of action is to forms hydrogen bond with the D-Ala-D-Ala group on the bacterial cell wall and it prevents the conjugation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. The cell wall synthesis process is immediately inhibited and the cytoplasmic membrane is damaged as a secondary effect. [10]

The key indication of vancomycin is for MRSA bacteraemia, serious soft tissue infection (SSTI) and bone infection.

Bacteraemia - It is suggested the treatment duration of glycopeptides for uncomplicated bacteraemia should be at a minimum length of 14 days. Patients with, or at high risk of endocarditis should receive longer treatment.

SSTI - For non hospitalized patients, vancomycin should be used when the strains of MRSA are resistant to doxycycline or clindamycin.

- For hospitalized patients, use of vancomycin should be considered for severe SSTI and if the risk of bacteraemia is high.

Bone infection - Choice of antibiotics depends on the surgical management plan. As the data from clinical trials on the efficacy of the new agents are not sufficient to support their use, parenteral glycopeptides with or without adjunctive agents remains the only recommendation.

[7]

2.4 VSSA, h-VISA, VISA and VRSA

The first identification of vancomycin-resistant S. aureus (VRSA, MIC>16mg/L) was in the United States in 2002, due to the acquisition of the vanA gene from vancomycin-resistant enterococci. However, only eleven cases have been reported so far, with nine from the US, and the remaining from India and Iran, which represents this strain is not widely spread. This review will not focus on this strain as it did not cause a large number of clinical issues. [16]

Heterogeneous vancomycin-intermediate S. aureus/Vancomycin-intermediate S. aureus (hVISA/VISA, MICs 4-8mg/L) were first isolated in Japan in 1996, from a spectrum of a patient with MRSA pneumonia who failed in standard vancomycin therapy. It has been found in many countries including US, Hong Kong, Thailand, Japan and the UK, with at least one study showing 86 out of 2550 patients in Liverpool have been colonized with VISA [17]. Although the resistance mechanism of VISA is not certain, VISA cell wall is shown to be thicker than fully susceptible S. aureus. Thickening of the cell wall protects the VISA from vacomycin, by preventing the inhibition of the peptidoglycan biosynthesis process and allow production of new cell wall peptidoglycan, which the cell is therefore vancomycin resistant. [18]

A term 'vancomycin creep' has been mentioned in recent years. It is associated with decreasing activity of vancomycin for MRSA infection. Certain isolates of MRSA remains susceptible to vancomycin but the MICs are raised. [5]

The reason why increased MICs of vancomysin for MRSA infection is a concern is that the risk of toxicity is raised and new, more expensive antimicrobial agents with insufficient clinical and efficacy data support have to be use as an alternative.

Therefore, to prevent spreading and stop the development of new strains, use of vancomycin should be controlled and in some situation is discouraged, including routine surgical prophylaxis unless the patient is severely ill and empiric antimicrobial therapy for a febrile neutropenic patient unless initial evidences support that the infection is caused by gram-positive organism. The Healthcare Infection Control Practices Advisory Committee (HICPAC) also suggests educating the hospital staff about vancomycin resistance, early detection and reporting of vancomycin resistance by the hospital microbiology laboratory and applying immediate infection control procedure to prevent transmission of the bacteria. [7, 19]

3. Daptomycin

3.1 Pharmacodynamic

Daptomycin is a cyclic lipopeptide natural product that is only active against Gram positive bacteria. It shows rapid concentration-dependent bactericidal activity. [20] Its mode of action is the calcium-dependent insertion of its lipophilic tail on the cytoplasmic membrane of the bacterial cell, causing a net efflux of potassium and therefore DNA, RNA and protein synthesis is inhibited. It does not penetrate the cytoplasmic membrane so no cell lysis occurs. Less allergic responses is the result as there is no release of molecules from the cytoplasm which inflammatory response can be diminished. [5, 6, 9] It exhibits concentration-dependent bactericidal activity in pharmacodynamic studies and in vitro. The duration of post-antibiotic effect of daptomycin is more than 6h at 16mg/L which is much longer and effective as compared with 1.3-1.8h time-dependent post-antibiotic effect of vancomycin.

[6]

3.2 Pharmacokinetic

Daptomycin is a highly protein bounded drug (92%) with a half-life of about 8h, which allows it to be administered once daily. [5] Single daily dose of 4-10mg/kg administered by intravenous infusion should be over 30 minutes for up to 14 days in individuals with normal renal function and steady-state concentration should be reached by the third daily dose. CYP450 mediated metabolism has no or little effect on metabolizing daptomycin and therefore no CYP450-related drug interaction is expected. It is mainly excreted by the kidney and therefore it should be used with caution and with regular renal function monitoring in renal impaired patients (Creatinine clearance <80ml/min). [9] Patients who are hepatic failed do not require dose adjustments, but is necessary in renal impaired patients and a complementary dose after haemodialysis is required as the 4-h dialysis section clears 15% of the drug. [5] Co-administration of medication that reduces renal filtration, such as NSAIDs and COX-2 inhibitors may lead to an increase in daptomycin plasma level as the clearance rate is lowered. Therefore, co-administration of daptomycin with any other medication that reduces renal function should be used with caution. [9]

3.3 Toxicity

Side effects such as diarrhea, rash, fungal infection are still common following antibiotic therapy, but one unique to daptomycin is skeletal muscle toxicity. Symptoms include muscle pain and decreased muscle strength. It is reversible if daptomycin is discontinued as soon as symptoms are observed. [5,9] It is found that the dosing frequency is the major factor causing toxicity. A dividing dose of daptomycin every 8h gives a greater increase in CPK and more severe degradation of myofibres than a large single daily dose. Co-therapy of daptomycin and statins is also thought to be a factor causing myopathy. Therefore, recommendations are made to have close monitoring of CPK and muscular function in all patients started on daptomycin and avoid co-administration with statins or other medication casuing myopathy. [21]

3.4 Resistance

Resistance of daptomycin is uncommon but it can develop as a result of prolonged treatment. Several mutations of the S. aureus genes are responsible for the reduction of susceptibility. The mprF gene encodes a duel function enzyme that binds phosphatidylglyerol (PG) to lysine and lysyl-PG (LPG) is then transferred to the surface of the outer membrane. LPG is less susceptible to daptomycin than PG as it is less acidic. The calcium-dependent insertion of the lipophilic tail is unfavorable and binding of daptomycin is reduced. Ration of LPG/PG in the outer membrane of the bacteria with mprF mutants is higher than the wide-type strain and bind less daptomycin is the result. [22]

One concern is the reduced or non-susceptibility of MRSA to daptomycin after failure in vancomycin therapy. Resistance or reduced susceptibility to vancomycin due to antibiotic pressure exerted by daptomycin, or vice versa and treatment failure is the result. [7] On the other hand, one study evaluated daptomycin and vancomycin against two strains of VSSA and four strains of VISA with endocardial vegetation in a pharmacokinetic/pharmacodynamic model. Daptomycin showed bactericidal activity against both VRSA and VISA isolates while vancomycin displayed little activity against VSSA isolates and little to no activity against hVISA. This study concluded by suggesting daptomycin can be a potential agent for treatment of serious infection caused by hVISA and an alternative if vancomycin therapy failed. [23] The results from both studies are contradicting and as there is no clear and well accepted clinical trial done, daptomycin is therefore not yet licensed for GISA and glycopeptides-resistance S. aureus (GRSA) infection. [7]

3.5 Indication

Daptomycin is recommended by the BSAC Guideline for MRSA SSTI and bacteraemia including right-side endocarditis. [7, 24] One study showed 45% versus 27% in complicated bacteraemia, 60% versus 45% in uncomplicated bacteraemia and 50% versus 50% in right-side endocarditis of the patients successfully treated with daptomycin and vancomycin plus gentamicin respectively. The data indicate that daptomycin is an effective alternative to vancomycin/gentamicin for bacteraemia or right-side endocarditis which MRSA is the causative organism. [25] Moreover, compare with vancomycin or isoxazoyl penicillin with gentamicin which was associated with nephrotoxicity, daptomycin casued less toxicity and is reported in another trial. Treatment failure of left-side endocarditis by daptomycin has also been shown. [7]

Patients with MRSA SSTI on daptomycin therapy should receive a daily dose of 4mg/kg and 6-10mg/kg for bacteraemia or endocarditis. Moreover, bone and joint infection has been successfully treated with daptomycin but randomized comparative trials have not been published. [5]

Study has shown all strains that cause complicated UTI are susceptible to daptomycin with MICs up to 2mg/L. Rate of bacteriological eradication is 83% and clinical success rate is 93%. However, BSAC indicates that 2mg/L should be classified as resistant .Therefore daptomycin is still not a licensed drug to treat UTI caused by MRSA but it is used empirically. [7]

Moreover, the use of daptomycin for MRSA pneumonia is discouraged. It is because daptopmycin is inactivated by binding of its lipophilic part to the pulmonary surfactant found in the lung. Its antimicrobial activity is therefore inhibited. [26]

4. Linezolid

4.1 Pharmacodynamic

Linezolid belongs to a new class of antibiotic class called oxazolidinones and it is the only member of this class marketed by the year 2009. It demonstrates in vivo and in vitro bacteriostatic activity against aerobic Gram positive bacteria and anaerobic micro-organisms, including MRSA and VISA. It binds to the 23S and 50S subunit on the bacterial ribosome and the formation of a functional 70S initiation complex is prevented. Bacterial protein synthesis is selectively inhibited as 70S is an essential component of the translation process. [6, 8]

4.2 Resistance

Due to it unique mechanism of action, cross-resistance of linezolid with other antibacterial agents (such as chloramphenicol, quinupristin-dalfopristinhas and tetracycline) has not been reported. [27] However, mutation on the 23S rRNA gene is the main cause of resistant of MRSA as the binding of linezolid to this 23S rRNA subunit is obstructed, which leds to an increase in the MICs. [28]

4.3 Pharmacokinetic

Linezolid can be administered by IV infusion or by oral route. Both dosage forms are bioequivalent. Oral absorption of the drug is rapid and complete, with bioavailability at about 100% that allows early switch to oral therapy as soon as the patients are clinically stable. It can reduce vancomycin use and the length of stay (LOS) in hospital lead to a reduction of the cost. [5, 6, 8, 29, 30] It reaches the peak plasma concentration after 2 hours of oral administration and it is rapidly disturbed into body tissue. [8, 29]. It is metabolized into two inactive metabolites by oxidation of the morpholine ring and non-renal clearance accounts for 65% of the total clearance of linezolid. 30% of the active drug is excreted in the urine and the last 5% is removed in the faeces. Linezolid is not metabolized by CYP450 and therefore no CYP450 -drug related interaction is expected. [8]

Linezolid is generally well tolerated, with approximately 22% of patients experienced non-life threatening adverse reactions. Those most commonly reported side effects are headache, diarrhoea, nausea, vomiting, metallic taste, abnormal liver function tests and vaginal and oral candidiasis. Most of the patients discontinued the treatment because of headache, diarrhoea, nausea and vomiting, with a rate of 3% of 2000 adult patients who received the recommended linezolid dose for up to 28days. [8, 29]

Linezolid itself is also a weak, reversible, non-selective monoamine oxidase inhibitor (MAOI). Therapeutic dosage used for antibacterial therapy is too low and no anti-depressive effect is shown. Drug-drug interaction is evaluated by limited studies and its use on patients with underlying conditions or on co-administration of mediation might put them at risk from MAOI inhibition. Close monitoring is necessary if use of linezolid is the only therapeutic option in these conditions. Moreover, large amount of tyramine intake should also be restricted to avoid 'cheese syndrome'. Food with rich tyramine content includes mature cheese, pickled meat, fish and yogurt. [8, 29]

Serotonin syndromes have been reported with the concomitant use of linezolid and serotonergic agent such as serotonin reuptake inhibitors (SSRIs). Therefore, unless the co-administration of linezolid and serotonergic agents is vital, either of them should be avoided. Close observation and monitoring for the signs and symptoms of serotonin syndrome inducing hyperpyrexia, cognitive dysfunction, hyperreflexia and incoordination is essential. Discontinuing of either one or both agents should be considered noticing that discontinuation symptoms may develop followed by the withdrawal of the serotonergic agent. [8]

4.4 Toxicity

Myelotoxicity and neurotoxicity are the major severe side effects as a result of linezolid therapy.

Mytoxicity has been reported when the duration of treatment exceeded 10 days and especially occurring in patients with pre-existing myelosuppresion or receiving another myelotoxic drug. Complications include anaemia, leukopenia, pancytopenia, and thrombocytopenia are observed. Renally impaired patients experience a drop in platelet count more commonly. These patients should have close monitoring on their platelet counts and haemoglobin levels. Recommendation is also made to monitor complete blood counts weekly for patients who are receiving linezolid treatment exceeding 14 days, receiving co-current drugs that are also myelotoxic, with pre-existing myelosuppreion, or those with a chronic infection who have received previous or concomitant antibiotic therapy. [29]

Neurotoxicity may be induced by prolonged use of linezolid. Symptoms include both peripheral and optic neuropathy, which can be exacerbated by several risk factors such as pre-existing neurologic problem, alcohol abuse, diabetes and concomitant of a serotonin reuptake inhibitor or antihistamine. Close neurological monitoring is therefore recommended in prolonged linezolid therapy and with concomitant risk factors. [31, 32] A maximum duration of 28 days treatment course has also been suggested by the manufacturers and clinical studies. [5]

4.5 Indication

Serious soft-tissue infection is one of the licensed indications of linezolid, especially complicated SSTI and . In a randomized, open-label, comparator-controlled, multicenter and multinational study, involving 1180 patients, oral linezolid was compared with i.v. vancomycin in patients with cSSTI infection that involves substantial area of skin or deeper soft tissues such as cellulitis, abscesses, infected ulcers or burns. Clinical successful rate was 92.2% and 88.5% for the linezolid group and vancomycin respectively which was equivalent. Similar number of cases of drug-related side effects has also been reported, with a more common rate of 3.5% of patients developed thrombocytopenia in the linezolid group. However, 88.6% of the linezolid group showed better outcome than the vancomycin group at the test-of-cure (TOC) visit which suggested linezolid is a better choice when treating cSSTI caused by MRSA. [33] Another study which was a meta-analysis of randomized controlled trials also indicated that patients treated with linezolid (89%) have a slightly higher successful rate of cure than vancomycin (86%). [34]

Another condition when linezolid is often chosen as an option of treatment is pneumonia, especially ventilator-associated pneumonia (VAP). Clinical successful rate between linezolid and vancomycin showed no significant different. However, the length of ICU stay and hospitalization of the linezolid group (12.2d, 18.8d respectively) is shorter than that of the vancomycin group (16.2d, 20.1d respectively), which enable an earlier discharge, reduces exposure time to nosocomial pathogens and allows efficient use of resources for patients treated with linezolid.

[35]

Linezolid is always being used to treat bone and joint infections and central nervous system infections, including meningitis and brain abscesses. Although it is not licensed for the treatment of both conditions because of the risk of adverse effects development, it is still used empirically. [5, 7]

Linezolid is also suggested for treating PVL-positive MRSA infections. Panton-Valentine leucocidin (PVL) is a white blood cell destroying toxin and a staphylococci virulence factor produced by some strains of S. aureus/MRSA and more commonly CA-MRSA. Severe SSTIs and severe necrotizing pneumonia can be caused by this toxin and may require more advanced diagnosis and treatment plan. Linezolid is used in these cases in combination with vancomycin or other antibacterial agents such as clindamycin, rifampicin and co-trimoxazole because of its ability to inhibit the production of PVL from the PVL-positive MRSA strains. Clinical successful rate is also higher when patients are treated with linezolid-combined therapy than that of other antibiotics. [7,37]

4.6 Cost-effectiveness

Other than the efficacy of the antibacterial agent which is undoubtedly the main factor on choosing treatment option, the cost of the drug is also important. Therefore, studies are carried out to investigate the cost-effectiveness of linezolid versus vancomycin. Regarding to the shorter length of stay (LOS) and earlier discharge from hospital, the average cost per patient treated with oral linezolid is 28.5% and 22.3% less than the i.v. vancomycin group and the group treted with i.v. vancomycin followed by oral linezolid, respectively. Although a single dose of linezolid is more expensive than an equivalence dose of vancomcyin, the difference in the price of the drug is overcame by the saving on the reduced hospitalization period. Linezolid is therefore a more cost-effective antibacterial agent for MRSA infection than vancomycin. [36]

5. Discussion

Vancomycin, daptomycin and linezolid are three antibiotics from different antibacterial family that are licensed for MRSA infections. They are not the only three choices but they are the three most important and most widely used antibiotics for MRSA infections. Clinicians have to judge and decision is based on patient's acceptability, resistance, side-effects, route of administration, site of infection and cost.

Choosing the proper antibiotics for different infections is crucial. According to the "Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom", all three of them are licensed for bacteraemia and SSTI but there are little differences between them.

Linezolid has shown to have better clinical outcome than vancomycin for the treatment of MRSA SSTIs and bacteraemia. [guideline] It can be considered as a replacement of vancomycin for the choice of first line treatment. [7, 39] As linezolid is only more cost-effective than vancomycin in patients requiring hospitalization (such as pneumonia and bacteraemia), vancomycin and daptomycin are still more cost-effective than linezolid for outpatient therapy in moderately severe SSTIs; Daptomycin is unlicensed for UTI but is used empirically. Further clinical trials are in progress to have daptomycin proven for its uses in more conditions (except pneumonia which is already proven as ineffective). [38]

Patients with multiple medical conditions and on multi-drugs therapy can also complicate the situation. Use of drugs on this group of patients should be with cautions and with close monitoring. Combine therapy of vancomycin with an aminoglycoside has a higher nephrotoxicity incident rate than mono-vancomycin therapy and may have further worsening of renal function for patients with preexisting renal problem. Linezolid can be an alternative in this case. It can also be used, instead of vancomycin for patients who are middle-aged or elderly with previous hearing loss to avoid further damage to the hearing ability. Notice that co-administration of linezolid and a serotonergic agent such as SSRIs should be avoided.

In summary, we have looked at the pharmacokinetics, pharmacodynamic, resistance, indication and side effects of these three antibiotics. We have also compared the efficacy of vancomycin/linezolid. Daptomycin is not compared in this review because of insufficient data published. Limited clinical studies have done on daptomycin versus vancomycin for MRSA infections.

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