MULTIDRUG RESISTANT STAPHYLOCOCCUS AUREUS
Dr. Ashok Dutta*, Dr. Manisha Paul**
Director, Prof. & HOD Pediatrics.*, Senior Resident, Lady Hardinge Medical College, New Delhi. **
Abstract
During the past century, the excitement of discovering antibiotics as a treatment for infectious diseases has given way to a sense of complacency and acceptance that when faced with antimicrobial resistance, there will always be new and better antimicrobial agents to use. Now, with clear indications of decline in pharmaceutical companies' interest in anti-infective research and at the same time when multi-drug resistant micro-organisms continue to be reported, it is very important to review the prudent use of available agents to fight these micro-organisms. In the past seven decades, clinicians have seen a spectrum of anti-microbial agents ranging from sulphonamides to receptor directed anti-viral agents. A number of previously fatal diseases have been tamed, while new infectious agents continue to emerge. Still some old microbes (e.g., Mycobacterium tuberculosis and Neisseria gonorrhea) keep evolving to acquire resistance to the drugs that were once effective. About forty years ago, emergence of penicillin-resistant Staphylococcus aureus was a concern. Today, methicillin-resistant Staphylococcus aureus (MRSA) is prevalent in all continents and Vancomycin-resistant Staphylococcus aureus is looming on the horizon.
Types of Multidrug Resistant Staphylococcus Aureus
Colonization with Staphylococcus aureus or Methicillin-resistant Staphylococcus aureus (MRSA) is relatively common in both healthy and hospitalized individuals, most often involves the anterior nares, and is frequently Asymptomatic. Colonization increases the risk of infection. Outbreaks of hospital-acquired MRSA (HA-MRSA) are typically the result of clonal spread of MRSA being transferred from patient, frequently using health care personnel as intermediaries. HA-MRSA strains are usually multidrug resistant.(1) Apart from this, community-acquired Staphylococcus aureus (CA-MRSA) is also emerging as a public health concern. CA-MRSA is frequently associated with skin infections usually necrotic lesions, often with cellulites or abscesses. Necrotizing pneumonia is less common. Hemoptysis, shock, leucopenia, and multilobar alveolar infiltrates that usually form abscesses are classical, and blood cultures are usually positive. Toxic shock like illness, septic shock, Asymptomatic carriage, orbital cellulites, septic arthritis, and osteomyelitis have also been described. Characteristically, CA-MRSA encodes the genetic element Staphylococcus Cassette Chromosome mec (SCC mec) type IV, which confers resistance to B-lactams but not other antibiotic classes; consequently they are not usually multi-drug resistant.(2)

Mechanism of Resistance

MRSA has traditionally been considered a nosocomial pathogen. However, recent reports of MRSA infections arising in the community, in patients without traditional risk factors (such as hospitalization, dialysis, prolonged antimicrobial therapy, malignancy, or intravenous drug abuse, suggest a potential shift in the epidemiology of MRSA infection.

In Staphylococcus aureus, the methicillin resistance gene, mec A, which encodes an altered penicillin binding protein (PBP2a) and confers resistance to semisynthetic penicillinase-resistant B-lactams (such as oxacillin) and cephalosporin, is carried on a mobile genetic element termed the staphylococcal cassette chromosome mec (SCC mec). In addition to carrying the mec gene complex, this large genetic island also may contain multiple non-B-lactam antibiotic resistance complex, and there are 3 homologous for each of the recombinase genes found in the SCmec element. Hospital-associated MRSA clones have been found to belong to 3 distinct SCCmec complexes (I, II and III).(3) In MRSA isolates from the community, the mecA gene has been found on a novel allelic form, termed SCCmec type IV. This determinant confers resistance only to B-lactams and is smaller in size compared with SCCmec I to III.(4,5)

In June 2002, the first isolate of Vancomycin Resistant Staphylococcus Aureus (VRSA: MIC > 128 ug/ml) causing bacteremia was reported. This patient had been treated with long term vancomycin, and both VRSA and Vancomycin resistant Enterococcus faecalis were recovered from the infected ulcer. The presence of van A gene in the S. aureus isolate suggests that the resistance determinant was acquired by exchange of genetic material from vancomycin resistant E. faecalis isolated from the same patient. A second case of clinical infection carried by VRSA (MIC >= 32 u/ml) contained the van A gene has also been published. The factors responsible for spread of Van A from Enterococcus to Staphylococcus are not known, however in view of known potential for Staphylococcus to spread by clonal dissemination, the recent identification of VRSA is of great concern. (6, 7, 8, 9)

Treatment

1. Vancomycin

Vancomycin is considered the workhorse for the treatment of most drug-resistant Gram positive bacterial infections.

Chemistry: It is a glycopeptide antibiotic discovered in 1956.

Mechanism of action: It inhibits bacterial cell wall synthesis.

Pharmacokinetics: It is not absorbed orally. After IV administration, it is widely distributed, penetrates serous cavities, inflamed meninges and is excreted by glomerular filtration with a t1/2 of 6 hours. Dose reduction is needed in renal insufficiency.

Adverse effects: Systemic toxicity of vancomycin is high. It can cause plasma concentration dependant nerve deafness. Kidney damage is also dose related. Skin allergy, phlebitis, shock are also seen with IV injection. Rapid IV injection has caused chills, fever, urticaria and intense flushing - called Red Man Syndrome.

Use: Given orally, it is the drug of choice in antibiotic associated pseudomembranous enterocolitis. Systemic use is restricted to serious MRSA infections for which it is the most effective drug. It is also used in penicillin resistant pneumococcal infections and as a penicillin substitute (in allergic patients) for enterococcal endocarditis.

Dose: 40-60 mg/kg/day IV 6-8 hrly (IV infusion over 1 hour or more).

2. Quinupristin-Dalfopristin

Concerns have been raised regarding the increasing rates of vancomycin-resistant enterococci and the clinical shortcomings of vancomycin in the treatment of invasive Staphylococcus aureus infections.

Chemistry: It belongs to the macrolide lincosamide-streptogramin group of antibiotics approved by the U.S. FDA in September 1999.

Mechanism of action: It is bactericidal. The main target is the bacterial 50s ribosome that results in inhibition of protein synthesis.(10)

Pharmacokinetics: Quinupristin and dalfopristin are the active components circulating in plasma. Both are converted to active metabolites that contribute to the antimicrobial activity of the formulation. The t1/2 of quinupristin is approximately 3 hours, whereas the t1/2 of dalfopristin is approximately 1 hour. About 75% of the given dose is eliminated by the gastrointestinal tract, while urinary excretion accounts for 15% of the quinupristin dose and 19% of the dalfopristin dose.

Adverse effects: The most common adverse effects were pain and inflammation at the infusion site. Other side-effects include arthralgia (9%) and myalgia (6%), nausea (4.6%), diarrhea (2%), vomiting (2.7%), rash 2.5%), headache (1.6%), pruritis (1.5%) and pain (1.5%).(11)

Use: The most frequent indication for treatment were bacteremia of unknown focus, bone and joint infections, catheter-related bacteremia, intra-abdominal infection, skin structure infection and urinary tract infection.

Dose: 7.5 mg/kg given IV every 12 hours

3. Linezolid

It was originally developed as monoamine oxidase inhibitor for the treatment of depression, but later was discovered to have antimicrobial activity.

Chemistry: They are first of the new class of antimicrobial agents; the oxazolidinones approved by the US FDA in 2000. They are unique as they are totally synthetic. Mechanism of action: They are considered bacteriostatic. They bind to a site on the 50s ribosomal subunit near its interface with the 30s unit, thus preventing the formation of the 70s initiation complex(12, 13, 14)

Pharmacokinetics: Linezolid is 100% bioavailable, both when given orally or intravenously. Maximum plasma concentrations are available 1 to 2 hours after an oral dose. Taking the drug orally with food may slightly delay its uptake, but the total amount of drug absorbed is unchanged.

Adverse effects: A few cases of reversible thrombocytopenia were noted in the Phase III human trials. Therefore, it is recommended that complete blood counts be monitored weekly in patients who receive linezolid, especially those receiving the drug for more than 2 weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, and those with chronic infection who have received previous or concomitant antibiotic therapy.

Use: The US FDA has approved linezolid for the treatment of vancomycin-resistant Pneumonia, Enterococcus faecium infections; pneumonia caused by Streptococcus pneumoniae or Staphylococcus aureus (methicillin susceptible and methicillin resistant strains), complicated skin and soft tissue infections caused by S. aureus (methicillin susceptible and methicillin resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae; and uncomplicated skin and soft tissue infections caused by S. aureus (methicillin susceptible only) or Streptococcus pyogenes.(15)

Dose: 20 mg/kg/day PO or IV q12 hourly in neonates. 30 mg/kg/day PO or IV q8 hourly.


4. Daptomycin

Daptomycin is the first agent of a new class of antibiotics called cyclic lipopeptides approved by the US FDA in 2003.16

Chemistry: Is a cyclic lipopeptide.

Mechanism of action: Daptomycin has a unique but not fully understood mechanism of action. It binds to bacterial membranes and causes rapid depolarization of membrane cell potential. This results in inhibition of proteins, DNA, and RNA synthesis resulting in death.(17, 18, 19, 20)

Pharmacokinetics: Daptomycin exhibited linear pharmacokinetics at 4 mg/kg and 6 mg/kg dosages. The 8 mg/kg dose, however, exhibited slightly less linearity, as Cmax was 2.2 times higher than that of the 4 mg/kg dose. Daptomycin was shown to penetrate well into cantharidin-induced inflammatory blisters.(21)

Adverse effects: The most commonly reported side-effect of Daptomycin is elevation of CPK. In addition arthralgia, back pain, myalgia, muscle cramps were also reported. Another rare but serious side effect is neuropathy. Bell's palsy was reported in 2 patients. Serious adverse effects (SAE) occurred in 10.9%.22

Use: There is an ongoing clinical study of treatment of right-sided endocarditis/bacteremia due to S. aureus. It has also shown encouraging results in the treatment of osteomyelitis.

Dose: 4 mg/kg IV once daily for 7-14 days. Paediatric dosing is currently not available.

Prevention:
It is undeniable that antibiotic use (and overuse) contributes to development of resistance. Thus an antibiotic should be used only when indicated, choosing a cost-effective agent which provides appropriate antimicrobial coverage for the diagnosis that is suspected and prescribing the optimal dose and duration of the antimicrobial. Prevention of transmission of nosocomial MRSA include improved antibiotic stewardship, staff cohorting, maintenance of appropriate staffing ratios, reduction in length of hospital stays, contact isolation, active microbiologic surveillance, and better staff education.(23)
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