MRSA ANTIBIOTIC RESISTANCE MECHANISM MRSA is a dangerous infectious disease caused by resistant strains of Staphylococcus aureus (Golden Staph.). Full name of this disease is Methicillin-resistant Staphylococcus aureus infection. Different types of antibacterials (except drugs included in the group of beta-lactam antibiotics) can be used to treat resistant staph infection. It should be noted that about half of all drugs used to treat bacterial infections are beta-lactam antibiotics. Therefore, to choose antibiotics for MRSA is much more difficult than for the treatment of other types of bacterial infections. When treating MRSA, it is important to choose antibiotics that work, help quickly get rid of the infection and prevent transmission of dangerous bacteria from an infected person to healthy people. Before starting antibiotic therapy, it is necessary to find out what tissues and organs are already infected with Staphylococcus aureus. In cases if strains of staph infect blood, heart, bone tissue, skin, or lower respiratory tract, intravenously (IV) drugs for MRSA can be administered. IV antibiotics are used to treat severe MRSA in patients who have failed to respond to other drugs. IV injections or Vancomycin infusions (Vancoled, Vancor, Vancocin, Lyphocin) are used as the first-line therapy of MRSA. For successfully MRSA cure, this IV antibiotic can be administered in combination with other antibacterials from the rifamycin group (e.g., Rifapentine, Rifampin, Rifabutin) or aminoglycoside group (e.g., Gentamicin, Kanamycin, Neomycin, Paromomycin, Spectinomycin, Streptomycin, Tobramycin). Unfortunately, not all patients with MRSA manage to cure a dangerous infectious disease after the first course of antibiotic therapy. For the re-treatment of MRSA, IV infusions of antibiotics Linezolid, Daptomycin or Tigecycline can be used. All the listed antibiotics for MRSA really work and help quickly to stop the development of infection. However, very often, MRSA is complicated by other types of bacterial infections. In such cases, patients should be prescribed with drugs containing several antibacterial agents. Advantage of antibacterial cocktail drugs is that their active ingredients have different mechanisms of action. Therefore, drugs for MRSA containing two antimicrobial agents have an extended range of antibacterial activity. One of the most prescribed combination antibiotics for MRSA is Synercid. This injectable drug includes antibacterial agents Dalfopristin and Quinupristin. It should be noted that injection therapy of MRSA is very effective, but is very expensive. Therefore, many patients have to use cheap oral antibiotics for MRSA treatment. Some of the most effective oral drugs for MRSA are Bactrim, Cotrim, Septra, Sulfatrim, Sulmeprim (contain antibacterial agents Trimethoprim and Sulfamethoxazole), as well as Zyvox oral tablets (contain antibacterial agent Linezolid). Less effective oral antibiotics for MRSA treatment are Clindamycin (Cleocin, Calindamin, Clindamyk), Erythromycin (Erymax, ERYC, Eryped, Erythrolar). Particular attention should be paid to oral antibacterials from the group of quinolones (such as, Ciprofloxacin, Levofloxacin, Moxifloxacin, Ofloxacin, Norfloxacin, Gemifloxacin). Drugs of this group have a bactericidal effect. Therefore, they can be administered to treat MRSA in patients with bacteremia.
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diagnosis of MRSA was made in the outpatient setting or by culture positive for MRSA within 48 hours after hospital admission; no medical history of MRSA infection or colonization; no medical history in the past year of hospitalization, admission to a nursing home, skilled nursing facility, or hospice, or surgery; no permanent indwelling catheters or medical devices that pass through the skin into the body.
Other differences between HA-MRSA and CA-MRSA exist. Fortunately, CA-MRSA isolates are usually susceptible to more antibiotic agents than HA-MRSA isolates, which tend to be resistant to multiple antibiotics. CA-MRSA isolates are more likely to produce specific virulence factors or exotoxins. An important virulence factor produced by many MRSA strains is Panton-Valentine leukocidin (PVL), a cytotoxin. Infection with a PVL-producing strain can result in serious clinical illness, such as osteomyelitis or hemorrhagic necrotizing pneumonia. Illness due to CA-MRSA most commonly results in skin and soft tissue infections, such as cellulitis, abscess formation or folliculitis. Patients may initially present to primary care clinicians complaining of “spider bites.” However, CA-MRSA infection may also result in serious or fatal disease. Case reports or series of necrotizing pneumonia, empyema, osteomyelitis or sepsis occurring in adults and children have been published. In 1999, the CDC published case reports of fatal CA-MRSA infection in four infants and children. Genotype differences Genotypes of CA-MRSA strains are distinct from HA-MRSA isolates. The mecA gene in staphylococci is responsible for resistance to beta-lactam antibiotics. The mecA gene is transported on a mobile genetic element known as a staphylococcal cassette chromosome (SCC). Five SCCmec complex types have been found for Staphylococcus aureus. HA-MRSA strains contain primarily SCCmec types I, II and III. These genes are associated with resistance to multiple drug classes, in addition to beta-lactam antibiotics. SCCmec types IV and V encode for resistance to beta-lactam antibiotics and are found primarily in CA-MRSA isolates.
Another important characteristic differentiating CA-MRSA strains from HA-MRSA strains is the production of unique toxins and virulence factors. Analyses have revealed differing genes and toxins isolated from CA-MRSA strains that have not been found in HA-MRSA isolates. A clinically significant virulence factor unique to CA-MRSA strains is the PVL toxin. This cytotoxin damages human leukocytes and can produce severe tissue necrosis. Case reports of previously healthy children and adults affected with CA-MRSA infection and the resulting necrotic clinical manifestations, which have been fatal in some cases, have been published. Although the true prevalence of PVL toxin production in CA-MRSA is not known, some reports indicate that the majority of CA-MRSA isolates are able to secrete this highly potent toxin. The most common CA-MRSA clone circulating in the United States, USA300, carries the genes encoding PVL. However, the USA 300 CA-MRSA clone is being increasing recognized as a nosocomial pathogen and so the molecular characteristics of CA-MRSA and HA-MRSA strains are becoming blurred. Antibiotic treatment Due to the genotypic differences described above, CA-MRSA isolates are primarily resistant to betalactam antibiotics (penicillins, cephalosporins, carbapenems) and macrolides. Thus, additional treatment options are available to clinicians treating CA-MRSA infection. However, no data from controlled trials are available assessing which antibiotics are most likely to be effective when treating infants and children. Data available come primarily from case reports and retrospective studies. Treatment choice is guided by strain-specific antibiotic susceptibilities, clinical severity, patient allergy status, cost, tolerability and age. Initiation of antibiotic therapy may not be necessary in all children with skin and soft tissue infections caused by CA-MRSA. Lee and colleagues described an observational study of 62 children (mean age 5.5 years) with culture-proven CA-MRSA skin and soft tissue abscess infection. All children received antibiotics and 96% of children received wound incision and drainage. Initial antibiotic therapy for 62 children, prior to culture results, consisted of an ineffective antibiotic (based upon susceptibility studies). For 37 children, therapy was not changed to an antibiotic to which the pathogen was susceptible, whereas therapy was changed to an appropriate antibiotic for 21 children. There was no difference in outcome in children who received an appropriate antibiotic compared with children who did not receive an appropriate antibiotic. Of the four children hospitalized on the first follow-up visit, none had received an appropriate antibiotic. A significant predictor of hospitalization was initial lesion size – children with a lesion more than 5 cm were more likely to be admitted. Receipt of an initial antibiotic to which the CA-MRSA isolate was not susceptible was not a significant predictor of hospitalization. Thus, incision and drainage without adjunctive antibiotic treatment was an effective therapy in children with CA-MRSA skin and soft tissue abscess infection when the lesion was five cm or less. Other published studies have also concluded that incision and drainage, without antibiotic therapy, can be employed as successful treatment of skin and soft tissue abscess formation, including CA-MRSA infection. Oral antibiotic choices most likely to be used by pediatric clinicians include clindamycin, trimethoprimsulfamethoxazole, doxycycline, minocycline, rifampin and linezolid. Data describing the effectiveness of these agents in children with CA-MRSA infection come primarily from observational studies and case
reports. Data are not available from controlled trials, and thus more definitive treatment recommendations and guidelines are not currently available. The 2006 Red Book lists TMP-SMX or clindamycin as antibiotic choices for skin/soft tissue infection or pneumonia, and vancomycin for lifethreatening infection.
TMP-SMX, clindamycin, vanco TMP-SMX is a viable initial antibiotic for CA-MRSA infection, as many, but not all, isolates have been reported to be susceptible to this agent. Documentation of the effectiveness of TMP-SMX comes from case reports and anecdotal recommendations. Sensitivity studies documenting the susceptibility of CAMRSA to TMP-SMX should be obtained with its use. Because TMP-SMX contains a sulfonamide antibiotic, it should not be used in children with a history of a documented true allergic reaction to previous sulfonamide use. As CA-MRSA infection may also occur in newborns, caution should be used when prescribing TMP-SMX in these patients. As TMP-SMX may displace bilirubin from albumin binding sites, this antibiotic should not be used in newborns with increased bilirubin. Because TMP-SMX does not provide adequate activity toward group A streptococcus, it should not be used if this pathogen is suspected (eg, infection associated with lymphangitis, concomitant streptococcal pharyngitis, erysipelas) or is grown upon culture. Clindamycin is another antibiotic frequently recommended as an initial therapeutic option. Most CAMRSA isolates are susceptible to clindamycin. However, it is important that inducible resistance be tested for when using clindamycin. Resistance may develop rapidly with clindamycin use, despite an initial sensitivity report indicating that the MRSA isolate is susceptible. Most, if not all, microbiology laboratories can utilize the disk diffusion method (D-zone test) to test for inducible macrolidelincosamide-streptogramin B (MLSB) resistance. Clindamycin should not be used if the D-test is positive, which indicates inducible resistance. Clindamycin is a viable option for infants aged younger than 2 months with CA-MRSA infection. Clindamycin is available in liquid formation, although it is not particularly palatable. Parenthetically, many pharmacies are able to flavor liquid medication products with commercially available flavoring systems. Vancomycin is generally considered the drug of choice for severe CA-MRSA infections. Although MRSA is usually sensitive to vancomycin, strains with intermediate susceptibility, or, more rarely, resistant strains have been reported. What Is the Prognosis of MRSA Infections? According to the U.S. National Institutes of Health, the outcome (prognosis) of MRSA infection varies according to the severity of the infection and the general condition of the person who has the infection. People with good general health who have mild CA-MRSA that is appropriately treated recover in almost every case. Mild skin infections and even some moderate infections (boils, small abscess) can have an excellent prognosis if treated early and effectively. Other more serious or extensive MRSA infections have
a range of prognoses (outcomes) from good to poor. MRSA pneumonia and sepsis (blood poisoning) have high death rates. The calculated death rate of invasive MRSA is about 20%. Data are sparse on the on recurrence of MRSA infections. The recurrence rate of MRSA infection in mild cases is thought to be very low, but some investigators report that patients may be carriers for up to 30 months, so it is possible for a carrier to have a contagious period for this length of time. One group of investigators reports a 21% recurrence rate in HIV patients nine months after the initial diagnosis. Other investigators report a recurrence rate of 41% in individuals with MRSA skin infections. Most investigators agree that strict hygiene helps reduce the risk of recurrent infections. As mentioned above, complications of MRSA can be serious and include sepsis, pneumonia, organ damage, tissue loss and scarring due to necessary surgery. Additionally, a serious complications of antibiotic treatment is intestinal infection by the anaerobic organism Clostridium difficile. This organism and the problems it causes merit another article (see reference 4); it, too, is treatable but it may markedly extend the recovery time for a MRSA-infected patient Doxycycline, minocycline, linezolid and rifampin Doxycycline and minocycline have been reported in a small number of adult case reports to be effective therapy for MRSA infection, including skin and soft tissue infections caused by CA-MRSA. As both of these agents are members of the tetracycline class, they should not be used in children aged younger than 9 years. No data are available for their use in children. Minocycline may rarely cause significant adverse effects. Linezolid (Zyvox) is a unique antibiotic, a member of the oxazolidinone class. Linezolid provides good in vitro activity toward MRSA, although resistance has been reported. Data on its use and effectiveness in treating CA-MRSA are limited. As linezolid is FDA-labeled for use in newborn infants and older, this agent is an option for very young patients. Linezolid should not be used initially for mild CA-MRSA treatment as it is expensive and is limited by its adverse effect profile, including thrombocytopenia and peripheral neuropathy. Pyridoxine at a dosage of 50 mg daily may modify linezolid-induced thrombocytopenia. Linezolid can be used for serious infection and is equivalent in efficacy to vancomycin for serious MRSA infection. Linezolid is available in an oral liquid formulation and intravenous formulation. An important theoretical but unproven beneficial effect of linezolid and clindamycin may be the ability of these agents to modify CA-MRSA toxin production. A case report published in 2005 (Micek) described four adults with severe respiratory CA-MRSA infection, in which all the isolates were positive for PVL. Three patients failed therapy with vancomycin but responded to linezolid or clindamycin. As linezolid and clindamycin both function to inhibit protein synthesis, this mechanism may be valuable in modifying exotoxin production.
Rifampin may possess good in vitro activity toward CA-MRSA. Case reports have been published describing the use of rifampin in combination with another antibiotic, such as TMP-SMX, clindamycin, or
doxycycline/minocycline. There are no data documenting increased efficacy by adding rifampin compared with single drug therapy. Rifampin should not be used as monotherapy as resistance may develop rapidly. As rifampin is a potent hepatic drug metabolizing enzyme inducer, the potential for drug-drug interactions should be considered when it is employed. Conclusion Culture and susceptibility studies should be obtained in all patients with suspected CA-MRSA infection. Incision and drainage is helpful, and it may be sufficient alone without antibiotics in mild cases. In children with mild-moderate illness (eg, febrile, systemic symptoms), it is appropriate to add systemic antibiotic therapy. TMP-SMX, doxycycline/minocycline or clindamycin are reasonable antibiotics to use empirically, prior to susceptibility study results. However, if local or regional CA-MRSA susceptibility data indicate that resistance to clindamycin is greater than 15%, it has been recommended to avoid using clindamycin empirically. Treatment for severe illness should include vancomycin or linezolid. Clindamycin may be used empirically if local resistance patterns are low. Some evidence suggests that therapy with linezolid or clindamycin may be beneficial in PVL-positive CA-MRSA infection. Consideration may be given to adding rifampin or gentamicin to vancomycin for serious illness. When using vancomycin empirically, it is appropriate to initially prescribe nafcillin or oxacillin additionally, as these agents provide more rapid bactericidal action toward methicillin-susceptible Staphylococcus aureus. Nasal application of mupirocin may be beneficial in some patients to prevent recurrence of infection. However, it is likely that recolonization will occur shortly. What Is the Prognosis of MRSA Infections? According to the U.S. National Institutes of Health, the outcome (prognosis) of MRSA infection varies according to the severity of the infection and the general condition of the person who has the infection. People with good general health who have mild CA-MRSA that is appropriately treated recover in almost every case. Mild skin infections and even some moderate infections (boils, small abscess) can have an excellent prognosis if treated early and effectively. Other more serious or extensive MRSA infections have a range of prognoses (outcomes) from good to poor. MRSA pneumonia and sepsis (blood poisoning) have high death rates. The calculated death rate of invasive MRSA is about 20%. Data are sparse on the on recurrence of MRSA infections. The recurrence rate of MRSA infection in mild cases is thought to be very low, but some investigators report that patients may be carriers for up to 30 months, so it is possible for a carrier to have a contagious period for this length of time. One group of investigators reports a 21% recurrence rate in HIV patients nine months after the initial diagnosis. Other investigators report a recurrence rate of 41% in individuals with MRSA skin infections. Most investigators agree that strict hygiene helps reduce the risk of recurrent infections. As mentioned above, complications of MRSA can be serious and include sepsis, pneumonia, organ damage, tissue loss and scarring due to necessary surgery. Additionally, a serious complications of antibiotic treatment is intestinal infection by the anaerobic organism Clostridium difficile. This organism and the problems it causes merit another article (see reference 4); it, too, is treatable but it may markedly extend the recovery time for a MRSA-infected patient.
MRSA and Pregnancy If a pregnant woman is a MRSA carrier, there is no research evidence that her pregnancy will be compromised. In general, MRSA screening is not done routinely during pregnancy. However, if a woman has been diagnosed previously with MRSA and is having a planned C-section, she has a high risk for complications, has a MRSA-positive household member, or has been hospitalized in the last three months, she may be screened for MRSA. Some clinicians will offer treatment to suppress the bacteria; other clinicians may not, depending on the mother’s circumstances. Pregnant women who get MRSA infections are treated with antibiotics; if they pass MRSA to their infant, the baby can also be treated. Fortunately, serious MRSA infections in infants are rare. Pregnant women with MRSA infections should be treated by specialists, usually a team consisting of an ob-gyn and infectious disease consultant, since careful choices in antibiotics and close follow-up yield the best outcomes for the mother and baby. How Is MRSA Diagnosed? Your health care provider will examine the area and be able to run lab tests to see if you have MRSA. If you have an infection on the skin, your doctor will take a culture from the infected area. Depending on your symptoms, your doctor also might test blood, urine, or sputum (mucus coughed up from the respiratory tract). What Are the Treatments for MRSA? MRSA is treatable. By definition, MRSA is resistant to some antibiotics. But other kinds of antibiotics still work. If you have a severe infection, or MRSA in the bloodstream, you will need intravenous antibiotics. Unfortunately, there is emerging antibiotic resistance being seen with some of these medications. Antibiotics, however, aren’t always necessary. If you have a small skin boil caused by MRSA, your doctor may just make an incision and drain it. If you are prescribed antibiotics, follow your health care provider’s instructions precisely. Never stop taking your medicine, even if you’re feeling better. If you don’t take all of your medicine, some of the staphbacteria may survive, requiring re-treatment. Inadequate treatment also increases the development of antibiotic resistance in the surviving staph population. If you still have staph you can infect someone else.
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