Differences in the in vitro potency of the penicillin-resistant penicillins are small, with modal minimum inhibitory concentrations MICs in the range of 0. Cephalospori ns: Cephalosporins show variable stability to staphylococcal beta-lactamase, depending on their chemical structure. Cephalothin is relatively resistant, while cefazolin is more sensitive to staphylococcal beta-lactamase degradation , Although this in vitro phenomenon has not been clearly demonstrated to be clinically significant, some prefer cephalothin for the treatment of life-threatening S.
Data from animal studies suggest that cephalosporins are probably less effective than the penicillinase-resistant penicillins for treatment of serious staphylococcal infections. Cefazolin and cephalothin were less effective than nafcillin in the rabbit model of endocarditis 49 , Compared with first-generation cephalosporins, the second-and third-generation cephalosporins in general have inferior in vitro activity against S. With the exception of cefamandole, cefuroxime, and possibly cefaclor, cephalosporins of later generations generally have lower activity against staphylococci and offer no advantages over first-generation cephalosporins when they need to be used in the management of staphylococcal infection.
However, almost all cephalosporins have sufficient activity to provide initial coverage pending the results of laboratory investigations.
Cephalosporins are not active against MRSA strains in vivo , despite the fact that some strains may appear susceptible in routine laboratory tests. Exceptions to this rule have been found in new cephalosporin molecules under development, such as ceftobiprole, LB and RWJ , , Thus, combination of these inhibitors with beta-lactamase-labile penicillins restores activity against penicillin-resistant, methicillin-susceptible staphylococci Table 2.
Like cephalosporins, they are not active against MRSA strains. Carbapenems : Imipenem and meropenem have a very broad spectrum of activity that includes S. Although some strains of MRSA appear susceptible to carbapenems in vitro , they are not susceptible in vivo 28 , Macrolides : In general, the macrolides show a fairly uniform activity against staphylococci 16 , 20 , Resistance to erythromycin is also prevalent worldwide in community-acquired MSSA strains.
The newer macrolides -- dirithromycin, roxithromycin, clarithromycin, and azithromycin -- have activity similar to that of erythromycin against staphylococci Table 2. Strains resistant to erythromycin are also resistant to these newer macrolides. A new class of agents that are derivatives of macrolides, the ketolides, are active against erythromycin-susceptible staphylococci, but not against resistant strains of S. Lin cosamides Clindamycin and Lincomycin : S.
Inducibly-resistant strains test as susceptible to lincosamides in vitro when tested alone, but as resistant when tested in the presence of erythromycin. Strains that are constitutively resistant test as resistant to lincosamides The clinical significance of inducible resistance in unknown, as formal prospective studies have not been conducted to determine whether inducibly-resistant strains respond to treatment with lincosamides.
Recent in vitro evidence shows that they have a higher rate of mutation to lincosamide resistance than erythromycin-susceptible strains , There is anecdotal evidence that they respond clinically, but that selection of resistance during treatment and relapse are common , , , , , A consensus is emerging that infections caused by strains with inducible resistance should not be treated with clindamycin unless the infection is minor In a rabbit model of endocarditis, clindamycin is associated with a relatively slow rate of eradication of organisms from the infected vegetation, and relapse was more likely in rabbits given clindamycin than in those treated with penicillin or vancomycin Fluoroquinolones : Fluoroquinolones are DNA gyrase inhibitors that are active in vitro and in vivo against S.
In terms of gram-positive activity, and activity against staphylococci, the older quinolones such as ciprofloxacin, ofloxacin and levofloxacin are less potent than the new generation agents such as trovafloxacin, moxifloxacin, gatifloxacin and garenoxacin.
The MICs of ciprofloxacin are typically between 0. Most strains of MORSA are now resistant to fluoroquinolones 92 , , , including the new generation. Both altered gyrase and energy-dependent efflux mechanisms account for the development of resistance to fluoroquinolones Newer quinolones such as levofloxacin and trovafloxacin have been shown in animal models to be as effective as vancomycin in the treatment of S. MICs range between 0. However, vancomycin is slowly and incompletely bactericidal against MSSA in vitro compared with nafcillin 23 , , Newer glycopeptides under development oritavancin , dalbavancin , telavancin show potential advantages over other glycopeptides , , They are rapidly bactericidal, and is active against VISA , other refs.
Oritavancin shows efficacy equivalent to vancomycin in the rabbit endocarditis model Teicoplanin not available in the United States is another glycopeptide with a spectrum of activity similar to that of vancomycin but which may be less active against some coagulase-negative staphylococci.
In animal models, teicoplanin has activity equivalent to that of vancomycin for treatment of experimental endocarditis caused by both MSSA and MRSA 9 , Mariani-Kurkdjian P. Monitoring seru m vancomycin concentrations in the treatment of Staphylococcus infections in children. Arch Pediatr. Stryjewski ME et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms.
Clin Infect Dis. Tetracyclines : Resistance to tetracyclines is common in community-acquired strains of S. Some tetracycline-resistant strains appear susceptible to minocycline and doxycycline. In vitro susceptibility of S.
There is recently evidence of efficacy against tetracycline-susceptible MRSA. Minocycline and vancomycin are equally effective in reducing bacterial density in infected vegetations in a rabbit model of MRSA endocarditis Glycylcyclines : Glycylcyclines are chemical modifications of tetracyclines The only agent in this class so far to have reached and advanced stage of development is tigecycline.
Like tetracycline, tigecycline has quite a broad spectrum, and has the advantage of having activity against almost all tetracycline-resistant strains. Its potential as an important antistaphylococcal agent has not been explored, but phase III studies in an array of infections, including complicated skin and skin structure infection , have shown efficacy when S.
Mupirocin : Mupirocin is used as a topical agent for the treatment of superficial skin infections and S. Some nasal and non-nasal S. Fusidic Acid : Fusidic acid available in Europe and some Western Pacific countries is the only marketed antibiotic in a class of agents that has a unique mechanism of action and a distinct Gram-positive spectrum excluding streptococci.
Fusidic acid-resistant mutants are harbored at relatively high frequencies. However, the rates of resistance have remained low in almost all regions where fusidic acid is regularly used Fosfomycin : Fosfomycin is an epoxide antibiotic that has a different structure and mode of action from other antimicrobials.
Rifampin : Rifampin rifampicin is highly active against staphylococci, with an MIC 50 for about 0. Resistant mutants can be easily selected in vitro and are thought to be naturally present in susceptible populations at frequencies of 10 -6 to 10 -7 , Because of this resistance, rifampin is almost always used in combination with other anti-staphylococcal drugs when treating established infection.
Streptogramins : Streptogramins are antibiotics that are a combination of two types: streptogramins A and B. Streptogramins B share the same site of action as macrolides and lincosamides, while streptogramins A act at a separate site on the ribosome that enhances the effect of the streptogramins A The original agent in the class, pristinamycin, has been available as an oral medication in France for many years.
More recently, a semisynthetic injectable streptogramin combination, quinupristin-dalfopristin, has been developed particularly aimed at the treatment of multi-resistant Gram-positive infections. The advantage of these agents is that activity is usually retained against staphylococci and other gram-positives that are resistant to macrolides and lincosamides 36 , , and thus all forms of MRSA.
Resistance to quinupristin-dalfopristin is currently very rare , Oxazolidinones : Oxazolidinones are synthetic agents, the original members of which were MAO inhibitors One, linezolid, is now available in some countries for the treatment of resistant staphylococcal infection These drugs have a novel mechanism of action on ribosomal protein synthesis, and are active against strains resistant to other classes of antibiotics Linezolid can be given orally as well as parenterally.
Daptomycin : Daptomycin is the first of a novel class of cyclic lipopeptides. Originally developed by Eli Lilly, its development was dropped, and was later taken up and completed by Cubist. Its unique mechanism of action involves calcium-dependent binding to the cell membrane, membrane depolarization, cessation of protein and DNA synthesis, potassium leakage and cell death.
It is active against all types of S. Addition of gentamicin to nafcillin produces an enhanced bactericidal effect in vitro , If synergism is defined as a decrease in colony counts of at least fold at 24 h with the combination compared with that of the most active single drug, vancomycin-gentamicin synergism is not predictable for strains of MRSA with gentamicin MICs of 0.
The in vitro effect of rifampin in combination with semisynthetic penicillins, vancomycin, and aminoglycosides is highly variable , , , Rifampin reduces the extracellular bactericidal activity of dicloxacillin but not fusidic acid, but neither of the latter agents reduce the intracellular killing effect of rifampin against S.
Resistance in vitro does not appear to emerge if MRSA are exposed to a combination of fusidic acid and rifampin , and sub-MIC concentrations of trimethoprim also appear to be able to prevent selection of rifampin resistant-mutants Similarly, rifampin can suppress the emergence of ciprofloxacin resistance in an in vitro pharmacodynamic model Combinations of older agents to overcome resistance is a possibility only now being explored.
An in vitro pharmacodynamic model has shown that combinations of cefepime with a wide range of other agents such as aminoglycosides, and the more recent agents linezolid, daptomycin and tigecycline Narita M.
In Vitro and animal studies of antibiotic synergy for newer antistaphylococcal agents for Staphylococcus aureus. In Vivo Animal Studies. Adding gentamicin to nafcillin accelerates killing of MSSA within experimentally induced cardiac vegetations in animal models The addition of MiKasome, a new liposome-encapsulated formulation of conventional amikacin, enhances the in vivo bactericidal effects of oxacillin in S.
Some animal models favor the use of rifampin , In animal studies, rifampin has been shown to play a unique role in the complete sterilization of foreign bodies infected by S. Addition of rifampin to combination antibiotic regimens has proven highly effective in an animal model of MRSA osteomyelitis In animal models, use of quinolone combinations with rifampin may prevent resistance to both drugs , Several studies have evaluated the effectiveness of quinupristin-dalfopristin combined with other antimicrobial agents.
In animal models of S. The combination of quinupristin-dalfopristin and rifampin is highly synergistic in experimental S. Drug of Choice Guided Medline Search. Treatment of staphylococcal infections depends on the site and severity of infection, the antibiotic susceptibility pattern of the organism and the presence of any patient allergy or drug intolerance.
Penicillin-Susceptible S. Penicillin-susceptible S. Phenoxymethylpenicillin penicillin V and amoxycillin can both be used as oral agents for penicillin-sensitive S. Methicillin-Susceptible S. These agents have gained wide acceptance because they are bactericidal and, like other penicillins, have a low incidence of adverse reactions. A variety of penicillinase-resistant penicillins are available, including the isoxazoyl penicillins cloxacillin , dicloxacillin , flucloxacillin, and oxacillin for both oral and parenteral use and methicillin and nafcillin for parenteral use.
There are no apparent differences in efficacy between these agents, and they have similar pharmacokinetic profiles. Continuous infusions of these agents are being used increasing in serious staphylococcal infection, especially as outpatient therapy, with satisfactory outcomes In most countries, methicillin has been superseded by the other agents in this group because of its association with a higher incidence of adverse reactions, especially hypersensitivity and interstitial nephritis.
A serious reaction to flucloxacillin, characterized by prolonged hepatic cholestasis, has been described with some frequency and has been associated with both parenteral and oral therapy , Cephalosporins, particularly those of the first generation, have proven useful alternatives to penicillinase-resistant penicillins, since they are relatively stable to staphylococcal beta-lactamase.
They are most commonly used in patients with a history of allergy or intolerance to penicillins. However, it is considered imprudent to administer them to patients with a history of accelerated reactions e. Patients with this type of history should not be given beta-lactams of any class, and other antistaphylococcal agents such as clindamycin or vancomycin should be used.
Cephaloridine, the cephalosporin with the greatest potency in vitro against staphylococci, has been abandoned due to the risk of nephrotoxicity and relative instability to staphylococcal beta-lactamases.
Suitable first-generation cephalosporins for staphylococcal infections include cephalothin, cefazolin , cefapirin and cephradine for parenteral use and cephalexin , cefapirin and cephradine for oral use. These combinations have no in vitro or in vivo superiority over penicillinase-resistant penicillins, but they do have the advantage of possessing a broad spectrum of activity against Gram-negative bacteria, including anaerobes.
Therefore, they should not be used as substitutes for penicillinase-resistant penicillins when staphylococci are the sole pathogens. However, their broader spectrum gives them a significant advantage when staphylococci are involved in mixed infections with enteric Gram-negative organisms and anaerobes.
Imip enem and meropenem provide adequate staphylococcal coverage in mixed infections but, again, have no role in the specific treatment of pure staphylococcal infection.
Erythromycin has been used extensively for treatment of both minor and serious staphylococcal infections. It is bacteriostatic against staphylococci and, for this reason, has generally lost favor for the management of serious and life-threatening infection, being largely supplanted by penicillinase-resistant penicillins. Moreover, the role of erythromycin in empirical treatment is further limited because of drug resistance.
Nevertheless, oral erythromycin is still suitable for minor skin infections caused by S. For erythromycin-susceptible strains, other macrolides are likely to be equally effective. The ne wer macrolides, roxithromycin , clarithromycin , dirithromycin, and azithromycin , have activity similar to that of erythromycin against staphylococci.
In general, strains resistant to erythromycin are also resistant to these newer macrolides. The latter two agents have very high tissue penetration, which may be of advantage in some sequestrated staphylococcal infections. Although there is good experience with the newer macrolides for staphylococcal skin infections, there is little experience with these drugs in the treatment of osteomyelitis. These drugs are not currently recommended for the treatment of bacteremia or endocarditis.
Like erythromycin, lincosamides clindamycin and lincomycin have been available for many years and have been used frequently for treatment of staphylococcal infections. They are also bacteriostatic and have been mostly relegated to reserve agents. However, the lincosamides are perhaps more useful second-line agents than macrolides, and are gaining acceptance as first-line agents for the treatment of caMRSA Clindamycin is better absorbed than lincomycin when administered orally and is the preferred agent for oral use.
It demonstrates good penetration into tissues, notably bone, and oral clindamycin in particular is less likely than erythromycin to cause gastrointestinal upset at high doses. This makes clindamycin potentially useful in patients with a history of accelerated reactions to penicillins, when cephalosporins are contraindicated. Fluoroquinolones have been used but never strongly advocated for the treatment of S. They do provide some coverage when S.
It is likely that the new generation fluoroquinolones will supersede ciprofloxacin , and lev ofloxacin in this setting due to their greater intrinsic activity.
Vancomycin and teicoplanin may occasionally be considered for treatment of life-threatening staphylococcal infection in patients with a history of accelerated allergic reactions to beta-lactams. It is not clear whether they are superior to macrolides or lincosamides in this setting, but they are usually preferred because of greater experience gained in the management of life-threatening MRSA infections.
However, there is growing concern about their efficacy compared to beta-lactams. Caveats for their use are given below. The new classes of drugs, the streptogramins, oxazolidinones and lipopeptides, should be reserved for MRSA infections. Antimicrob Agents Chemother ; Methic illin-Resistant S.
Vancomycin is the drug of choice for serious infections caused by S. Vancomycin treatment of deep-seated staphylococcal infections such as endocarditis has been reported to clear bacteremia more slowly than beta-lactam treatment Bacteremia is often prolonged more than 6 days in patients receiving vancomycin therapy , , , In contrast, almost all the blood cultures of the patients receiving nafcillin or other beta-lactams become sterile within 6 days 56 , , Higher rates of relapse, complications, treatment failure and mortality in S.
The slower bactericidal rate than beta-lactams has been suggested as a possible reason for the higher failure rate seen with vancomycin therapy in patients with MSSA endocarditis However, it is possible that tolerance to vancomycin in some strains may also play a part , Slower eradication by vancomycin was considered an important factor in the delayed clinical response in a recent study of intensive care patients with S. It is possible that high doses may result in better efficacy.
In an effort to reduce costs and selective pressure for resistance, once daily dosing of vancomycin has been tried. However, early experience suggests that the risk of failure is high in patients with normal renal function , , , Antimicrob Agents Chemother.
Lodise TP, Lomaestro B, et al. Antimicrob Agents Chemother Jan 28 [Epub ahead of print]. Soriano A, Marco F, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia.
Clin Infect Dis ;46 2 Hall RG 2nd, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. Lee DH et al. For pati ents with bacteremia, it is not mandatory to have chosen effective antibiotic therapy prior to blood cultures results This is particularly important in settings where MRSA is prevalent. Thus, when S. However, when MRSA is documented, failure to switch to an effective antimicrobial is associated with increased morbidity and mortality For teicoplanin to be efficacious in the treatment of S.
Long-term teicoplanin therapy can rarely result in emergence of strains resistant to teicoplanin; however, these strains remain susceptible to vancomycin The use of alternatives to vancomycin and teicoplanin might be considered for serious infections caused by caMRSA. Clindamycin is possibly the best choice if the organism is erythromycin susceptible. For strains with inducible clindamycin resistance, the weight of evidence suggests that there is a significant risk of failure or relapse, and clindamycin should not be used unless the infection is minor There are a number of alternatives for oral therapy for less serious infection or step-down therapy.
In general, combination oral therapy with two active agents is recommended for haMRSA. Most experience has been gained with rifampin , fluoroquinolones, and in countries where it is available fusidic acid. Chloramphenicol was used in the past but has fallen into disfavour. Linezolid is a suitable alternative as a single agent and has proven effective in the short and long term management of bone and joint including prosthetic infections 18 , , Pristinamycin has found a role in MRSA infections when patients are intolerant of other drugs Ther e has been a resurgence of interest in the role of trimethoprim-sulfamethoxazole for MRSA infections, given that the great majority of caMRSA are susceptible.
A recent review of clinical studies suggested that while evidence of efficacy is still largely anecdotal, that in general this combination agent is effective The optimum treatment for vancomycin intermediate S. In Japan, most experience has been gained with the combinations of agents such as ampicillin-sulbactam and arbekacin, an aminoglycoside approved specifically for MRSA treatment in Japan Current options include quinupristin-dalfopristin and linezolid. There is some animal model experience to support the use of ampicillin-sulbactam 14 and combinations of vancomycin and nafcillin Other agents used over the years for the treatment of serious MRSA infections might also be considered, depending on their availability, such as fosfomycin Some promise is being shown with lysostaphin, a peptidase produced by Staphylococcus similans , in experimental endocarditis models 82 , Considera tions in the Choice of Regimen: The traditional approach to serious and deep staphylococcal infections has been to use high dose therapy intravenously for a number of weeks.
With the exception of line sepsis with a removable focus and no evidence of metastatic seeding, where 10 to 14 days therapy is considered adequate, the general approach to deep infections has been to administer treatment for 4 to 6 weeks. In the past, this treatment has been administered intravenously and in hospital, but now many infections are managed by i completing the intravenous course as an outpatient OPAT , , or ii by a switch to high dose oral therapy after an adequate intravenous course, such has been practiced for osteomyelitis in children for many years , Use of or combinations such as fluoroquinolones with rifampin have also been shown to be effective when introduced early in management , Outpat ient intravenous therapy is now a reasonable alternative in most situations where prolonged intravenous administration is felt to be optimum For OPAT generally, drugs with prolonged half-lives such as ceftriaxone or teicoplanin are preferred as the number of administration visits is minimized.
However, although ceftriaxone is thought to have only marginal activity against S. The short half-lives of the antistaphylococcal penicillins have made standard scheduling of these drugs impractical for outpatient use. Instead, continuous infusion is recommended for these agents and early experience with cloxacillin flucloxacillin and oxacillin is very favourable.
In many clinical circumstances it is probable that switch to high-dose oral therapy for completion of the course is adequate. Important exceptions are meningitis and endocarditis, where the high levels achieved by maximum IV doses are necessary to ensure adequate delivery of antibiotic.
Apart from the published experience in pediatric osteomyelitis , and orthopedic implant infections , , , there are limited published data. Nevertheless, there is considerable experience with this approach, and hence Table 3 provides some suggestions for oral regimens following initial intravenous treatment. Suggested antibiotics, doses, and duration for treatment of S.
Some special situations are discussed below. M ost causes of cellulitis are caused by streptococci and S. Parenteral cefazolin 1. Oral antibiotics for established MSSA infections include clindamycin , dicloxacillin , doxycycline , trimethoprim-sulfamethoxazole. If MRSA is the suspected cause nosocomial infection or infection with community acquired MRSA in areas of prevalence of such strains and in penicillin-allergic individuals, vancomycin 1.
For invasive cellulitis unresponsive to standard therapy, combination agents including rifampin and gentamicin low dose are often added, although clinical data supporting these additions are based on anecdotes. Rajendran PM, Young D, et al. A switch to oral therapy e. First generation oral cephalosporins cephradine, cephalexin, or cefadroxil are common alternatives.
Linezolid gm. If MRSA is suspected, tigecycline might be an ideal choice. Bro adening the spectrum of initial antimicrobial therapy for additional bacterial species may be indicated in specific clinical settings.
In the setting of cellulitis after an abrasion or laceration occurring with salt water exposure, where Vibrio vulnificus might be the pathogen, treatment with doxycycline mg intravenously per day in two divided doses might be preferred.
Doxycycline also covers MSSA. In the setting of cellulitis after an abrasion or laceration occurring with fresh water exposure, where Aeromonas hydrophila might be involved, treatment with ciprofloxacin mg intravenously every 12 hours might be preferred. Quinolones also cover MSSA, but are not the antibiotics of choice. A combination of ceftazidime plus gentamicin may be added to antistaphylococcal antibiotics for invasive infection in immunosuppressed patients.
Awa d SS, et al. Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy. Am J Surg ; 5 Proctor RA. Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureus infection. Pallin DJ , et al. Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus.
Ann Emerg Med. Epub Jan R ecurrent or Persistent Staphylococcus aureus Skin and Soft Tissue Infection: A number of approaches have been devised although none of these have yet been validated in controlled trials. Sustained and regular application bathing with a disinfectant.
Add 1 cup of household bleach per bathtub or 20 gallons. Soak for no longer than 20 minutes twice a week for 3 months. No data exists for the comparative superiority or the ease of use for any of. Nasal mupirocin b. Reculture anterior nares at 6 months a. Keep nails clipped and short. Avoid scratching of pruritic areas. Wear light clothing to minimize perspiration. Use antibacterial soap for hand washing. Aerate intertriginous areas. Eradicate nasal carriage with Mupirocin in spouses. Administration of oral antimicrobial agents is discouraged for long-term use because of risk for emergence of S.
For severe cases, an initial day course of minocycline or trimethoprim-sulfamethoxazole TMP-SMZ might be given if the cutaneous infection has been persistent; addition of rifampin for combination therapy is also an option. Most skin infections will heal within a few weeks. More serious skin infections can take longer to heal if treatment is delayed or if ineffective treatment is given.
Some serious S. Transmission S. The skin and mucous membranes are usually an effective barrier against infection.
However, if these barriers are breached e. Persons who are immunocompromised or who have invasive medical devices are particularly vulnerable to infection.
Staph bacteria are very adaptable, and many varieties have become resistant to one or more antibiotics. The rise of antibiotic-resistant strains of staph bacteria—often described as methicillin-resistant S. To prevent staph infections, practice proper hand hygiene, keep infected areas covered and clean, and avoid sharing personal items like razors, towels, and needles. What's this?
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