Treatment Of Staphylococcal Infections Research Articles

Antimicrobial Agents in Orthopaedic Surgery

The pathogenesis of implant-associated infection involves interaction between the microorganisms (biofilm formation), the implant and the host. Despite improvement of perioperative prophylaxis, orthopaedic implants still remain highly susceptible to bacterial or fungal contamination, generally resulting in persistent implant-associated infection. Therefore, perioperative and life-long prevention of infection is important. For perioperative prophylaxis, a first- or second-generation cephalosporin is recommended, which should be administered between 60 and 30 minutes before incision. The duration of prophylaxis should not exceed 1 day. In centres with a low incidence of infection, a single dose is sufficient. Treatment of infections associated with orthopaedic devices usually requires appropriate surgical intervention combined with prolonged antimicrobial therapy. The choice of the antimicrobial regimen depends on the duration and pathogenesis of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the surrounding soft tissue. The role of rifampicin (rifampin), which has excellent activity on adherent staphylococci, in combination with beta-lactams, glycopeptides, fluoroquinolones, minocycline, cotrimoxazole or fusidic acid, in the treatment of staphylococcal infections is outlined. Increasing antimicrobial resistance requires the use of alternative agents, such as quinupristin/dalfopristin, linezolid and daptomycin, but results of clinical trials with these agents are limited. Also reviewed are potential new antimicrobial agents currently undergoing investigation, such as the novel oxazolidinone RWJ-416457, the new glycopeptide dalbavancin, the glycylcycline compound tigecycline, the new carbacephem BP-102 and novel rifamycin derivatives. Vaccination against Staphylococcus aureus with StaphVAX induced specific antibodies potentially preventing bacteraemia; however, there are no studies on efficacy in the prophylaxis of device-associated infections with this vaccine.

Antibiotic resistance in Staphylococcus aureus and its relevance in therapy

Staphylococcus aureus is a major cause of infections. Only ∼ 20% of the strains remain sensitive to penicillin. β-lactamase stable penicillins such as flucloxacillin form the mainstay of treatment of staphylococcal infection. Meticillin-resistant S. aureus (MRSA) are resistant to all β-lactam antibiotics. Glycopeptide antibiotics are effective against most MRSA strains but, in the last few years, isolates of MRSA that have reduced susceptibility to glycopeptides (glycopeptide-intermediate S. aureus) have been isolated. Some strains exhibit frank resistance to glycopeptides (vancomycin-resistant S. aureus). Infections due to these strains are difficult to treat. This review summarises the therapeutic options for MRSA, glycopeptide-intermediate S. aureus and vancomycin-resistant S. aureus. Novel therapeutic strategies such as immunotherapy and vaccines are also discussed.

Immunochemical detection of flucloxacillin adduct formation in livers of treated rats

Flucloxacillin is a semi-synthetic penicillin widely used in the prophylaxis and treatment of staphylococcal infections. Severe liver reactions, characterised by delayed cholestatic hepatitis and a prolonged course of recovery, are associated with flucloxacillin therapy. Clinical findings are suggestive of an immune mediated reaction but there exists little supporting experimental evidence. The formation of drug modified hepatic protein adducts has been proposed to play an important role in the hepatotoxicity of many drugs. The aim of the present study was to investigate whether flucloxacillin treatment results in adduct formation in vivo. Flucloxacillin was conjugated to rabbit serum albumin by formation of a penicilloyl determinant and used as an immunogen to raise a polyclonal antiserum specific for flucloxacillin-modified proteins. Antibody specificity was confirmed by competitive enzyme-linked immunosorbent assay (ELISA) with free drug. The antiserum was used in combination with western blotting to detect adduct formation in the livers of flucloxacillin treated rats. Western blot analysis of rat liver subcellular fractions revealed the formation of six flucloxacillin adducts in various subcellular fractions. These studies demonstrate for the first time that treatment with flucloxacillin results in the formation of hepatic protein adducts.

Antistaphylococcal activity of the novel cephalosporin CB-181963 (CAB-175)

We examined the antistaphylococcal activity of the novel cephalosporin CB-181963 (formerly known as CAB-175), with emphasis on its microbiological activity and penicillin-binding protein specificities. Using established procedures, we examined the activity of CB-181963 against methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains of Staphylococcus aureus in both planktonic and biofilm culture. We also determined whether CB-181963 exhibited a post-antibiotic effect (PAE). A radioactive competition assay with (3)H-labelled benzylpenicillin was used to determine penicillin-binding protein (PBP) affinities of CB-181963, including binding to PBP2a from MRSA. The potential for emergence of CB-181963-resistant mutants in MSSA and MRSA strains was examined using plating procedures. CB-181963 showed excellent activity against MRSA strains resistant to other cephalosporins in both planktonic and biofilm cultures. However, in common with other cephalosporins it was unable to eradicate biofilms. CB-181963 had a short PAE compared with other beta-lactam antibiotics. CB-181963 retained activity against a strain expressing type A beta-lactamase and demonstrated affinity for PBP2a of MRSA. Mutants resistant to CB-181963 were not recovered in either MSSA or MRSA. CB-181963 is a potent antistaphylococcal agent with better activity against MRSA than other cephalosporins. The anti-MRSA activity is correlated with elevated binding to PBP2a. CB-181963 may have a role in the treatment of staphylococcal infections, including those caused by MRSA and in the prophylaxis of biofilm-associated MSSA and MRSA infections. However, because of its short PAE, CB-181963 may have to be administered more frequently than other beta-lactam antibiotics, or given via prolonged infusion.

Newer antistaphylococcal agents

As antibiotic resistance in staphylococci continues to evolve, the ability to treat infections in children with confidence using first-generation cephalosporins, penicillins, and macrolides is decreasing. Knowledge of the local trends in resistance is important in making decisions of empiric antibiotic therapy. The antibiotic resistance pattern for the child's pathogen should be assessed whenever possible, to allow the practitioner to properly judge the risks and benefits of alternative antibiotic agents, should they be required for definitive therapy. Options for therapy of most methicillin-resistant and macrolide-resistant community-acquired strains of Staphylococcus aureus include vancomycin, linezolid, and, in communities with a high proportion of susceptible strains, clindamycin. Daptomycin, a lipopeptide antibiotic with activity against virtually all strains of S. aureus, was recently approved by the United States Food and Drug Administration for adults. Second-generation glycopeptide antibiotics similar to vancomycin are in clinical trials in adults, including dalbavancin and oritavancin. Several new compounds, including cephalosporins active against methicillin-resistant S. aureus, are in preclinical development as well. The recent worldwide emergence and rapid spread of community-acquired methicillin-resistant S. aureus has prompted a change in the approach to therapy of staphylococcal infections in both the outpatient clinic and the hospital. Newer agents active against methicillin-resistant S. aureus such as linezolid have been recently approved for children and other agents recently approved for adults are under investigation in children. Older agents for which relatively few data from prospective, controlled, comparative studies exist in the treatment of staphylococcal infections may also offer effective and less costly options for therapy.

Antibiotic Resistance Patterns ofmecA-PositiveStaphylococcus aureusIsolates from Clinical Specimens and Nasal Carriage

The present study demonstrates that the nasal carriage rate of Staphylococcus aureus was 40% in Jordanian healthy young adult population, and 19% of nasal S. aureus and 57% of clinical isolates over the same period were resistant to oxacillin (MRSA), respectively. The mecA gene was detected in all MRSA isolates in both groups. Most of MRSA isolates were multiresistant to three antibiotic classes (beta-lactams, aminoglycosides, macrolides-lincosamides). This result suggests a serious problem may be encountered in treatment of staphylococcal infections in Jordan.

Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: genomic island SCC.

Staphylococci are ubiquitous colonizers of the skin and mucous membranes and Staphylococcus aureus is the most pathogenic species. The spread of antibiotic resistance among S. aureus strains is a major concern in the treatment of staphylococcal infections. Acquisition of resistance may involve mutation of a bacterial gene on the chromosome or transfer of a resistance gene from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Completion of whole genome sequences of three methicillin-resistant S. aureus (MRSA) strains has provided us a bird's-eye view of the distribution of the mobile genetic elements in the bacterial chromosome that encode antibiotic resistance as well as pathogenicity in S. aureus.

Demonstration of in vitro antagonism between fusidic acid and quinolones.

Fusidic acid is an antibiotic active against staphylococci and other bacterial pathogens. It is used in the treatment of staphylococcal infections usually in combination with other antibacterial agents. Reports of the clinical effects of antimicrobial combinations containing fusidic acid have been somewhat inconsistent. The aim of this study was to investigate the in vitro antagonism of fusidic acid and quinolones. Twenty-six staphylococci strains isolated from various clinical samples were tested. After detecting the diameter of the zone of inhibition around fusidic acid, levofloxacin, ciprofloxacin, ofloxacin and moxifloxacin for each strain, in vitro antagonism between fusidic acid and each quinolone was investigated using disk approximation. In all 26 strains, quinolones and fusidic acid were antagonist in vitro. The reason for this antagonistic effect and its clinical implications are not known. However, care should be exercised in prescribing quinolones and fusidic acid in combination.

Principes thérapeutiques des infections à staphylocoques Place et limites des molécules classiques

Antibiotic therapy plays an important (but not exclusive) role in the treatment of staphylococcal infections. Measures aimed at reducing the bacterial inoculum through local procedures must be envisaged as often as possible. The removal of any foreign, infected materials is essential to success. In this article, we review the different, active antibiotics available, their advantages and disadvantages and their indications. In the light of these data, we propose a therapeutic approach to severe bacterial infection caused by a cluster of Gram-positive cocci. Staphylococcal infections pose daily therapeutic problems, whether in open-care practice or intensive care units. The specificity of staphylococcal infections encountered in an intensive care setting require a therapeutic approach which takes account of the context, and particularly of the incidence of resistant staphylococcal infections.

ANTISTAPHYLOCOCCAL (MSSA, MRSA, MSSE, MRSE) ANTIBIOTICS

S. aureus and coagulase-negative staphylococci such as S. epidermidis are important causes of infection of the bloodstream, cardiac valves, implanted devices, and skin, with repercussions on mortality and increased economic costs. Treatment of staphylococcal infections is made difficult by the increasing emergence of resistance to beta-lactams and other antimicrobials, including reduced susceptibility to glycopeptides. Penicillin must be used for infrequent penicillin-susceptible isolates, oxacillin and nafcillin are to be considered the major option for penicillin-resistant staphylococci, and glycopeptides are the drugs of choice for infections caused by methicillin-resistant strains. Co-trimoxazole, lincosamides, macrolides, tetracyclines, and fluoroquinolones are alternative agents, primarily in subjects allergic to beta-lactams. Newly introduced or experimental drugs, such as streptogramins (quinupristin-dalfopristin), oxazolidinones (linezolid), carbapenems (LY 333328), everninomicins (SCH 27899), and derivatives of tetracyclines (glycylcyclines), could be useful for therapy of infections caused by multiresistant staphylococci.

Effect of Varidase (Streptokinase) on Biofilm Formed by Staphylococcus aureus

Staphylococcus aureus forms a fibrin-rich biofilm in the presence of plasma which is highly resistant to attack by the human immune system and to chemotherapy. Varidase, composed mainly of streptokinase, is used for hydrolyzing clots. In this study, we attempted to destroy the biofilm of S. aureus with Varidase and to apply this drug in the treatment of staphylococcal infections. Four clinical isolates were used in the experiments. These organisms formed a several-millimeter-thick biofilm on type IV collagen coated coverslips in trypticase soy broth containing 50% human plasma. The biofilm was composed of bacterial cell which adhered to fibrillar fibers and of sediment derived from plasma. 10,000 U/ml of Varidase, the dose which is used clinically, removed the sediment and reduced the number of live bacteria in biofilms to less than 20% of control. 200 U/ml of Varidase was also effective against biofilms of the organisms. An equal combination of Varidase and ofloxacin had an additive effect on the bacteria. The results of this study demonstrate that Varidase is highly effective in destroying biofilms of S. aureus in vitro and suggest that this drug would be useful for treating staphylococcal infections.

Identification, characterization and purification of the lantibiotic staphylococcin T, a natural gallidermin variant.

Staphylococcin T (StT), an antibacterial agent produced by a Staphylococcus cohnii T strain, was purified to homogeneity by ammonium sulphate precipitation, gel filtration, cation exchange and fast performance liquid chromatography (FPLC). The final yield was about 20%, and over a 1000-fold increase in the specific activity was obtained. Mass determination (2166 Da), amino acid sequencing (Ile-Ala-Xaa-Lys-Phe-Leu-Xaa-Xaa-Pro-Gly-Xaa-Ala-Lys-block) and DNA sequencing demonstrated that StT is identical to gallidermin, a lanthionine-containing antimicrobial peptide. StT has a broad spectrum of bactericidal activity against Gram-positive and some Gram-negative bacteria. StT appears to damage cell membrane, and as a result causes an efflux of ions and an immediate block in macromolecular synthesis. Moreover, electron microscopic observations reveal morphological changes, with a loss of ribosomes and condensation of the nucleoid DNA. These changes are followed by a dissolution of the cell contents resulting in a bacterial ghost composed of seemingly intact cell walls with remnants of the cytoplasmic membrane and internal structure. Since StT exhibits antimicrobial activity especially against the Staphylococcus species, this compound may be of use in the treatment of staphylococcal infections.

Fusidin down-regulates the production of IL-6 in septic patients: a pilot study

Septic shock is characterized by pathophysiological derangements in the function of multiple organs. Many of the manifestations of shock have been related to high levels of circulating cytokines. Fusidic acid is an antiotic with a tetracyclic structure. Its chief clinical use is in the treatment of staphylococcal infections. It has been proposed, that the acid form as well as the sodium salt of the drug (Fusidin) possess antiinflammatory properties.

Activity of quinupristin/dalfopristin against gram-positive bacteria: clinical applications and therapeutic potential.

In recent years there has been a dramatic worldwide increase in the prevalence of multiple drug-resistant strains of common Gram-positive bacteria. This highlights the need for a new class of antibiotic with activity against these organisms. Quinupristin/dalfopristin, the first injectable streptogramin antibiotic, has a unique spectrum of activity, encompassing most Gram-positive cocci (including multi-drug-resistant strains), respiratory pathogens and anaerobes, Gram-positive, and a prolonged post-antibiotic effect. Quinupristin/ dalfopristin is active in vitro against multi-drug-resistant isolates of Staphylococcus aureus, coagulase-negative staphylococci, penicillin-resistant pneumococci and vancomycin-resistant Enterococcus faecium. Clinical case reports have shown that the combination is active against intra-abdominal, aortic graft, bacteraemia and hydrocephalus shunt infections caused by multi-drug-resistant enterococci, particularly E. faecium. In almost all of these clinical situations the enterococcal infection had displayed resistance to all other antimicrobial therapies. Preliminary clinical data have demonstrated the activity of quinupristin/ dalfopristin against S. aureus bacteraemia, and quinupristin/dalfopristin may also prove useful in the treatment of pneumococcal infections. Thus, possible future applications of the combination include the treatment of multi-drug-resistant strains of staphylococci, streptococci and enterococci. Quinupristin/dalfopristin may prove useful in the treatment of staphylococcal infections in children, invasive systemic pneumococcal infections, and nosocomial and community-acquired Gram-positive infections in patients unable to tolerate beta-lactam antimicrobial agents or glycopeptide antibiotics.

The treatment of staphylococcal infections with special reference to pharmacokinetic, pharmacodynamic and pharmacoeconomic considerations.

The choice of antibiotics for the treatment of staphylococcal infections depends to a high degree on the susceptibility patterns in the hospital in question. These may be highly variable and considerable differences between countries and hospitals exist. The insight into the pharmacodynamic aspects of antimicrobial agents has increased considerably in the last 5 years, resulting in new treatments, such as once daily administration of aminoglycosides and continuous infusion of betalactam antibiotics. The antibiotic policy in Dutch hospitals for the treatment of staphylococcal infections is discussed. In most Western countries with a relatively low incidence of MRSA, penicillin-derivatives, such as flucloxacillin (or cloxacillin, methicillin and nafcillin) will be the drug of choice, because of their good in-vitro activity, low toxicity, good clinical efficacy and relatively low cost. If the incidence of MRSA increases, drugs such as the glycopeptides will be of more importance. This will of course have a clear economic impact, as both vancomycin and teicoplanin are considerably more expensive than agents such as flucloxacillin and oral treatment is not possible. Pharmacoeconomic aspects also play a role. As a rule, intravenous antimicrobial agents are considerably more expensive than the oral formulations. Before oral administration can be recommended, a reliable oral absorption, also in seriously ill patients, must have been demonstrated. Other aspects that influence the cost of therapy are hospital stay and the possibility of outpatient treatment.

Fusidic acid and insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is a major cause of morbidity and mortality from long-standing complications. The autoimmune nature of IDDM has encouraged use of immunosuppressive and antiinflammatory strategies to better preserve residual pancreatic beta-cell function at the time of diagnosis. Fusidic acid and its sodium salt, fusidin, is a relatively atoxic antibiotic used mainly in the treatment of staphylococcal infections. Recently, fusidin has been demonstrated to possess immunosuppressive functions in vitro and in vivo, and the drug has shown promise in preventing the disease in animal models of IDDM and in a preliminary trial in IDDM patients.

Cefotaxime in the treatment of staphylococcal infections: Comparison of in vitro and in vivo studies

Staphylococcus aureus strains are well-established pathogens that may cause mild to serious life-threatening disease. Coagulase-negative staphylococci, particularly Staphylococcus epidermidis, also have a pathogenic role in humans and cause infections primarily associated with prosthetic devices and indwelling catheters, whereas Staphylococcus saprophyticus usually causes urinary tract infections. Cefotaxime is a “third-generation” cephalosporin that is stable to the staphylococcal β-lactamases. In vitro studies over the last 15 years have shown that this patenteral cephalosporin has remained highly active (MIC 90 ranges of ≤2–8 μg/ml) against oxacillin-susceptible staphylococci. Cefotaxime therapy of staphylococcal infections has resulted in clinical curelimprovement rates ranging from 78%–100% and bacteriologic eradication rates ranging from 85%–100% in a wide variety of infections. Contrary to contemporary dogma, this “third-generation” cephalosporin appears to be efficacious against staphylococcal infections from a review of 15 years of clinical experience.

Treatment of staphylococcal infections

Treatment of staphylococcal infections

Interaction between ciprofloxacin and vancomycin against staphylococci.

The interaction between ciprofloxacin and vancomycin against nine isolates of Staphylococcus epidermidis from cases of infective endocarditis and three strains of S. aureus was studied. Killing curves indicated the presence of antagonism in the early stages, the clinical significance of which is uncertain. No synergy was found and the combination therefore does not appear to offer any advantages over vancomycin alone for the treatment of staphylococcal infections.

Review of the new second-generation cephalosporins: cefonicid, ceforanide, and cefuroxime.

The new second-generation cephalosporins, cefonicid, ceforanide, and cefuroxime, have recently become available. These agents are generally less active against gram-positive cocci than first-generation cephalosporins and, at best, equal to cefoxitin and cefamandole against many gram-negative bacteria. Cefuroxime, however, is the most active cephalosporin for beta-lactamase-producing Haemophilus influenzae. These newer agents have superior pharmacokinetic characteristics over cefoxitin and cefamandole. Smaller doses, longer dosing intervals and, potentially, a reduction in total drug cost may be the real advantage of these agents. Open trials and a limited number of comparative studies have documented the effectiveness of cefonicid, ceforanide, and cefuroxime in the treatment of most mild-to-serious infectious diseases, although failures with cefonicid in the treatment of staphylococcal infections have been reported. Notably, cefuroxime has received approval for the treatment of common pediatric bacterial meningitis infections. Replacement of cefamandole or cefoxitin with one of these "longer-acting" agents may be cost-beneficial; however, clinicians must be on alert for the development of bacterial resistance or decreased efficacy.