Foreign body infections due to Staphylococcus epidermidis

Abstract

Staphylococcal infections are one of the main causes of complications in patients with implanted foreign prosthetic material. Implants are associated with a significant reduction of the threshold at which contaminating Gram-positive bacteria, particularly Staphylococcus epidermidis, become infectious and develop a biofilm with phenotypic resistance to almost all antibiotics. A 1000-fold increase in minimal bactericidal levels against most antibiotics except rifampin has been repeatedly observed. Since only removal of the foreign material reverses these phenomena, the clinical challenge consists in finding approaches to cure the infection without removal of the implanted device. Rifampin combinations with other antibiotics, administration of exceedingly high antibiotic concentrations in situ, and early therapy before biofilm development are efficacious. Although these strategies have dramatically improved the outcome of foreign body infections, an improved understanding of biofilm-grown S. epidermidis is necessary to develop new antibacterial agents. Here, we review the pathogenesis, prevention, and treatment of implant infections due to S. epidermidis and highlight some new compounds with already promising in vitro results.

• Biofilm
• catheter
• foreign body infection
• implant
• Staphylococcus epidermidis

Introduction

Implanted medical devices such as central venous catheters (CVC) or joint prostheses are among the most remarkable advances in medicine. The current shift in the demographics of developed countries towards an increasingly aged population has resulted also in the significantly increased use of this medical technology 1. In the USA, approximately 400,000 total hip and knee replacements are carried out annually at present 1, 2. Although the infection rate has been reduced to <1% for hip and <2% for knee orthopaedic implants 3, the overall number of patients with infected prostheses has increased due to the increasing number of replacements required 2. In the case of infected hip or knee prostheses, treatment costs are 5.3–7.2-fold higher than the initial operations 4. Similarly, 250,000–500,000 primary blood-stream infections result each year from the 150 million intravascular devices implanted in the USA 5. For CVC-related blood-stream infection, extra costs for each case range from US$4,000 (2560 euro) to US$56,000 (35,840 euro) 5. To the best of our knowledge, cost analysis for Europe as a whole or Asia are not available.

Biofilm-associated infection, often caused by coagulase-negative staphylococci (CoNS), in particular Staphylococcus epidermidis, is of increasing importance and related to the high use of implanted devices 6, 7. This review focuses on S. epidermidis infections of joint prostheses and CVC as the most frequent examples of implant-associated infections.

Methods

We conducted a search of the PubMed database to identify articles in English, French, and German published before 15 September 2007 using the following terms: ‘foreign body’, ‘biofilm’, ‘prosthesis’, ‘implant’, ‘catheter infection’, ‘antibiotic lock technique’, and paired in a second step with ‘Staphylococcus epidermidis’ or ‘coagulase-negative staphylococci’. Among 1738 different publications retrieved, only a minority focused on foreign body infections due to S. epidermidis in the aforementioned search languages and were considered as relevant. Bibliographies of these articles were also hand-searched for additional references. Finally, 165 articles have been consulted and retained for this review.

Key messages

• In biofilms, a 1000-fold increase in minimal bactericidal levels against most antibiotics except rifampin has been repeatedly observed.

• Rifampin combinations with other antibiotics are efficacious against implant-related infections due to S. epidermidis.

Abbreviations

Table

CVC	central venous catheters
CoNS	coagulase-negative staphylococci
MIC	minimal inhibitory concentration
MRSE	methicillin-resistant Staphylococcus epidermidis
PCR	polymerase chain reaction
MRSA	methicillin-resistant Staphylococcus aureus

Epidemiology

Joint replacement

Staphylococcus aureus and CoNS cause approximately two-thirds of joint replacement infections 1, 3. Infections associated with prosthetic joints can be classified as early (those that develop less than 3 months after surgery), subacute (3–24 months after surgery), or late (more than 24 months after surgery, predominantly acquired by haematogenous seeding). Early infections typically manifest as an acute onset of joint pain, effusion, erythema at the implant site, and fever, and are commonly caused by S. aureus. Patients with subacute infection usually present with subtle signs and symptoms such as implant loosening, persistent joint pain, or both, which may be difficult to distinguish from S. epidermidis 3. Of approximately 600 prosthetic joint infections treated over a 5-year period at the Mayo Clinic, Rochester, USA, 30% were due to S. epidermidis 8. Among 112 patients with prosthetic joint infections, CoNS were the most frequently isolated pathogens in Oxford, United Kingdom 9.

Central venous catheters

On average, microbiologically documented, device-related blood-stream infections occur in 4–5/1000 CVCs with approximately two episodes per 1000 CVC days 5. However, these rates are likely underestimated since many episodes of catheter-related sepsis can be culture-negative 10, 11. Data from the National Nosocomial Infections Surveillance System (NNIS) in the USA from 1990 to 1999 showed that CoNS are the most commonly isolated pathogens (37%) from blood-stream infections in intensive care unit patients 12. Other reports confirmed this predominance of CoNS in at least one-third of cases 13, 14, especially in neonates 15. Overall, S. epidermidis accounts for at least 60% of CVC infections with CoNS 10. Over the past two decades, the incidence of CoNS primary bacteraemia has increased 16, probably due to an improved awareness among clinicians, changes in blood culture techniques, and an increase in the numbers of blood cultures performed and the use of intravascular devices 17, 18. CVC-related blood-stream infections due to S. epidermidis can reveal a significant mortality, although higher rates are cited in older 19 rather than in recent publications 18. According to a meta-analysis published in 1998, mortality associated with primary CoNS bacteraemia varies between 5% and 28% 17.

Pathogenesis

S. epidermidis is a skin commensal 6, 7. Most surgical site infections are believed to be acquired at the time of surgery and are caused by endogenous flora 20, 21. Arguments to support this hypothesis are the efficacy of peroperative antibiotic prophylaxis, and laminar air-flow conditions in the operating room, together with the similarity of skin flora and pathogens. Studies have demonstrated a significant association between distal catheter tip colonization and CVC-related bacteraemia 10. Although bacterial colonization may be present at an early stage of infection, it does not necessarily indicate infection. The ultimate proof of implant-associated infection requires the presence of clinical manifestations, infection signs adjacent to the implant, and the growth of S. epidermidis in several microbiological samples 1.

Staphylococcus epidermidis

S. epidermidis frequently shows multiresistance to many antibiotics 22 acquired through common mechanisms such as efflux pumps, modifying enzymes, target mutations 23, and staphylococcal cassette chromosome mec (SCCmec) islands conferring the genomic mec element for methicillin resistance 24. According to the 1999 NNIS report, 80% of CoNS had become resistant to methicillin during the previous decade. Resistance to gentamicin has risen to 60%–70%, whereas resistance to rifampin has remained at 10% 12. In 1996, the first episode of blood-stream infection in the USA caused by a vancomycin-intermediate S. epidermidis isolate (minimal inhibitory concentration (MIC) 8–6 µg/mL) was reported in the USA 25. Methicillin-resistant S. epidermidis (MRSE) is now the most commonly encountered variant of S. epidermidis in many health care institutions 12, 26, 27. As an example, Table I shows the resistance pattern of S. epidermidis at the University of Geneva Hospitals in 2006. Due to the emergence of resistant S. epidermidis isolates through the high use of beta-lactam antibiotics, physicians are obliged to rely on an armamentarium which is increasingly restricted to glycopeptides.

Table I.  Antibiotic resistance among all Staphylococcus epidermidis isolates at the University of Geneva Hospitals, January–December 2006.

Antibiotic class	Antibiotic	Proportion of resistant isolates
Beta-lactam	penicillin	95%
	methicillin	70%
	cephalosporins	70%
Aminoglycosides	amikacin	51%
	gentamicin	44%
Quinolones	ciprofloxacin	61%
Lincosamides	clindamycin	47%
	erythromycin	65%
Others	cotrimoxazole	58%
	rifampicin	14%
	linezolid	0%
Glycopeptides	teicoplanin	1%
	vancomycin	0%

Microbiological procedures: The tissue specimens and swabs were inoculated on home-made blood and chocolate agar culture media, Center for Disease Control and Prevention (CDC) anaerobic agar, and Brain Heart Infusion liquid. Coagulase-negative staphylococci were identified as catalase-positive, slidex agglutination-negative (Pastorex®, BIO-RAD) and DNAse-negative (home-made). They were further characterized to the species level by the ID32 Staphylococcus Gallery (bioMérieux, Marcy L'Etoile, France) and/or the Vitek ID system. Susceptibility testing was performed according to CLSI guidelines 95.

Apart from antibiotic resistance, a polyclonal expansion of joint 28, prosthetic valve 29, or CVC-related bacteraemia with S. epidermidis 30, has potential implications for the choice of antibiotic regimens. This polyclonality could be one of the explanations for the clinical failure of treatment for foreign body infections or bacteraemias as laboratories do not always perform antibiotic susceptibility testing for all isolates. Thus, a S. epidermidis isolate may be present, but not covered by the antibiotic due to the absence of antibiogram data 30. In addition, small-colony variants of S. epidermidis, a phenomenon well known in S. aureus 31, can emerge during glycopeptide therapy 32. Small colony variants constitute a subpopulation of bacteria and exhibit a slow growth rate, atypical colony morphology, and unusual biochemical characteristics, thus making them a challenge for clinical microbiologists to identify. Clinically, small colony variants are better able to persist in mammalian cells and are less susceptible to antibiotics than their wild-type counterparts, thus more prone to be responsible for recurrent infections 33.

S. epidermidis undergoes undefined and complex metabolic changes which, in combination with biofilm formation, allow it to persist on the foreign body and become less susceptible not only to the immune system but also to antibiotics 34, 35. It is probable that only a small part of these metabolic changes have been explored so far.

Biofilm

Upon introduction into the human body, foreign bodies become rapidly coated by host components. Pathogen attachment is the second step 36. Virulence factors such as adhesive proteins, enzymes, and toxins play a role 35, 37. Interactions involve non-specific physicochemical forces such as van der Waal's forces, hydrophobic interactions, and polarity 37, 38. Intercellular adhesion requires the synthesis of the polysaccharide intercellular adhesin (PIA) under the control of an intercellular adhesion (ica) operon 38, considered as one of the main genetic determinants involved in the accumulation phase during biofilm formation, even if ica or PIA-negative biofilm-forming S. epidermidis infections occur 39. In the case of S. epidermidis, exposure to foreign bodies in vitro and in vivo induces a sharp increase in ica expression 40 which is significantly correlated with the ability for biofilm formation in contrast to ica-negative isolates 39.

Finally, the cells that attach irreversibly to surfaces form microcolonies and produce extracellular polymers that define a biofilm (Figure 1). Its structure is heterogeneous, both in space and over time, with channels that allow the transport of nutrients and oxygen 37. S. epidermidis produces large-size biofilms more frequently than S. aureus 41. However, not all S. epidermidis isolates form biofilms 42.

Figure 1.  A: Intraluminal biofilm on a central venous catheter (with detachment). Scanning electron microscopy (magnification×180). B: Biofilm of Staphylococcus epidermidis on a catheter surface with embedded staphylococcal cells within the matrix. The arrow shows dividing cocci. Scanning electron microscopy (magnification×15,000). 1µ=1µm=0.001 mm.

The staphylococcal biofilm has potent immunomodulatory properties. Chemotactic responsiveness is diminished and degranulation of specific granule content is increased. Additionally, the biofilm inhibits the genesis of mononuclear cells, T and B lymphocytes, thus adversely acting both on cytotoxic and humoral defence responses 41. Vandecasteele and colleagues observed an impressive decrease in bacterial metabolism and protein synthesis in vitro 43. The authors measured directly the amount of 16S rRNA by quantitative polymerase chain reaction (PCR) as a surrogate marker of the actual metabolic activity of S. epidermidis. The initial 16S rRNA content was similar to that observed during the in vitro exponential growth phase. However, an extensive decrease in the 16S rRNA content was reported already beginning only 2 hours after. The ica operon was mainly transcribed during early, but not late infection 43.

Biofilms provide significant resistance to antibiotics and innate host defences. Common mechanisms such as drug-modifying enzymes, mutations, and efflux pumps are not involved. Antibiotics penetrate poorly into the thick, acidic matrix. Bacteria in deep layers are metabolically inactive and have an inherent lack of susceptibility to antibiotics 44, whereas planktonic cultures of the same organism do not 45. This resistance is lost once the biofilm-attached bacteria revert to planktonic growth 44. To date, no standardized antimicrobial susceptibility tests are available to evaluate drug activity on adherent bacteria 45. Minimal inhibitory concentration and minimal bactericidal concentration evaluate only drug efficacy on planktonic bacteria in the logarithmic phases of growth 46. For cell wall active antibiotics to be effective in biofilms, 100 to 1000 times the standard concentration is often required 45.

Group behaviour is an important intercellular communication mechanism in bacteria. Small signalling molecules are released in the natural environment and trigger specific responses in a co-ordinated manner in neighbouring bacteria of the same species. This is known as ‘quorum sensing’ and plays an important role in biofilm formation in S. epidermidis 47, 48.

Neutrophil defects

The interaction of neutrophils with the foreign body can induce a neutrophil defect, enhancing the susceptibility to infection 49, 50. The inoculum of staphylococci required to induce infection is reduced by several orders of magnitude to as few as 100 colony-forming units 49. Ultra-high molecular weight polyethylene wear particles released by prosthetic material may further compromise neutrophil antibacterial activity 51.

Prevention

Prevention of prostheses infection: antibiotic prophylaxis

Established risk factors for surgical site infections have been described 52. First- and second-generation cephalosporins are generally used in surgery because of their good intrinsic activity against staphylococci, few side-effects, and lower costs 53. On the other hand, nosocomial S. epidermidis isolates are often resistant to methicillin and thus to all cephalosporins 18, 22, 26, 54, 55 (Table I). To our knowledge, there are only two studies, both using cefuroxime as prophylaxis, which evaluated the impact of cephalosporins on the prevention of implant infections due to CoNS. The first study reported that 40% of all positive tissue cultures removed before hip replacement in operating rooms grew MRSE. In the follow-up period, 25% of patients revealed MRSE skin colonization on admission 26. The second study reported that 24% of tissue samples in arthroplasty patients were MRSE-positive 55. Strikingly, patients with MRSE infections demonstrated lower survival rates than patients with methicillin-sensitive infections. These findings led the authors to introduce a preoperative screening for MRSE carriage in addition to methicillin-resistant S. aureus (MRSA) 55. So far, it remains unknown at what moment patients become colonized with MRSE upon hospital admission. Probably colonization occurs very fast. In a Swedish study, the majority of patients on an orthopaedic ward were colonized with methicillin-resistant CoNS at day 14 of admission 27. In a prospective survey among surgical patients in Switzerland, only 20% of CoNS sampled from the future surgical site were methicillin-resistant upon admission, but 47% were immediately after elective surgery on the same site 56.

Despite these two studies, neither routine MRSE screening nor systematic vancomycin prophylaxis, even for medical implants, should be warranted 57 for the following reasons. First, the above-mentioned studies 26, 55 were retrospective and non-randomized. Second, a large proportion of CoNS isolates may still be susceptible to cephalosporins (Table I). Third, there is an emergence of vancomycin-resistance among enterococci and CoNS 12. An increase in the MIC of S. epidermidis against glycopeptide antibiotics has been also observed in vivo 58, 59. Fourth, vancomycin needs slow infusion to avoid excessive histamine liberation (known as the ‘red man’-syndrome) which makes its use more difficult in a setting where the accurate timing of administration is of the utmost importance 60. Fifth, the incidence of prosthetic joint infections due to S. epidermidis is usually low 8, 9. Sixth, a routine glycopeptide prophylaxis is not a guarantee for decreased infection rates due to methicillin-resistant staphylococci 61. A review of four randomized trials comparing prophylactic teicoplanin versus a prophylactic cephalosporin in settings with a high MRSE prevalence identified the same infection rates in both groups 61. A recent systematic review and economic model of switching from non-glycopeptide to glycopeptide antibiotic prophylaxis for surgery in endemic MRSA settings failed to show increased efficacy in preventing surgical sites infection due to methicillin-resistant staphylococci 62. Even for MRSA, there is insufficient evidence to determine whether there is a threshold prevalence to justify a switch to general glycopeptides prophylaxis 62.

Prevention of catheter infection

Implementation of specific guide-lines is known to reduce catheter infection rates 63. Prevention strategies 10 with a sustained impact over several years have been reported 64. Large-scale interventions, including a continuing quality improvement programme and using a multimodal approach, have proven to be effective 10, 65. According to a meta-analysis, antibiotic and chlorhexidine-silver sulfadiazine coatings are effective to decrease catheter colonization and blood-stream infections for short (∼1 week) insertion durations. In contrast, there is no evidence for a positive effect of silver-impregnated collagen cuffs for either short- or long-term catheter insertion times 66. Importantly, no antibiotic prophylaxis for CVC insertion is required 63

Treatment

Treatment of infected prostheses due to S. epidermidis

There are no established guide-lines for the treatment of S. epidermidis prosthetic infections due to the absence of randomized trials. Normally, antibiotics should be initially administered parenterally for 2 weeks and followed by an oral therapy for a total treatment duration of 3 months in patients with hip prostheses and 6 months in those with knee prostheses 1, 3, 67. In North America, débridement with device retention and a one-stage exchange (in which the infected prosthesis is removed and a new one implanted in the same procedure) is performed less frequently than in Europe. The interval between resection and reimplantation of the prosthesis in a two-stage exchange is typically 6 weeks 1, 3, 67. Débridement with retention is a reasonable option for patients with an early postoperative or acute haematogenous infection if the duration of clinical signs and symptoms is less than 3 weeks, the implant is stable, the soft tissue is in good condition, and an agent with activity against biofilm micro-organisms is available 3. The activity of antibiotic-containing bone cement against S. epidermidis has been proven in vitro 68, but no data from large human studies exist. In practice, many centres use gentamicin-containing cement already at primary prosthetic surgery. Resistance to gentamicin, the most widely used compound in cements, which is frequent among S. epidermidis isolates, represents an additional issue 12 (Table I).

Ideally, the antimicrobial agent should have bactericidal activity against slow-growing and biofilm-producing bacteria and reveal good bone penetration and oral bioavailability. Rifampin fulfils most of these criteria and can penetrate phagocytes and kill intracellular bacteria 69, but may lead to the rapid emergence of rifampin-resistant S. epidermidis during monotherapy. For this reason, rifampin should always be used in combination 46, 70 and early in the infection process 43 before the biofilm has been established. Monzon and colleagues reported a dramatically decreased effect of the vancomycin-rifampin combination for S. epidermidis in biofilms older than 6 hours 70.

The only blinded, randomized study hitherto with staphylococcal implant infections (including S. epidermidis) used rifampin in combination with ciprofloxacin. The clinical cure rate was 100% in the ciprofloxacin-rifampin group compared with 58% in the ciprofloxacin-placebo group (P = 0.02) 71. Widmer et al. conducted a prospective study of 11 patients with orthopaedic implant infections in whom the device could not be removed, and used rifampin in combination with a beta-lactam antibiotic or ciprofloxacin. The treatment was successful in 9 (82%) of 11 patients 72. Drancourt et al. achieved an overall success rate of 74% using a combination of rifampin and ofloxacin for treatment of staphylococcal infections of orthopaedic implants 73. Taken together, considering the ease of administration, peroral bioavailability, side-effects, and costs, rifampin administered in combination was revealed to be the most potent choice in vivo (Table II).

Table II.  Treatment of foreign body infections due to Staphylococcus epidermidis, 1987–2006, selected reports with references.

First author, Journal	Hosts	Material	Antibiotics	Duration	Results
Evans 96, Antimicrob Agents Chemother 1987	In vitro	Silicone	Vancomycin versus placebo	1–10 days	No difference in biofilm bacterial count
Zimmerli 71, JAMA 1988	Humans	Different prostheses metals	Ciprofloxacin / rifampicin, ciprofloxacin / placebo	3–6 months	100% success only in rifampicin group
Widmer 46, J Infect Dis 1990	Guinea pigs	Tissue cage	Vancomycin, daptomycin, teicoplanin, ciprofloxacin, rifampin, netilmicin	4 days	Rifampin combined with other antibiotics sterilized all implant infections
Gagnon 81, Adv Perit Dial 1994	In vitro	Not reported	Cloxacillin, cephalothin, cefazolin, cefamandole, vancomycin, rifampin ciprofloxacin, fusidic acid, clindamycin, tetracycline, tobramycin, gentamicin	5 days	Synergy of rifampin with most of the other antibiotics
Pascual 97, Eur J Clin Microbiol Infect Dis 1994	In vitro	Teflon, vialon, polyurethane, polyvinyl chloride	Vancomycin, teicoplanin, amikacin, rifampin	24 hours	Amikacin or rifampin increased the activity of glycopeptides on adherent bacteria
Isiklar 80, Clin Orthop Relat Res 1996	Rabbits	Steel	Vancomycin, minocyclin, rifampicin	2 weeks	Only combination with rifampicin cured
Monzon 70, J Antimicrob Chemother 2001	In vitro	96-well microtitre plate	Cephalothin, minocyclin, rifampicin, vancomycin, clindamycin, cotrimoxazole	24 hours	Combination is more bactericidal. The best: vancomycin-rifampicin
Peck 98, Chemotherapy 2003	In vitro	Polyurethane	Vancomycin with either rifampicin, erythromycin, or gentamicin	2 days	Combination with rifampicin was most active
Lee 87, J Antimicrob Chemother 2006	In vitro	Polyurethane antibiotic lock	Vancomycin, teicoplanin, ciprofloxacin, rifampicin, cefazolin, gentamicin, nafcillin, erythromycin	1–14 days	Rifampicin, vancomycin, and ciprofloxacin could eradicate with antibiotic lock
Saginur 75, Antimicrob Agents Chemother 2006	In vitro	Calgary biofilm device 45	Azithromycin, cefazolin, ciprofloxacin, gentamicin, linezolid, oxacillin, rifampin, vancomycin, fusidic acid	24 hours	Rifampin is the most active antibiotic combination in biofilm

A panel of different antibiotics have been used in combination with rifampin, such as cotrimoxazole 57, 74, fusidic acid 57, 73, 75, tigecycline 57, 76, daptomycin 46, 57, 77, linezolid 22, 75, 78, quinupristin/dalfopristin 22, 57, 79, dalbavancin 57, minocycline 74, 80, ofloxacin 81, ciprofloxacin 71, 72, and levofloxacin 82, 83. The efficacy of most of these possible combinations is not evidence-based in humans. For instance, the combination of rifampin with lincosamides (clindamycin, macrolides) or moxifloxacin is still uncertain in humans 83. Table III summarizes the activity of new antibiotics in the treatment of foreign body infections due to S. epidermidis.

Table III.  Key elements of more recently developed antibiotics in foreign body infection due to Staphylococcus epidermidis, selected reports with references.

Antibiotic	Key elements
Linezolid 22, 75, 78	Approved by the US Food and Drug Administration (FDA) 18 April 2000.
Tigecycline 57, 76	Only intravenous. Four times more active than vancomycin or daptomycin on adherent bacteria. Cure with rifampin in experimental osteomyelitis
Daptomycin 46, 57, 77	Low activity on adherent bacteria. Possible synergy with rifampicin
Quinupristin/dalfopristin 22, 57, 79	Enhanced cure rates with rifampicin in the rabbit model
Newer quinolones 82, 83	Experimental data
Dalbavancin 57	Long half-life. Excellent activity against S. epidermidis. Experimental data

Treatment of central venous catheter infection due to S. epidermidis

No prospective, randomized studies have been performed to evaluate the optimal therapeutic option for CVC infections. Catheter removal is mandatory in situations of septic shock, persistent fever, endocarditis, distant metastatic infections, or bacteraemia due to virulent and difficult-to-treat pathogens such as S. aureus, Pseudomonas aeruginosa, or fungi 10, 63, 84. For S. epidermidis, some authors do not recommend any antibiotic treatment after catheter removal. Others, including the authors of this review, prefer to treat CoNS catheter-related infections with intravenous antibiotics for 5–7 days 10 because of substantial morbidity and mortality 16.

Antibiotic lock technique

For S. epidermidis-related catheter infections, catheter removal can be postponed if the patient's status quickly improves during antibiotic therapy or a new intravascular access is difficult to obtain, such as surgically implanted central venous ports. For this situation, the antibiotic lock technique may be particularly helpful. Presently, there is no evidence-based recommendation for the optimal concentration of antibiotic and/or heparin, or on optimal intraluminal dwell duration 63. In practice, an antibiotic solution of 2–5 mg/mL is instilled into the lumen and allowed to dwell for several hours or days 85, 86, thus enabling the in vitro eradication of S. epidermidis biofilms within 5 days 87. Most antibiotics lack anticoagulant characteristics and need to be combined with heparin 86. The lock technique can also be performed with ethanol or taurolidine 84, 86 and should not be used as prophylaxis.

Guide-lines published by the Infectious Diseases Society of America 63 advocate daily catheter locking for 14 days in addition to 7–14 days of systemic administration of antibiotics via the infected lumen for uncomplicated catheter infections caused by CoNS, even if this duration is not evidence-based. For S. epidermidis, cure rates are sufficiently high 63 and can even reach 92% 88. While combination locking seems to be more effective in vitro against CoNS compared to monotherapy, similar outcomes are not evidence-based in vivo yet 84.

Perspectives

Despite significant progress in the understanding of foreign body infections due to S. epidermidis, improved knowledge of metabolic properties of biofilm-grown bacteria is still needed. The high genetic variability of the S. epidermidis genome and the discovery of specific genomic elements promoting its invasiveness 89 may offer the possibility to develop new drug targets. For example, Balaban and colleagues proposed to prevent S. epidermidis foreign body infections in rats by using a quorum-sensing inhibitor 90. Additional prospective trials need to be performed before this concept and other innovative approaches such as urokinase 91, bacteriophages 92, ultrasonically enhanced antibiotic activity 93, or electric current treatment of biofilm 94 may prove to be superior to established combined antibiotic therapies.

Acknowledgements

We are indebted to Rosemary Sudan for editorial assistance and to Dr P. Rohner and Professor J. Schrenzel from the Central Laboratory of Bacteriology of the University of Geneva Hospitals for the information provided in Table I.

Declaration of interest: The authors report no conflicts of interest: no financial support, grants, financial interests or consultancy that could lead to a conflict of interest. The authors alone are responsible for the content and writing of the paper.

All authors state that they have read and approved the manuscript. It has not been published elsewhere, nor is it under consideration for publication elsewhere. Parts of this review have been presented on 11 October 2006 as an abstract and oral presentation at the Third International Symposium on Resistant Gram-Positive Infections, Niagara-on-the Lake, Canada.