Antibiotics for treatment of infections caused by MRSA and elimination of MRSA carriage. What are the choices?

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Antimicrobial Agents ELSEVIER

International Journal of Antimicrobial Agents 9 (1997) l-19

Review

article

Antibiotics for treatment of infections caused by MRSA and elimination of MRSA carriage. What are the choices? Franz-Josef

Schmitz a*b**,Mark

E. Jones a

aEijkmun- Wink&r I,wtitute for Medical Microbiology, Unirersitv Hospital Utrecht, AZU G04.515, Heidelberglaan 100. 3584CX Utrechi. The Netherlands b Institute JFor Medical Microbiologic alzd Virology, Heinri&Heine Uniuersitiit, Diisseldorf. Germany

Accepted 28 April 1997

Abstract The widespread appearance of methicillin resistant Staphylococcus aureus (MRSA) has significantly undermined the efficacy of currently available antibiotic therapies as strains tend to be multi-resistant. Clinicians are therefore faced with a restricted choice in effective anti-MRSA therapies for infection or elimination of carriage. MRSA remain uniformly susceptible to glycopeptides vancomycin and teicoplanin which remain drugs of choice in treatment of infections. Centres with a high incidence of MRSA should use glycopeptides as empirical monotherapies against these organisms. The low toxicity of teicoplanin makes it an alternative for patients unable to tolerate vancomycin. Only mupirocin is truly effective for use as a topical agent in elimination of MRSA colonisation. For systemic use developmental glycopeptides such as daptomycin, MDL 63246, and LY191145 show better in vitro activity than vancomycin. New cephalosporins TOC-39 and FK-037 show promising anti-MRSA potential with low MICs, as does carbapenem BO-2727 which has a high in vitro activity. Whether the new cephalosporins and carbapenems with good in vitro and/or in vivo activities against MRSA will be clinically effective remains to be determined. New fluoroquinolones levofloxacin, temafloxacin and spafloxacin have enhanced in vitro anti-MRSA activity, although the emergence of resistance, and subsequent cross resistance to related compounds during therapy is a problem. BAY 12-8039, DV-7751 and CS-940 are developmental fluoroquinolones with better in vitro activity and lower spontaneous mutation rates than related compounds. Co-trimoxazole shows good in vivo anti-MRSA activity, comparable to vancomycin, however, severe infections do not respond well and many strains are resistant to this drug. Rifampicin has excellent bactericidal activity but rapidly emerging resistance undermines its use as a monotherapy. Its use in a combination therapy offers limited potential as an alternative. Arbekacin shows good in vitro activity against many MRSA isolates, although resistance to related aminoglycosides is a problem. Streptogramins, virginiamicin and RP 59500 (dalfopristin/quinupristin), and the everninomicin SCH 27899, show excellent activity in vitro and in vivo activity against MRSA and real future potential as alternative agents to vancomycin. Azeleic acid and ramoplanin show future potential as agents for topical use against MSRA. In conclusion only vancomycin as a systemic agent and mupirocin as a topical agent, offer sufficient reliability for use against MSRA. Alternatives to glycopeptides and mupirocin rest with the development of new drugs from several classes of compounds. 0 1997 Elsevier Science B.V. Keywords: MRSA;

Glycopepides;

Mupirocin;

Therapy;

Elimination;

1960s and world-wide

1. Introduction Methicillin were isolated

Antibiotics

resistant Staphylococcus atmus (MRSA) soon after the drug was introduced in the

* Corresponding author. In The Netherlands. Tel: + 31 302507625; fax: + 31 30-2541770. 0924~8579/97/$32.00 0 1997 Elsevier Science B.V. All rights reserved. PII SO924-8579(97)00027-7

have subsequently become a persistent problem. In the US, the percentage

and

of MRSA among all hospitals in the NNIS system increased from 2.4% in 1975 to 29% in 1991. The incidence varied according the number of beds within the hospital, with hospitals of < 200 beds reporting 14.9% of S. aureus isolates as MRSA, and hospitals of 2 500

2

F.-J. Schmitt,

M.E. Jones /International

beds reporting a 38.3% frequency [l]. Within European countries a systematic survey of 40 laboratories documented a wide variation in prevalence ranging from 0.1% in Northern European countries to > 30% in Spain, France and Italy [2,3]. Community acquisition of MRSA is becoming more common, with residence within a nursing home, recent hospitalisation, and prior antibiotic use identified as risk factors [4]. In some areas, MRSA is an important pathogen among intravenous drug users [5]. Patients at highest risk for MRSA infection are those in large tertiary-care hospitals, particularly the elderly and immunocompromised, those in intensive care units, burns patients, those with surgical wounds, or patients with intravenous lines. Duration of hospitalisation, previous antibiotic treatment, and proximity to a patient colonised or infected with the organism also predispose to MRSA infection [6]. In acute care and nursing facilities, colonised and infected patients are the major MRSA reservoir [7]. Person to person transmission of MRSA usually occurs via the hands of healthcare workers [8]. MRSA produce an additional penicillin binding protein (PBP), termed PBP2a or PBP2’, with reduced p-lactam affinity that is absent from susceptible strains. The 2-kilobase gene encoding PBP2a, mecA, is carried on a 40- to 60-kilobase segment of DNA inserted into the staphylococcal chromosome. The added DNA often contains genes encoding resistance to other antimicrobials, insertion sequence-like elements, and genes regulating the expression of mecA, although in some strains the latter have been deleted or inactivated [9]. Strains with the same amount of PBP2a can vary widely in their MIC to methicillin, and many MRSA isolates are heteroresistant, with as few as 10 - ’ of the population expressing high-level resistance [lo]. More than a dozen auxiliary genes influencing expression of methicillin resistance have been identified [ll]. A few low-level methicillin resistant strains lack PBP2a but have other detectable PBP alterations [ 121 or produce large amounts of /?lactamase concomitant with an increase in intrinsic resistance [ 131. Methicillin resistance mediates clinically inadequate susceptibility to all currently available /3-lactam antibiotics and are typically resistant to several other antimicrobial agents, including aminoglycosides, chloramphenicol, clindamycin, fluoroquinolones, and macrolides. Multiple resistance varies greatly geographically so that in planning treatment it is imperative to carry out susceptibility testing. So far clinical isolates have been uniformly susceptible to vancomycin. Teicoplanin should be regarded as equally effective, but with a lower toxicity. Therefore, the glycopeptides vancomycin and teicoplanin are the agents of choice for MRSA infections. In the laboratory,

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9 (1997) 1~ 19

resistance has been transferred from Enterococcus faecalis to S. aureus and is stably expressed

vancomycin

[14]. Should this occur in nature, alternative MRSA therapies would be urgently needed. Careless prescription of drugs which are active against MRSA will probably result in the emergence of resistance against that agent. Responsible antibiotic prescription thus mandates close and frequent consultation between prescribing physicians and medical microbiologists. These considerations thus make it imperative to explore vigorously all possible avenues for alternative agents to use in MRSA infections. This review will discuss the efficacy of antibiotic options currently available for MRSA therapies and discuss the potential of developmental compounds that show good anti-MRSA activity, for use in treatment of MRSA.

2. Infections with MRSA 2.1. Glycopeptide antibiotics

Glycopeptides are the antibiotics of choice for infections caused by MRSA, as all isolates to date have remained uniformly susceptible [ 15-291. Glycopeptide antibiotics are large, rigid molecules that inhibit a late step in bacterial cell wall synthesis by forming hydrogen bonds with the D-alanyl-D-analine terminus of the peptidoglycan (PDG) side chains, a mechanism different to that of the p-lactams [27]; thus they are potentially active against all S. aureus strains including MRSA. The use of a glycopeptides are particularly indicated in neutropenic patients, since many of the Gram-positive blood isolates recovered from this population, are resistant to a-lactams and aminoglycosides [30,31]. However, the optimal timing for adding the glycopeptide to the empirical regimen is still in question [30-321. Recently, an initial empirical regimen that includes a glycopeptide antibiotic has been recommended for centres that display a high incidence of MRSA [31]. Resistance to glycopeptides has emerged in both coagulase-negative staphylococci [33] and enterococci [8], and it is known that genetic elements encoding aminoglycoside resistance or p-lactamase enzyme can be exchanged between these species and S. aureus [14]. Thus it seems uncertain for how much longer glycopeptides can be relied upon to remain active against MRSA. 2. I. I. Vancomycin The best known glycopeptide is vancomycin, an amphoteric glycopeptide produced by Streptomyces orien -

F.-J. Schmitz, M.E. Jones /International

talis [29], which has been available since the mid-1950s.

Currently vancomycin and teicoplanin are the drugs of choice for treatment of infections due to MRSA [20,25]. until recently vancomycin was somewhat impure and caused a range of adverse effects that discouraged its use. A recent preparation (Vancocin CP) is claimed to be chromatographically pure and to cause less side effects. However, evidence that this purified form is less toxic than its immediate predecessor has not been documented in the literature. Mainly because of their toxicity the existing glycopeptides are by no means ideal antibiotics for therapy [34], and it has been suggested that vancomycin may be a less effective antistaphylococcal agent than hitherto perceived [22]. Vancomycin, in comparison with antistaphylococcal penicillins, exhibits slower killing rates in vitro against staphylococci [23,35-371. Furthermore, its activity against deep seated staphylococcal infections is not always optimal [2:!,23] and frequently requires the parallel administration of other antimicrobial agents [20,25]. Additionally, there have been several reports of therapeutic failures in patients with S. aureus endocarditis treated with vancomycin as monotherapy [38,39]. Even in animal models of endocarditis, vancomycin has been described as ‘surprisingly unsuccessful’ against MRSA endocarditis [40]. Resistance to vancomycin has not been observed in clinical isolates of S. aureus, although it has been detected in some clinical is,olates of S. haemolyticus [33]. In these cases the organisms were reported to sequester vancomycin molecules within the cell wall thus raising the MIC, in contrast to true resistance exhibited by vancomycin resistant ente:rococcal species which exhibit an alternative PDG structure, often plasmid encoded. In both instances, tolerant strains were recovered from patients who had prolonged exposure to vancomycin, sometimes at sub-inhibitory concentrations. Tolerance of MRSA to vancomycin, probably due to sequestering of molecules within the I’DG, has also been reported and associated with therapeutic failure 1151.When failure is suspected, a second drug, such as rifampin [ 18,381, an aminoglycoside [18], or fusidic acid [18] should be added. Controversy surrounds the use of combination therapy for endocarditis caused by MRSA. Few published studies are available for vancomycin, but failure rates of up to 42% have been reported [39]. In a recent study using a rabbit model of aortic valve endocarditis, the efficacy of vancomycin alone or in combination with netilmicin and/or rifampin against a MRSA also resistant to gentamicin strain of S. aureus was studied [42]. No resistance to rifampin or netilmicin emerged during therapy, but vancomycin as monotherapy was as efficacious as the triple combination and a 12-day course was more effective than a 6-day course [42].

Journal

of Antimicrobial Agents 9 (1997) l-19

3

The usual daily intravenous dose of vancomycin in adults with normal renal function is 30 mg/kg. It may be administered by intermittent doses given every 6- 12 h. The plasma elimination half-life is generally given as 6-7.5 h, but there is a wider inter-patient variation, probably as a result of variations in renal function. Doses for neonates are adjusted for chronological and gestational age [28,43]. For older children, the recommended dose is 40 mg/kg [43]. Intermittent doses should be given over 1 h to avoid infusion-related adverse events [44]. These events include hypotension [45], muscle pain and spasm in the chest and lower back [46], and the so called red man’s syndrome [47]. The latter syndrome is due to histamine release and is related to rapid infusion of vancomycin [48]. Increasing the infusion time to 1 h or longer and pre-treating the patient with an antihistamine such as hydroxyzine will usually prevent this reaction [49]. Peak and trough serum concentrations should be monitored to ensure effective dosing and to avoid ototoxicity and nephrotoxicity. There is a lack of adequate data correlating serum vancomycin levels with outcome. Recommended peak levels (drawn 1 h after completion of the infusion) and trough levels are 20-40 pg/ml and 5-10 lug/ml, respectively. These often quoted dose recommendations are based on an assumption made decades ago, that trough levels should remain above 2 @g/ml, higher than the MICs of most staphylococci. Vancomycin is cleared primarily by glomerular filtration. Hence the dose should be adjusted for renal insufficiency in accordance with a published nomogram [50], this is particularly so in burns patients in whom considerable renal tubular excretion makes prediction of dose requirements on the basis of serum creatinine levels unreliable. The drug is not removed by hemodialysis 1511.Anuric patients may be safely and effectively treated with a dose of 1 g given every 7-10 days [52]. Topical vancomycin has been used for conjunctivitis due to MRSA [53]. Meningitis and Ommaya reservoir infections due to MRSA may require the use of small doses (5-20 mg) of vancomycin administered intra-ventricularly as well as larger systemic doses [54]. The low pH ( < 3) of vancomycin solutions precludes it being used by the intramuscular route, and makes intraocular and intrathecal use difficult. The exclusive intravenous route for administration of this agent leads to extensive hospital stay and high costs. 2.1.2. Teicoplanin Teicoplanin is a glycopeptide structurally related to vancomycin derived from the actinomycete Actino planes teichomyceticus. Teicoplanin is a complex of five closely related high molecular weight glycopeptides which have neutral pH [55] and has a longer half-life than vancomycin (40-100 h) [56]. Teicoplanin is not significantly well absorbed across the gastrointes-

4

F.-J. Schmitt, M.E. Jones /International Journal of Antimicrobial Agents 9 (1997) I-19

tinal tract so must be administered intravenously (either by infusion or by injection) or intramuscularly. The extent of metabolism of teicoplanin is minimal (about 3% of dose) and is almost entirely eliminated by passive glomerular filtration [57]. Its long half-life allows once a day administration, and appears to cause fewer adverse events than vancomycin. Side effects associated with teicoplanin treatment are local hypersensitivity reactions, such as itching and drug induced fever. Anaphylactic reactions are seldom observed. It is at least as active against MRSA and methicillin sensitive S. aureu~ in vitro as is vancomycin and appears to be less ototoxic and nephrotoxic, especially when administered in combination with an aminoglycoside. Its activity and low toxicity make teicoplanin an alternative to vancomycin and a suitable drug for patients unable to tolerate vancomycin [57,58]. For reliable clinical results it is important to give a loading dose (of at least 800 mg) followed by 400 mg or more once daily. The currently recommended dose is 12 mg/kg daily for the first few days, followed by 6 mg/kg daily after blood cultures are no longer positive [57]. Using a very high-dose regimen (15 mg/kg), high levels of drug in serum ( > 30 pg/ml) which were equivalent to 30 times the MICs of teicoplanin for susceptible isolates of S. uureus, were continuously present in patients [59].These levels were sufficient to overcome protein binding by serum components [59]. Lower doses have been associated with clinical failures in some patients with S. aureus bacteremia [60,61]. In children under 12 years, 3 loading doses of 10 mg/kg at 12-h intervals followed by single daily doses of 6 or 10 mg/kg should be given, depending on the severity of infection [57]. In patients with renal failure, teicoplanin can be given at the recommended dose for 4 days. Following this, the dosage should be lowered to onehalf or one-third of the normal dose if creatinine clearance is between 40 and 60 ml/min or below 40 ml/min, respectively [57]. In non comparative studies, teicoplanin monotherapy at maintenance dosages of 400 to 800 mg daily was shown to achieve clinical and bacteriological cure in 84 to 93% of non-neutropenia patients suffering with bacteraemia caused by S. aureus [62]. Long-term treatment with teicoplanin proved efficacious in the treatment of bone infections caused by MRSA [59,63]. The prolonged half-life of teicoplanin offers the advantage of treating infections where extended antimicrobial therapy is warranted [57]. Furthermore, the prophylactic and therapeutic activities of teicoplanin were evaluated in two different experimental models of foreign body infections caused by MRSA [64]. In a guinea pig model of prophylaxis, subcutaneously implanted tissue cages were infected by MRSA [64]. A single dose of 30 mg/kg teicoplanin administered intraperitoneally 6 h before bacterial challenge was as effective as vancomycin in preventing experi-

mental infection in tissue cages infected by MRSA. In a rat model evaluating the therapy of chronic tissue cage infection caused by MRSA, the efficacy of a 7-day high dose (30 mg/kg once daily) regimen of teicoplanin was compared with that of vancomycin (50 mg/kg twice daily). Although high levels of teicoplanin were found in tissue cage fluid, no significant reduction in the viable count of MRSA occurred during therapy. In contrast, either vancomycin alone or a combined regimen of high-dose teicoplanin plus rifampin (25 mg/kg twice daily) could significantly decrease the viable counts in tissue cage fluids. Whereas the bacteria recovered from tissue cage fluids during therapy showed no evidence of teicoplanin resistance, they failed to be killed even by high doses of this antimicrobial agent. The altered susceptibility of in vivo growing bacteria to teicoplanin killing might in part explain the low activity of teicoplanin when used as monotherapy against chronic, S. aureus infections. These data may indicate the need for a combined regimen of teicoplanin with other agents such as rifampin to optimise the therapy of severe staphylococcal infections [64-671. 2.1.3. Other glycopeptides Daptomycin is an acidic semisynthetic lipopeptide derived from Streptomyces roseosporus that inhibits the synthesis of lipoteichoic acid. Its in vitro activity is comparable to vancomycin and teicoplanin [56,68]. Few clinical studies have been published to date although a study in healthy volunteers showed good in vivo activity against MRSA [16]. Its usefulness is limited by its toxicity although daptomycin has been shown to decrease the nephrotoxicity of gentamicin in a rat model [69]. Due to its toxicity the clinical usefulness of daptomycin has yet to be demonstrated. Several new glycopeptide derived antibiotics are under development that may offer future therapeutic alternatives to established glycopeptide compounds. MDL 63246, a semisynthetic derivative of the naturally occurring glycopeptide antibiotic MDL 62476 (A40926), was more active in vitro against S. aureus than MDL 63476, teicoplanin and vancomycin [70,71]. Furthermore it was more active than teicoplanin and vancomycin against acute staphylococcal septicaemia in immunocompetent and neutropenic mice [70]. It was highly efficacious in reducing the bacterial load in staphylococcal endocarditis experiments [70]. The excellent in vivo activity of MDL 63246 appears to correlate with its in vitro antibacterial activity. LY191145 is another investigational semisynthetic glycopeptide antibiotic, derived from Amycolatopsis orientalis. It has a structure-activity relationship similar to that of vanThis mono-N-p-chlorobenzyl derivative comycin. demonstrates excellent in vitro activity against 99.9% of all strains of S. aureus and MRSA tested with a MIC values of 0.25 to 0.5 mg/ml [72,73]. LY191145 exhibited

F.-J. Schmitr.

M.E.

Jones /International Journal of Antimicrobial Agents 9 (1997) l-19

more rapid bactericidal activity than vancomycin against S. uureus, and a concentration 16-fold greater than the MIC appears to be optimal [72]. MDL 63246, LY 191145 or other semisynthetic glycopeptides with similar antibacterial activities and pharmacokinetics still in early stages of development, could be therapeutically efficacious at lower dosages and longer treatment intervals than those currently used for vancomycin and teicoplanin. 2.2. jl-lactam

antibiotics

In vitro, several p-lactam compounds appear to be active against MRSA [74], however, in experimental models of endocarditis, they have proved ineffective [75]. Moreover, there are numerous reports of clinical failures when /3-lactams have been used to treat serious MRSA infections [76,77]. .4 variety of new compounds have shown encouraging results against MRSA in vitro, but great care must be ta’ken in extrapolating from in vitro results to clinical effectiveness with P-lactams. /?-lactams should not be considered as agents as choice in MRSA infections, Most clinical isolates of MRSA contain two mechanisms for resistance to ,!?-lactam agents; they produce both a-lactamase and an additional PBP, PBP 2a. Therefore, any j?-lactam antimicrobial agent of potential clinical use must be resistant to enzymatic degradation and have high affinity for PBP 2a. The addition of a /?-lactamase inhibitor to penicillinase-sensitive compounds with high native affinity for PBP 2a may increase the efficacy of these antimicrobial agents against MRSA isolates by preventing enzymatic hydrolysis of the compound. However, the role of a-lactam antibiotics in the treatment of MRSA infections have not been widely studied. Investigators have reported good in vitro activity of some j’-lactam antibiotic agents against MRSA [78], but in vivo studies have shown discrepant results [79-811. 2.2. I. Penam compounds The ,$-lactam compounds with the greatest activity in vitro against MRSA are penicillin, ampicillin, and amoxycillin, which have relative affinities for PBP 2a 10 to 15 times greater than ,that of penicillinase-resistant methicillin [81] and bind PBP 2a at concentrations of 15-50 pg/ml [36]. Unfortunately, these concentrations are at the upper limits or above clinically achievable concentrations, and in addition these drugs are degraded by p-lactamase. Ampicillin or amoxycillin administered at very large dosages (6255800 mg/kg/day) in combination with a p-lactamase inhibitor (sulbactam or clavulanic acid) is efficacious in rat and rabbit models of MRSA endocarditis [81-831. However, ampicillin/sulbactam at 300 mg/kg/day failed to eradicate resistant cells from vegetations of rabbits with

5

endocarditis caused by a heterogeneously resistant strain of S. aweus. Because of the very large doses necessary for efficacy of even the most active p-lactam antibiotics, it is not known whether they would be useful clinically. In a recent study, Chambers et al. [36] examined the effect of adding rifampin to ampicillin/ sulbactam in the rabbit model of aortic valve endocarditis caused by MRSA in order to determine whether the addition of rifampin would permit the use of lower doses of p-lactam antibiotics without emergence of resistance and loss of efficacy [36]. Ampicillin or amoxycillin at 625-800 mg/kg/day, in combination with a /3-lactamase inhibitor, was as effective as vancomycin in animal models of MRSA endocarditis. The efficacy of ampicillin/sulbactam (300/l 50 or 150/75 mg/ kg/day intramuscularly, in three divided doses) in combination with rifampin (5 mg/kg intramuscularly, three times daily) was as effective as vancomycin (25 mg/kg intravenously, twice daily, or 30 mg/kg intramuscularly, three times daily). The ampicillin/sulbactdm/rifampin regimen may be an alternative to vancomycin in treatment of MRSA infection, particularly for patients who cannot tolerate vancomycin and for those who remain persistently bacteremic or show no clinical response to therapy [36]. For reasons that are not known, most cells in a heterogeneously resistant MRSA population remain susceptible to low concentrations of b-lactam antibiotic even though they produce PBP 2a. However, P-lactam antibiotics alone are not effective in clearing infection as eventually the few highly B-lactam antibiotic-resistant cells that are present will emerge and cause treatment failure [84-861. The efficacy of the rifampin combination therefore is due to its activity against this highly resistant subpopulation. In addition, Fantin et al. [35] investigated the activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of S. aweus and its penicillinasenegative derivative in vitro and in a rabbit experimental endocarditis model. Penicillin was highly effective against penicillinase-negative MRSA. However, penicillinase production, rather than methicillin resistance, appeared to be the limiting factor for the activity of the penicillin-sulbactam combination against penicillinaseproducing MRSA [35]. Improved combinations of blactamase-sensitive with p -1actamase penicillins inhibitors and an additional antistaphylococcal antibiotic may offer a future treatment for MRSA infections [35,87,88].

2.2.2. Cephem compounds Whilst cephalosporins are generally active against S. aweus including j?-lactamase producing strains only the newer fourth generation cephalosporins offer any therapeutic benefits against MRSA.

6

F.-J. Schmitt,

M.E. Jones /International

Over the past few years, new cephalosporins with improved activity against S. aureus, such as flomoxef, cefpirome, cefepime and cefozopran have been developed. However, the activities of these agents against MRSA are still disappointing and insufficient for eradication of infection. Whether other new cephalosporins with activity against MRSA will be clinically effective remains to be determined. The new fourth generation parenteral cephalosporin FK-037 showed a good in vitro and in vivo antibacterial activity against MRSA, when compared with cefpirome, ceftazidime, flomoxef and cefepime [89], in fact on the basis of MIC90s, in one study, FK-037 was the most active of the cephalosporins tested which included cefpirome, ceftazidime, cefoperazone and ceftizoxime, although it was still less active than vancomycin [90,91]. Emergence of resistance to FK-037 was minimal in contrast to the relatively fast emergence of resistance to cefpirome and flomoxef by the selection of highly resistant cells from heterogeneous MRSA populations [92]. These in vitro findings suggest a higher protective activity of FK-037 against MRSA than that expected from its MIC in comparison with reference cephalosporins. The potent anti- MRSA activity of FK-037 could be dependent on its high affinity and rapid binding to PBP 2a in addition to high affinity to essential PBPs, 1, 2 and 3 [93-951. TOC-39, a new parenteral cephalosporin, was evaluated for antibacterial activity and showed excellent activity, stronger than that of methicillin, oxacillin, several cephalosporins, imipenem, gentamicin, minocycline, tobramycin, ofloxacin, and ciprofloxacin, against MRSA [96]. Furthermore, it had an MIC comparable to that of vancomycin and the activity of the compound against highly resistant MRSA was also comparable. No mutant resistant to TOC-39 or vancomycin was obtained from susceptible MRSA strains. In murine systemic infection models TOC-39 showed potent activity against S. aUYeUS [96]. These results may indicate that TOC-39, like FK-037, could be one of the first new cephalosporins to have sufficient activity against MRSA for effective clinical use although both drugs are still in early developmental phases. 2.2.3. Carbapenem compounds Carbapenem molecules are natural fermentation products of various Streptomycetes although unmodified are very unstable in vivo. Whilst highly stable to S. aweus p-lactamase clinically available semisynthetic carbapenems imipenem, meropenem and biapenem, derived from thienamycin, have low affinities for PBP 2a. Despite in vitro assays showing MRSA to be sensitive to imipenen, they should be regarded as clinically resistant. New carbapenem molecules are under development. Of a series of 41 developmental carbapenems [97-1001 seven were active in vitro against a laboratory MRSA strain. One compound (LY 206763)

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is of particular interest, showing good activity against a wide range of MRSA strains, a high affinity to PBP 2a, and a low binding affinity to human serum [97]. BO2727, like biapenem and meropenem, is a developmental parenteral carbapenem which has a methyl group at the 1-p position. The activity of BO-2727 against MRSA was considerably greater than those of the clinically available carbapenems such as biapenem, meropenem, and imipenem [loll. The binding affinity of BO-2727 to PBP 2a is higher than that of imipenem [102]. This may be one of the reasons for the high-level of activity of BO-2727 against MRSA. The potent efficacy of BO-2727 was confirmed in the lethal systemic infection models, in accordance with its potent in vitro activity and high levels in plasma [loll. Further development of carbapenem molecules with a higher affinity for PBP 2a and better in vivo stability may offer alternatives therapies to glycopeptides in less severe infections caused by MRSA. 2.3. Quinolones Quinolones are synthetic molecules first synthesised during the 1960s as nalidixic acid from which the fluoroquinolones were subsequently derived. The antistaphylococcal activity of existing fluoroquinolones is marginal and of the ‘first generation’ fluoroquinolones, ofloxacin has the lowest MIC values against MRSA [103]. The rapid emergence of resistance to quinolone compounds is a real problem and has undermined the usage of these drugs in therapy. During therapy blood levels may fall below inhibitory concentrations for quite long periods between doses [21]. Such sub-therapeutic levels may lead to the emergence of resistance which, very likely, is what has happened in MRSA infections due to the indiscriminate use of ciprofloxacin after its introduction in clinical use during the last decade [21,104,105]. Significant incidences of emergent resistance to ciprofloxacin have been reported in MRSA isolated in many places [lo66 1091, especially in Europe, South America, Japan and US. Among ciprofloxacin resistant strains, cross resistance to other fluoroquinolones, including ofloxacin, pefloxacin, enoxacin, and fleroxacin, is common [l lo]. New fluoroquinolones with enhanced activity against staphylococci, including MRSA, are currently being evaluated [I 1l- 1261. The most advanced of these include sparfloxacin, levofloxacin, trovafloxacin, tosufloxacin, grepafloxacin and clinafloxacin. Palmer et al. [123] compared levofloxacin, the L-isomer of ofloxacin versus vancomycin, with or without rifampin in an in vitro model with infected platelet fibrin clots simulating bacterial vegetations. Regimens included levofloxacin at dosages of 800 mg every 24 h and 400 mg every 12 h, vancomycin at 1 g every 12 h and rifampin at 600 mg every 24 h. All levoflaxin regimens

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were significantly better than vancomycin monotherapy against methicillin sensitive S. ~UY~U.S (MSSA) and MRSA. No difference between the levofloxacin monotherapy and combination therapy with rifampin against MRSA was seen. Development of resistance was not detected with. any regimen. Therefore, levofloxacin may be a useful therapeutic alternative in the treatment of staphylococcal endocarditis [123]. In an additional study the in vivo efficacy of levofloxacin was studied in an acute murine model of hematogenous pyelonephritis [ 1161. Its activity was compared with that of ciprofloxacin and tested against MSSA and MRSA. In a murine model, levofloxacin was superior to ciprofloxacin in preventing pyelonephritis and eradicating S. aureu,r. Furthermore, Cagni et al. [ 1131 tested the prophylactic and therapeutic activities of sparfloxacin, temafloxacin, and ciprofloxacin in two different experimental models of foreign-body infections caused by MRSA susceptible to quinolones. In conclusion, both temafloxacin and sparfloxacin were significantly more active than ciprofloxacin for the prophylaxis or treatment of experimental foreign-body infections caused by a susceptible strain of MRSA [113]. Of the many invl:stigational phase quinolone drugs, DV-7751 was superior in antimicrobial activity against MRSA when co-mpared to ciprofloxacin and ofloxacin [127,128] and CS-940, showed good in vitro activity against MRSA in preliminary studies [127,128]. BAY 12-8039 showed better in vitro activity against MRSA than either ciprofloxacin or sparfloxacin, and had lower spontaneous mutational rates giving rise to resistance [129]. These developmental compounds may provide improved quinolone antiMRSA therapies for future use. Clearly quinolone cornpounds offer good possibilities for the development of new compounds active against MRSA providing that the problems associated with phototoxicity can be overcome. However, their efficacy may be undermined by the problem of cross resistance amongst relat,ed compounds and as such several factors need to be taken into consideration before the widespread clinical use of new compounds is contemplated. The rate at which new compounds select resistant isolates must be investigated. Since cross-resistance between fluoroquinolones is common, the question remains whether these new compounds will be effective clinically against pre-existing ciprofloxacin-resistant strains. The potential use of other antistaphylococcal agents in combination with fluoroquinolones for increased therapeutic activity and minimal selection of quinolone-resistant phenotypes, must also be investigated. 2.4. Trimethoprim-sulfaml?thoxazole The combination

of trimethoprim

and sulfamethox-

7

azole (TMP/SMX) is active in vitro against many strains of S. aweus [130- 1371, with MICs ranging from 0.05-1.0 to 0.4-8.0 [138]. Time kill studies, show this combination to have a rapid bactericidal effect at concentrations four times the MIC [137]. In addition, synergistic bactericidal activity has been shown in a model of disseminated infection in mice [ 1311. When the efficacy of intravenous TMPjSMX was compared with vancomycin for treatment of endocarditis and other severe infections in intravenous drug users, patients with MSSA had a lower survival rate with TMP/SMX (73%) than with vancomycin (97%). Of the 47 patients with MRSA infection in this study, both TMPjSMX and vancomycin exhibited a 100% success rate in clearing infection [133]. In contrast to this, an experimental rabbit endocarditis model treatment of MRSA showed TMPjSMX to be significantly less effective than treatment with vancomycin or teicoplanin [132]. These data do not support the use of TMPjSMX in treatment of endocarditis and other severe staphylococcal infections with high bacterial counts [132]. Furthermore, some strains of MRSA are resistant to TMPjSMX [139], and susceptibilities should be determined before this combination is used. 2.5. Rifampin Rifampin is a semisynthetic derivative of rifamycin S, a natural product of Streptomyces mediterranei. Rifampin has excellent bactericidal activity against both MSSA and MRSA. However, rifampin alone is unreliable in clearing infections due to a single step mutation, occurring at a frequency of 1 in lo6 cells, that results in high-level resistance to the drug. Development of resistance can be prevented if rifampin is used in combination with a second effective antistaphylococcal agent. Resistance has been shown to emerge if rifampin is used in combination with a drug to which the infecting strain is resistant 11251. Rifampin has a large volume of distribution and can achieve therapeutic levels in tears, nasal secretions, and cerebrospinal fluid [140]. Limited clinical and experimental data indicate that rifampin combination regimens may be efficacious against staphylococcal infections [141-1431. This drug is synergistic with several other antistaphylococcal antibiotics and has been used effectively in combination with vancomycin [38,144], teicoplanin [67], ciprofloxacin [125], TMP/ SMX [145], novobiocin [146,136], fusidic acid [41], and minocycline [140]. The use of rifampin as adjunctive therapy in treatment of staphylococcal endocarditis is controversial. Numerous investigators have studied the combination of rifampin with other antistaphylococcal drugs and found conflicting results rang-

8

F.-J.

Sclwzifr. M.E. Jones /International Journal of’ Anrimicrohial Agents 9 (1997) I 19

ing from synergism to frank antagonism [120,147- 1541. A such rifampicin monotherapy is never used against MRSA infections and insufficient study data are available to recommend empirical combination therapies using this drug. 2.6. Clindwnycin Clindamycin belongs to the lincosamide group of antibiotics. In one report, clindamycin was used successfully in the treatment of five patients infected or colonised with susceptible strains of MRSA [155]. However, resistance, and the emergence of resistance to clindamycin during therapy, is common in MRSA particularly if the strain is already resistant to erythromycin [l-56]. The drug has been used successfully in treatment of hip and bone infections due to MRSA [157], however, because of the rapid emergence of resistance to clindamycin, the drug is never the first drug of choice, even for susceptible isolates [20]. 2.7. Fusidic acid Fusidic acid is a steroid-like antibiotic derived from Fusidium coccineum that interferes with bacterial protein synthesis. It is bactericidal at high concentrations against S. aureus [41]. Oral, intravenous, and topical preparations are available. Adverse reaction to fusidic acid include granulocytopenia, rash, hepatotoxicity, and thrombophlebitis with venospasm during intravenous infusion [ 16 11. Because resistance develops rapidly [162], combination therapy has been recommended [41]. Even still MRSA isolates have developed resistance to fusidic acid during concomitant vancomycin therapy [163] and to both gentamicin and fusidic acid during combination therapy [164]. ln an uncontrolled study of 49 severe infections due to S. uuwus treated with fusidic acid, cure rates for infections due to MSSA and MRSA were 75% and 67%, respectively [165]. Fusidic acid was used alone in only three patients. Drugs used in combination with fusidic acid included aminoglycosides, vancomycin, quinolones, and rifampin. Appropriate studies investigating combination regimens, taking advantage of the excellent activity of fusidic acid may provide some future potential for improved anti- MRSA therapies.

used aminoglycosides are susceptible to inactivation by enzymes commonly found in MRSA, such as AAD4’, 4” and the bifunctional APH 2”/AAC6’. Thus most MRSA are resistant to gentamicin, tobramycin, netilmicin and amikacin. However, arbekacin a derivative of kanamycin B and currently only licensed for anti-MRSA therapies in Japan [158], is active against many, but not all MRSA isolated in Japan [159]. Even when the infecting strain is susceptible in vitro, singleagent therapy with aminoglycosides has been associated with unacceptably high mortality rates [160]. The combination of vancomycin and an aminoglycoside is synergistic against some strains of MRSA [38] but, there are only sparse data available from clinical reports, and the combination is more nephrotoxic than either drug alone [44]. Aminoglycoside compounds are not considered as primary therapies for treatment of MRSA infection. 2.9. Glycylcylines The glycylcyclines are novel derivatives of tetracyclines, synthesised by substitution in the ninth position with N,N-dimethylglycylamide [ 1661. Those derived from minocycline and 6-demethyl, 6-deoxytetracycline are active against a wide range of tetracycline-resistant bacteria, including MRSA [167]. Many of the MRSA so far tested were sensitive to minocycline [168,169]. Minocycline is active against MRSA in vitro and acts synergistically with rifampin [I 52,170]. There are reports of the successful use of minocycline to treat staphylococcal infections, including MRSA endocarditis [171,172]. However, general use of this agent for the treatment of S. nUrez4s infections has not occurred [21]. The lack of minocycline use is likely related to its perceived inability to cure bacterial infections as a result of its presumed bacteriostatic rather than bactericidal activity. A recent study indicates that minocycline is a useful alternative agent to vancomycin for the treatment of MRSA endocarditis [172]. In addition to the favourable decline in the bacterial density of the vegetations. the good bio-availability when given orally makes it an attractive alternative in some situations 11721. However, before glycylcyclines can be considered as real alternative agents for the treatment of MRSA infections, more data are needed on their activity against minocycline-resistant strains.

2.8. Aminoglycosides 2.10. Novobiocin The aminoglycosides constitute a large group of naturally occurring and semisynthetic polycationic compounds that have long since been used in antistaphylococcal therapies, however, the advent of methicillin resistance in 5’. aureus has severely undermined their efficacy. Resistance to aminoglycosides is common among isolates of MRSA [21]. The clinically

and Coumermycin

Novobiocin is a bis-hydroxycoumarin compound derived from fermentation products of Streptomyces spheroides and Streptomyces niveus with in vitro activity against MRSA [173]. Its use has resulted in hypersensitivity reactions, hepatotoxocity, and bone marrow suppression. It has been used effectively in the past at

F.-J. Schmitt, M.E. Jones /International Journal of’ Antimicrobial Agents 9 (1997) l-19

doses up to 2 g daily to treat infections due to S. aureus [174] particularly in combination with sodium fusidate or rifampin. Coumermycin, derived from Streptomyces spinicoumerensis and Streptomyces rishiriensis, is another coumarin derivative. Again this drug has good anti staphylococcal activity. Both drugs inhibit DNA gyrase activity and have good in vitro activity against MRSA [175]. Neither drug can be used successfully as monotherapy because of the rapid emergence of resistance. Considerable severe side effects can be encountered with both drugs including abdominal pains, urticarial skin eruptions, Stephens-Johnson syndrome and severe thrombocytopenia. 2.11. Fosfomycin Fosfomycins are orgamc phosphonates derived from several different Streptomyces spp. that inhibit staphylococcal cell wall synthesis by inhibiting phosphoenolpyruvate transferase and are active in vitro against MRSA. It has been successfully used for treatment of three patients with bacteremia caused by MSRA [176]. Synergism has been noted with several /?-lactams and aminoglycosides. Resistant mutants, typically exhibiting loss of the G-6P-induced transport system, arise in vitro with a relatively high frequency of 10 -’ to IO- 5 [177] and for this reason its use against MRSA is limited and not recommended. 2.12. Streptogramins Streptogramins (or synergimycins) are mixtures of naturally occurring cyclic peptide compounds with synergistic inhibitory activity on microbes, including MRSA. Type A streptogramins (e.g. virginiamycin M) and type B components (e.g. virginiamycin S) both inhibit protein synthesis Iby binding to the SOS ribosoma1 subunit and are bactericidal in combination [178 19 l]. Macrolide and lincosamide antibiotics share common mechanisms of action and bacterial resistance with type B streptogramins. Collectively, these agents are referred to as MLS antibiotics [192]. Resistant staphylococci do occur, but are very uncommon at present. Resistance is due to either alteration of the target site (the bacterial ribosome), or inactivation of the antibiotic [190]. A water-soluble semisynthetic derivative of pristinamycin, RP 59500, is a new injectable streptogramin. It is composed of a streptogramin B, quinupristin, and a streptogramin A, dalfopristin, combined in a 30:70 ratio. Both compounds bind to the 23s RNA of the 50s ribosomal subunit. They act synergistically to inhibit protein synthesis and show good activity against MSRA. It is also effective against inducibly MLS-resistant strains, because quinupristin and dalfopristin are poor inducers of the methylase (erm) genes, encoding resistance to ery-

9

thromycin, the most frequent MLS resistance determinants in Gram-positive pathogens [189]. The binding of quinupristin and dalfopristin in an antibiotic-RNA complex confers efficacy of RP 59500 against all bacteria carrying erm genes. Therefore, the combination is able to circumvent MLS resistance in Gram-positive pathogens, a phenotype often encountered in multipleantibiotic resistant isolates, especially MRSA. In a recent study [184], the therapeutic efficacy of RP 59500 was compared with that of vancomycin against experimental endocarditis due to either erythromycin-susceptible or constitutively erythromycin-resistant MRSA. That study underlined the in vitro and in vivo antiMRSA activity of RP 59500. However, it also underlined the risk of in vivo sub-optimal medication against constitutively erythromycin resistant MRSA, due to the short life span of the limiting dalfopristin fraction of the drug in serum, since successful treatment was restored by artificially prolonging the dalfopristin levels. Thus, RP 59500 is a promising alternative to vancomycin against MRSA, provided that pharmacokinetic parameters can be adjusted to afford prolonged levels of both its constituents in serum [184]. On the basis of these results, it might be reasonable to administer RP 59500 three times a day or even in a continuous infusion to treat constitutively erythromycin resistant MRSA, since they constituted nearly 40% of all isolates. In addition, three daily doses of RP 59500 were more effective than two doses against experimental endocarditis due to constitutively erythromycin resistant MRSA in rabbits [184]. The misleading global kinetics of RP 59500 might also explain previous failures of the drug to cure experimental MRSA endocarditis [182]. In another study the bactericidal activity and emergence of resistance to RP 59500, when it was administered alone and in combination with vancomycin, was tested in an in vitro infected fibrin clot model [188]. Fibrin clots have been infected with MSSA and MRSA. Overall, RP 59500 demonstrated more potent bactericidal activity than vancomycin against S. aureus over 72 h. In the fibrin clot model, the most optimal therapy was the combination regimen. Emergence of resistance was noted after exposure to RP 59500 in the endocarditis model. There are several proposed mechanisms of resistance to MLS antibiotics, including target modification, antibiotic inactivation, and active efflux systems. On the basis of the changes in MICs of erythromycin and RP 59500 and the stability of the lincomycin MIC in that study [188], the resistance of isolates may be due to either target modification or an active efflux mechanism. Although detectable frequencies of spontaneous mutation to RP 59500 were demonstrable, the implications of these are unknown. Fortunately, the incidence of resistance to streptomycin antibiotics among S. aweus clinical isolates remains low [188]. Further in vitro and in vivo studies are needed to

10

F.-J. Schmitz, M.E. Jones/International

evaluate the role of RP 59500, alone or in various combinations, in the treatment of staphylococcal infections as well as the possible emergence of resistance during therapy. 2.13. Macrolides Macrolides form a large group of closely related compounds produced mostly by Streptomyces species. Extensive use of the older compounds has lead to widespread resistance. Almost all MRSA are resistant to erythromycin and the newer 14- and 15-membered macrolides (azithromycin, clarithromycin, roxithromycin, dirithromycin). The 16-membered macrolides (miocamycin, josamycin, spiramycin and rokitamycin), on the other hand, are active against MRSA strains in which resistance to erythromycin is inducible. Whether this extends to clinical effectiveness, remains to be determined and presently macrolides cannot be considered as effective therapies for MRSA infection. The 16-membered macrolides are not active against MRSA with constitutive resistance to erythromycin

VI. 2.14. Everninomicin Everinomicin is an antibiotic complex first reported 30 years ago, which has a unique chemical structure consisting of a 7-membered glycosidic-linked oligosaccharide unit, bearing substituents that include a nitro group [193]. Its development was halted due to low solubility in water, a problem recently solved by making a complex with cyclodextrin [194]. A novel everninomicin SCH 27899 has now reached an encouraging developmental stage. This new derivative is active against MRSA with low MIC90s, higher activity than both vancomycin and teicoplanin, and shows synergistic bactericidal activity with fosfomycin [ 1951961. Laboratory induced resistance to the compound occurred in a stepwise manner at a very low rate. Although still in developmental stages this novel antibiotic may provide a real alternative to glycopeptides in anti-MRSA therapies.

3. Carriage of MRSA The nose and skin are the primary sites implicated in the carriage of MRSA, but many other sites such as the axillae, groins and perineum may also be involved [197]. Risk factors for MRSA colonisation in a superflcial site include the administration of multiple antibiotics [198-2001. It is known that the nasal bacterial flora is modified when systemic antibiotics are given. Interestingly, older data indicate that increased environmental contamination with penicillin was an important

Journal of Antimicrobial Agents 9 (1997) I- 19

risk factor for colonisation of the nares of hospitalised patients with penicillin-resistant staphylococci or for the transmission of penicillin-resistant S. aureus to other patients [201]. It has also been shown that administration of tetracycline to patients colonised with tetracycline-resistant strains of S. aureus induced further dispersal of the organism in the environment [202]. Several authors have proposed that the carriage of MRSA poses an increased risk of infection over the carriage of MSSA. In CAPD patients, MRSA carriers were at increased risk for MRSA infections compared with non-carriers [203]. When comparing MRSA carriers with MSSA carriers, a higher rate of peritonitis, exit-site infections, catheter losses, and CAPD patient drop-outs was associated with MRSA carriage [203]. In a long-term care facility, MRSA carriers were at an increased risk for the development of S. aurexs infections [204]. Mest et al. [205] found that peri-operative colonisation with MRSA significantly increased the risk for postoperative MRSA infection in patients on the ICU. Pujol et al. [206] studied the rate of bacteremia in patients admitted to the ICU. Patients colonised with MSSA in the nares were at a significantly increased risk for the development of S. aureus bacteremia, but patients colonised with MRSA were at a much higher risk. It seems clear that MRSA carriage constitutes a greater risk for the development of S. aureus infection than MSSA carriage. Several studies have failed to show a difference between MRSA and MSSA in terms of virulence [200,207,208]. Therefore, it is most likely that the increased infection rate observed in carriers of MRSA is primarily due to the selection of a more vulnerable group of patients who become carriers of MRSA. 3.1. Rationale for elimination of A4RSA carriage In their consensus review Mulligan et al. [26] state that the primary reasons for eradicating MRSA are to prevent outbreaks in a health-care setting, or to prevent recurrent infections in an individual. In settings where MRSA is endemic, elimination of MRSA carriage has been found not cost-effective and therefore considered unnecessary. The effects of elimination strategies in settings where MRSA is endemic have not been studied extensively. One study in a surgical ICU reported a significant decrease of the colonisation and pulmonary tract infection rate when all patients were treated using intravenous therapies during the first week after admittance [209]. In an outbreak situation where MRSA are not endemic, the first goal should be to identify all carriers, including patients and health-care workers and to subsequently eliminate all MRSA organisms [26,210]. Although many studies did not include controlled trials, they provide additional suggestive evidence that eradicating nasal carriage of MRSA among

F.-J. Schmitz, M.E. Jones /International

patients and personnel is useful during epidemics. Most reports on the effects of elimination of MRSA carriage in outbreak situations also mention that other infection control measures were taken concomitantly, which may have played a significant role in controlling these outbreaks. One report mentioned the complete control of an outbreak when only simple infection control measures were taken [211], while others found that only extensive modification of local infection control practices were effective [ 198,2 12,2 131. Although many different agents and drug combinations have been used for eradicating nasal carriage of S. aureus, there is a consensus that topical mupirocin is presently the regimen of choice [214-2291. Attempts to remove nasal carriage of MRSA with local antiseptics (e.g. chlorhexidine or povidone iodine) or antibiotics (e.g. bacitracin) frequently fail. Chemotherapeutic agents for elimination include topical antimicrobials and antiseptics applied directly to the nares or other sites of carriage, systemic agents that achieve adequate concentrations in these sites and antiseptic soaps for bathing. 3.2. Topical antimicrobiah Various topical antimicrobials, including bacitracin, vancomycin, and gentamicin [230], have been employed to eliminate nasal staphylococcal carriage. Some have been effective in the short term, but recolonisation occurs frequently when these agents are used [217]. The topical agent of choice for eradication of nasal carriage of MRSA is mupirocin applied to the anterior nares 2-4 times daily for 5 days. Mupirocin, the generic name for pseudomonic acid A, is a fermentation product of Pseudomonas j&orestens NCIB 10586. It exhibits a narrow spectrum of activity and is most active against staphylococci and streptococci. The mode of action of mupirocin is unique in that it slows the activity of bacterial isoleucyl-tRNA synthetase (IRS) inhibiting protein synthesis [231]. Inhibition of IRS by mupirocin is irreversible, suggesting that the mupnocin-IRS complex is highly stable 12321. Although unsuitable for systemic use due to rapid hydrolysis in plasma, it is useful as a topical 2% preparation in either a lanolin or a polyethylene glycol base. Because the latter drug is an irritant, the lanolin base is preferred for intranasal application as polyethylene glycol base can cause localised mucosal irritation. Hill et al. [224] treated 32 patients with nasal staphylococcal carriage with mupirocin ointment applied to the anterior nares 4 times a day for 5 days. Initial success in eradicating nasal carriage was uniformly observed. Skin carriage at the wrist or the perineum was also decolonised immediately after treatment, and there was a dramatic reduction of the normal nasal

Journal

of Antimicrobial

Agents

9 (1997) l-19

11

flora. At 22 weeks, 56% of the cohort remained free of colonisation. Also, in a large non-comparative clinical study conducted in 102 hospitals, approximately 1500 individuals were treated with 2% mupirocin intranasally for 3 to 5 days [222]. Nasal carriage was eradicated in 97% of 628 persons with MRSA, and in 98% of 138 persons with MSSA. The long-term efficacy of mupirocin was not evaluated in this trial, since follow up cultures were performed 24 h after the last dose. However, studies by Doebbeling et al. [222] have demonstrated that 66% of individuals remained free of the initial colonising strain one year after therapy was completed. In outbreaks involving neonates, mupirocin was also applied to the umbilicus, which may be a reservoir of MRSA even after eradication from the anterior nares [220]. Scully et al. [174] found that colonisation with MRSA developed in 6 of 34 mupirocin treated subjects but in none of 36 placebotreated subjects. Because of concerns about emergence of mupirocin resistance, Casewell and Hill [218] studied the efficacy of minimal dose regimens. Single dose and 2-day treatments resulted in eradication of S. aureus, including MRSA, with 92% and 96% of subjects respectively, free of carriage 7 days after treatment [218]. Resistance to mupirocin has been detected in patients colonised with MRSA [233-2371. Resistance has been divided arbitrarily into two groups, low-level (MICs of 8 to 256 mg/l) and high-level (MICs 2 512 mg/l). Both can be selected in vitro and are likely the result of the additive selection of a number of independent, spontaneous mutational events [233]. In contrast, high-level resistance in clinical isolates is mediated by a large transferable plasmid which is easily lost when the cells are incubated at high temperature [235]. A review of the literature [238] indicates that since 1990, reports of mupirocin resistance have increased, but it is difficult to determine the overall resistance rates because the literature tends to focus on outbreaks, particularly associated with dermatology patients. Most of the reports focus on isolates from infected sites rather than those associated with nasal colonisation. There is a need to conduct general surveys to determine resistance rates among nasal isolates in order to monitor changes in resistance rates in this population as the use of the nasal preparation increases. Whether mupirocin resistance will become a widespread problem and whether short cause therapy will prevent it remain to be seen. Resistant strains are emerging [225,235] but most of them have only lowlevel resistance, and are still eradicated by the use of 2% nasal mupirocin ointment. The much less common highly resistant variants may cause treatment failure. It is clearly a potentially dangerous situation when so much reliance is placed on a single compound, and alternative agents for topical use are consequently being sought. Ramoplanin is a natural cyclic lipoglycopeptide

12

F.-J. Schitz,

M.E. Jones /ltrternational Journul of’ Atttitnicrobial Agents 9 (1997) I - 19

from Actinoplanes spp. and provides a possibility for future therapy as it exhibits good activity against MRSA [112]. Azelaic acid, a naturally occurring saturated dicarboxylic acid. has been used as a topical preparation in the treatment of acne [112], but also has attractive in vitro properties and definite potential use as a bacteriocidal topical agent against MSRA carriage. Azelaic acid has a similar activity against MRSA to mupirocin, and has not been shown to select for resistant mutants [227]. Nitrofurazone and silver sulphadiazine also show potential as topical agents for use in clearing MRSA carriage [227]. 3.3. Systemic antimicrobials Whilst topical intranasal mupirocin can efficiently eradicate nares MRSA carriage, it may be necessary to combine this therapy with a systemic agent, particularly if the patient has a large colonised wound or another extra-nasal site [215]. Rifdmpin is often used because of its good penetration into nasal secretions [140], but resistance emerges if it is used alone. Ward et al. [145] documented the effectiveness of combined topical bacitracin and oral rifampin given for 5 days, in eliminating nasal carriage of MRSA in all persons in whom this was the only site of involvement. Another study investigated 16 persons with extranasal sites of colonisation treated with oral TMPjSMZ for 5 days and, in addition, hexachlorophene baths for 2 days. Decolonisation was achieved in 13 (81%) of patients. In both regimens, failure occurred in patients with colonised surgical wounds. The combination of rifampin (600 mg daily) and TMPjSMZ (80 mg/400 mg orally twice daily for 5 days) [145] has been also been used with success rates of 50% to 75% in eliminating MRSA nasal carriage. Other systemic agents that have been employed, usually in combination with rifampin, include ciprofloxacin. and fusidic acid. The results with novobiocin, ciprofloxacin have been disappointing. Many isolates of MRSA demonstrate de novo resistance to ciprofloxacin and others developed resistance during therapy, even when used in combination with rifampin [104,105]. Walsh et al. [136] reported successful eradication of nasal MRSA carriage with a combination of novobiocin and rifampin in 30 of 45 patients (67%) compared with 26 of 49 (53%) treated with TMPjSMX and rifampin. Rifampin resistance developed in 14% of patients receiving TMP/SMX, but in only 1 of 45 patients (2%) receiving novobiocin. In an uncontrolled study [146] novobiocin was given in a daily dose of 500 mg orally in combination with rifampin (600 mg) to 12 patients in a rehabilitation ward who were colonised with MRSA. Successful eradication of carriage was achieved in 11 of 14 courses of treatment. Pearman et al. [239] reported success with rifampin (600 mg daily) and sodium fusidate, a steroid-like antibiotic (500 mg 3

times a day), in 17 of 22 (77%) hospital personnel with persistent MRSA carriage who failed to respond to topical chlorhexidine. In a recent study Parras et al. [228] compared the efficacy and safety of 2% mupirocin ointment versus those of oral co-trimoxazole plus topical fusidic acid (both regimens also used a daily or twice daily chlorhexidine scrub bath) for the eradication of MRSA from nasal and extra-nasal carriers. Both therapeutic regimens were administered during 5 days. The efficacy and safety of both regimens were similar. At the end of treatment, 100% of patients in both groups presented with nasal eradication of MRSA. Neither regimen completely or permanently eradicated MRSA from extranasal locations. The MRSA isolates were not resistant to the study drugs either before or after the study. Mupirocin was easier to use but was more expensive [228]. 3.4. Antiseptics Efforts to eradicate MRSA colonisation have often included bathing patients with antiseptic soaps containing povidone-iodine, chlorhexidine, hexachlorophene, or triclosan, often in conjunction with a topical or systemic antibiotic [213,239-2411. The extent to which these measures contribute to eradication of MRSA is not clear although they may provide potential for improved therapies against MRSA carriage [215]. The value of skin antiseptics for MRSA decolonisation might not be looked at in controlled studies but very well are world-wide recommended in elimination therapy. Optimal therapies to eliminate MRSA carriage, whilst not experimentally tested as yet, should probably combine antiseptic, nasal and systemic treatments.

4. Concluding

remarks

During the pre-antibiotic era S. aureus was the scourge of the hospital environment and a major cause of mortality. The introduction of penicillin provided a breakthrough in therapy, although this was short lived, owing to the rapid emergence of resistant strains producing /3-lactamase. Aminoglycosides, tetracyclines, chloramphenicol, and macrolides introduced during the 1950s provided choice in effective anti staphylococcal therapies for penicillin resistant strains, but soon lead to the evolution of ‘multi-resistant’ isolates. Semi-synthetic fi-lactamase stable penicillins introduced at the end of the 1960s together with the introduction of infection control measures, heralded a new era in treatment of S. aureus infections and for a while the therapeutic capability of the hospital pharmacy was in control, at least until the isolation of the first MRSA strains and their subsequent dissemination throughout

F.-J. Schmitz, M.E. Jones/International

healthcare institutes all over the world during the 1960s and 1970s. At first aminoglycosides, in particular gentamicin, were able to control MRSA infections, but resistance to these compounds was soon to emerge. Vancomycin, discovered during the 1950s took over as the last remaining effective antibiotic and has remained gold standard for treatment of serious infections ever since. Vancomycin or teicoplanin together with mupirocin, the only effective topical antibiotic, are the only drugs indicated for use against MRSA infection and colonisation respectively. Many of the other antibiotic groups still offer some degree of activity, particularly in combination therapies, but the multi-resistant nature of most MRSA isolates render these unreliable. Apart from extending the effective therapeutic life of existing antibiotics that remain marginally active by better defining acceptable combination therapies, the future for alternative treatments clearly lies with the many antibiotics in developmental phases, many of which are showing encouraging results. New drugs from existing classes of agents such as arbekacin, streptogramins RP 59500 and virginiamycin, glycopeptides MDL 63246 and LY 191145, alactams TOC-39, FK-03’7 and BO-2727, and the streptogramin RP 59500, offer real potential, and have shown excellent activity, comparable to vancomycin, both in vitro and in vivo, although cross resistance to related compounds or the further evolution of existing resistance mechanisms may compromise their long term efficacy. Perhaps the most exciting possibilities are the novel antibiotics such as the everninomicins for systemic use and azelaic acid and ramoplanin for use as topical agents. In conclusion, although the toxicity, and sub-optimal activity against S. uuyeus, shows glycopetides, not to be the ideal anti staphylococcal drugs, they remain the drugs of choice in treating MRSA infections. They are the only available antibiotics to which MRSA isolates remain uniformly susceptible, although it must be only a matter of time before glycopeptide resistance emerges in this :species. Considering the potential of S. aureus to cause disease in humans, reliance on this single antibiotic for effective systemic therapy, and mupirocin as the exclusive effective topical agent, is an intolerable clinical situation. The ability of S. aureus to acquire resistance to every antibiotic used as therapy, apart from the glycopeptides, should serve as a testament to the unlimited adaptive capabilities of this organism. The continued development of new antibiotics combined with the design and evaluation of effective and efficient ways to use the drugs, are mandatory if we are to prevent a return to the unacceptable levels of morality caused by untreatable S. aureus infections.

Journal of Antimicrobial Agents 9 (1997) I- 19

13

References [l] Panililio AL, Culver DH, Gaynes RP et al. Methicillin-resistant Staphylococcus aureus in US hospitals, 1975-1991. Infect Control Hosp Epidemiol 1992;13:582-6. [2] Voss A, Doebbeling BN. The world-wide prevalence of methicillin-resistant Staphylococcus aureus. Int J Antimicrobial Agents 1995;5:101-6. [3] Voss A, Milatovic D, Wallrauch-Schwarz C. Rosdahl VT, Braveny I. Methicillin-resistant Staphylococcus aureus in Europe. Eur J Clin Microbial Infect Dis 1994;13:50-5. [4] Layton MC, Hierholzer WJ, Patterson JE. The evolving epidemiology of methicillin-resistant Staphylococcus aureus at a university hospital. Infect Control Hosp Epidemiol 1995;16: 12-7. [5] Levine DP, Cushing RI), Jui J et al. Community acquired methicillin-resistant Staphylococcus aureus endocarditis in the Detroit Medical Centre. Ann Intern Med 1982:97:330-g. [6] Brumfitt W. Hamilton-Miller J. Methicillin-resistant Staphylococcus aureus. N Engl J Med 1989;320:1188-96. [7] Boyce JM, Jackson MM, Pugliese G et al. Methicillin-resistant Staphylococcus aureus (MRSA): a briefing for acute care hospital and nursing facilities. Infect Control Hosp Epidemiol 1994;15:105-15. [8] Jacoby GA. Antimicrobial-resistant pathogens in the 1990s. Annu Rev Med 1996;47:169-79. [91 Archer GL, Niemeyer DM. Origin and evolution of DNA associated with resistance to methicillin in staphylococci. Trends Microbial 1994;2:343-7. [lOI Tomasz A, Nachman S, Leaf H. Stable classes of phenotypic expression in methicillin-resistant clinical isolates of staphylococci. Antimicrob Agents Chemother 1991;35:124&9. H, Tomasz A. Reassessment of the number of [ill DeLencastre auxiliary genes essential for expression of high-level methicillinresistance in Staphylococcus aureus. Antimicrob Agents Chemother

1994;38:2590-8. HB, DeLencastre H et al. New mechanism for methicillin-resistance in Staphylococcus aureus: clinical isolates that lack the PBP 2a gene and contain normal penicillinbinding proteins with modified penicillin-binding capacity.

P21 Tomasz A, Drugeon

Antimicrob

Agents

u31 Barg N, Chambers

Chemother 1989;33:1869-74. H, Kernodle D. Borderline susceptibility

to

antistaphylococcal penicillins is not conferred exclusively by the hyperproduction of p-lactamase. Antimicrob Agents Chemother 1991;35:197559. of vancomycin 1141Nobel WC, Virani Z. Cree RGA. Co-transfer and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbial Lett 1992;93:19558. 1151Sorrel1 TC, Packham DR, Shanker S et al. Vancomycin therapy for methicillin-resistant Staphylococcus aureus. Ann Intern Med 1982;97:34&50. CJ, Chambers HF. Methicillin-resistant staphyloP61 Hackbarth cocci: detection methods and treatment of infections. Antimicrab Agents Chemother 1989;33:995-9. a review. Med Clin North Am u71 Levine JF. Vancomycin: 1987;71:1135545. C. Mode of action and in vitro activity of V81 Watanakunakorn vancomycin. J Antimicrob Chemother 1984;4(suppl D):7- Il. C. Treatment of infections due to methicillinu91 Watanakunakorn resistant Staphylococcus aureus. Ann Intern Med 1982;97:3768. JMT. The challenge of methiPO1 Brumfitt W, Hamilton-Miller cillin-resistant Staphylococcus aureus. Drugs Exptl Clin Res 1994;20:215524.

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[2l] Brumfitt W. Hamilton-Miller JMT. The world-problem of methicillin-resistant Stap/q/ococcus aureus. Drugs Exptl Clin Res 1990;16:205- 14. [22] Karchmer AW. Stap/qdococcus uureus and vancomycin: the sequel. Ann Int Med 1991;115:739-41. [23] Levine DP. Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin therapy among patients with methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991;115:674480. [24] Maple PAC, Hamilton-Miller JMT, Brumfitt W. World-wide antibiotic resistance in methicillin-resistant Staphylococcus aureus. Lancet 1989;i:537745. [25] Martin MA. Methicillin-resistant Staphylococcus aureus: the persistent resistant nosocomial pathogen. Curr Clin Top Infect Dis 1994;14:170&91. [26] Mulligan ME, Murray-Leisure KA, Ribner BS et al. Methicillin-resistant Staphylococcus uurcus: a consensus review of the microbiology, pathogenesis and epidemiology with implications for prevention an management. Am J Med 1993;94:313328. [27] Reynolds PE. Structure, biochemistry and mechanism of action of glycopeptide antibiotics. Eur J Clin Microbial Infect Dis 1989:8:943350. [28] Schaad UB. Nelson JD, McCracken GH. Pharmacology and efficacy of vancomycin for staphylococcal infections in children. Rev Infect Dis 1981;3 (Suppl):282-8. [29] Wise RI, Kory M. Reassessment of vancomycin - a potentially useful antibiotic. Rev Infect Dis 1981:3 (Suppl):l99-300. [30] Menichetti F, Del Favero A. The role of Gram-positive therapy in the neutropenic patient. J Antimicrob Chemother 1991;27 (Suppl B):51-60. [31] Menichetti F, Martin0 P, Bucaneve G et al. Effects of teicoplanin and those of vancomycin in initial empirical antibiotic regimen for febrile, neutropenic patients with hematologic malignancies. Antimicrob Agents Chemother 1994:38:2041-6. [32] EORTC International Antimicrobial Therapy Cooperative Group and the National Cancer Institute of Canada-Clinic Trials Group. Vancomycin added to empirical combination therapy for fever in granulocytopenic cancer patients. J Infect Dis 1991;163:951l8. [33] Vedch LA. Pfaller MA, Barrett M, Koontz FP, Wenzel RP. Vancomycin resistance in Staphylococcus haemolyticus causing colonization and blood stream infections. J Clin Microbial 1990;28:206&8. [34] Felmingham D. Towards the ideal glycopeptide. J Antimicrob Chemother 1993;32:663-6. [35] Fantin B, Pierre J, Castela-papin N et al. Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1996:40:1219924. [36] Chambers HF, Kartalija M, Sande M. Ampicillin, sulbactam, and rifampin combination treatment of experimental methicillin-resistant Staphylococcus aureus endocarditis in rabbits. J Infect Dis 1995:171:8977902. [37] Fasola EL, Fasching CE, Peterson LR. Molecular correlation between in vitro and in vivo activities of p-lacatamase inhibitor combinations against methicillin-resistant Staphylococcus aureus. J Lab Clin Med 1995:125:200-l I. [38] Faville RJ, Zaske DE, Kaplan EL et al. Staphylococcus nureus endocarditis: combined therapy with vancomycin and rifampin. J Am Med Assoc 1978;240:1963-5. [39] Geraci JE, Wilson WR. Vancomycin therapy for infective endocarditis. Rev Infect Dis 1981;3 (Suppl):250-8. [40] Chambers HF, Sande M. Teicoplanin versus nafcillin and vancomycin in the treatment of experimental endocarditis caused by methicillin-susceptible or -resistant Staphylococcus aureus. Antimicrob Agents Chemother 1984;26:61-4.

Journal of’ Antimicrobial Agents 9 (1997) l- 19 [41] Verbist L. The antimicrobial activity of fusidic acid. J Antimicrab Chemother 1990;25(Suppl B):l-5. [42] Perdikaris G, Giamarellou H, Pefanis A. Donta I, Karayiannakos P. Vancomycin or vancomycin plus netilmicin for Methicillin- and gentamicin-resistant StapllJdococcus aureus aortic valve experimental endocarditis. Antimicrob Agents Chemother 1995;39:2289-94. [43] Kaplan EL. Vancomycin in infants and children: a review of pharmacology and indications for therapy and prophylaxis. J Antimicrob Chemother 1984~14 (Suppl):59. [44] Sorrel] TC, Collingnon PJ. A propective study of adverse reactions associated with vancomycin therapy. J Antimicrob Chemother 1985;16:235541. [45] Southorn PA, Plevak DJ. Wright AJ et al. Adverse effects of vancomycin administered in the perioperative period. Majo Clinic Proc 1986:61:721-4. [46] Gatterer G. Spasmatic low back pain in patient receiving intravenous vancomycin during continuous ambulatory peritoneal dialysis. Clin Pharmacol 1984;3:87. [47] Garrelts JL, Peterie JD. Vancomycin and the “red man’s syndrome”. N Engl J Med 1985:312:245. [48] David RL, Smith AL, Koup JR. The “red man’s syndrome” and slow infusion of vancomycin (letter). Ann Intern Med 1986;104:28556. [49] Sahai J, Healy DB, Garris R, Berry A, Polk RE. Influence of antihistamine pretreatment of vancomycin-induced “red man’s syndrome”. J Infect Dis 1989;160:876681. [50] Mollering RC, Krogstad DJ, Greenblatt DJ. Vancomycin therapy in patients with impaired renal function: a nomogram for dosage. Ann Intern Med 1981;94:343. [51] Lindholm OD, Murray JS. Persistence of vancomycin in the blood during renal failure and its treatment by hemodialysis. N Engl J Med 1966;274:1047. [52] Barcenas CG. Fuller TJ. Elms J et al. Staphylococcal sepsis in patients on chronic hemodialysis regimens. Intravenous treatment with vancomycin given once weekly. Arch Intern Med 1976:136:1131. [53] Ross J. Abate MA. Topical vancomycin for the treatment of Staphylococcus epidermidis and methicillin-resistant Staphylococcus auretts conjunctivitis, DICP 1990;24:1050&3. [54] Hirsch BE, Amodii M, Einzig AI, Halevy R, Soeiro R. Instillation of vancomycin into a cerebrospinal fluid reservoir to clear infection: pharmacokinetic considerations. J Infect Dis 1991:163:1977200. [55] Davey PG. Emmerson AM, Gruneberg RN. Teicoplanin: laboratory and clinical developments. J Antimicrob Chemother 1991;27 (Suppl B):l-73. [56] Neu HC. Glycopeptides and lipopeptides: agents trying to meet the demands of the future. Antimicrobic Newsletter 1988;5:7784. [57] Lalla de F, Tramarin A. A risk-benefit assessment of teicoplanin in the treatment of infections. Drug Safety 1995;13:317728. [58] Greenwood D. Microbiological properties of teicoplanin. J Antimicrob Chemother 1988:21(Suppl A):1 13. [59] Greenberg RN. Treatment of bone, joint, and vascular-access associated with gram-positive bacteria1 infections with teicoplanin. Antimicrob Agents Chemother 1990;34:239227. [60] Gilbert DN. Wood CA, Kimbrough RC. Infectious Diseases Consortium of Oregon. Failure of treatment with teicoplanin at 6 milIigram/kilogram/day in patients with Staphylococcus aureus intravascular infection. Antimicrob Agents Chemother 1991;35:79-87. [61] Wilson AP. Gruneberg RN, Neu H. Dosage recommendations for teicoplanin. J Antimicrob Chemother 1993:32:792-6. [62] Livomese LL. Gold M, Johnson CC et al. Clinical evaluation of teicoplanin in the treatment of Gram-positive bacterial in-

F.-J. Schmitz, M.E. Jones /International

travascular infections. J An.timicrob Chemother l993;31: 1% 91. [63] Graniger W, Wenisch C, Wiesinger E, Menschil M, Karimi J, Pretserl E. Experience with outpatient intravenous teicoplanin therapy for chronic osteomyelitis. Eur J Clin Microbial Infect Dis 1995;14:643-7. [64] Schaad HJ, Chuard C, Vaudaux P, Waldvogel FA, Lew DP. Teicoplanin alone or combined with rifampin compared with vancomycin for prophylaxis and treatment of experimental foreign body infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1994,38:1703-JO. [65] Davey PG, Williams AH. A review of the safety profile of teicoplanin. J Antimicrob Chemother 1991;27 (Suppl B):69-73. [66] Lewis PJ, Martin0 P, Mosconi G, Harding I. Teicoplanin in endocarditis: A multicentre, open European study. Chemotherapy 1995:41:399-411. [67] Simon UC, Simon M. Antibacterial activity of teicoplanin and vancomycin in combinatio!l with rifampicin, fusidic acid or foscomycin against staphylococi on vein catheters. Stand J Infect Dis 1990;72 (Suppl): 14-9. [68] Brumfitt W, Hamilton-Miller JM. In vitro activity of daptomycin against a world-wide collection of methicillin-resistant Staphylococcus aureus. Drugs Exp Clin Res 1992;18:367-g. [69] Thibault N, Grenier L, Simard M, Bergeron MG, Beauchamp D. Protection against gentamicin nephrotoxicity by daptdmycinin nephrectomized rats. Life Sci 1995;56:1877-87. [701 Goldstein BP, Candiani Cr, Arain TM et al. Antimicrobial activity of MDL 63,246, a new semisynthetic glycopeptide antibiotic. Antimicrob Agents Chemother 1995;39:1580-8. [711 Kenny MT, Brackman MA, Dulworth JK. In vitro activity of the semisynthetic glycopept-de amide MDL 63246. Antimicrob Agents Chemother 1995;39:1589%90. 1721 Kang LS, Rybak MJ. Comparative in vitro activities of LY 191145, a new glycopeptide and vancomycin against Stuphylococcus aureus and Staphylococcus-infected fibrin clots. Antimicrab Agents Chemother 1995;39:2832-4. [731 Nagarajan R. Structure-acrivity relationships of vancomycintype glycopeptide antibiotics. J Antibiot 1993;46:1181- 95. 1741Sachdeva M, Hackbarth C, Stella FB, Chambers HF. Comparative activity of CGP 31608, nafcillin, cefamandole, imipenem, and vancomycin against methicillin-susceptible and methicillinresistant Antimicrob Agents Chemother staphylococci. 1987;31:1549-52. [751 Berry AJ, Johnston JL, Archer GL. Imipenem therapy of experimental Staphylococcus epidermidis endocarditis. Antimicrab Agents Chemother 1986;29:748-52. 1761Thompson RL, Cabezudo I, Wenzel RP. Epidemiology of nosocomial infections caused methicillin-resistant Staphylococcus aureus. J Ann Int Med 1982;97:309-17. [771 Klimek JJ, Marsik FJ, Bartlett RC, Weir B, Shea P, Quintilliani R. Clinical, epidemiologic and bacteriologic observations of an outbreak of methicillin-resistant Staphylococcus aureus at a large community hospital. Am J Med 1976;61:340&5. [781 Kernodle DS, Kaiser AB. Efficacy of prophylaxis with b-lactams and p-la&am-/?-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model. Antimicrob Agents Chemother 1993;37:702-7. t791 Chambers HF, Sachdeva M, Kennedy S. Binding-affinity for penicillin-binding protein correlates with in vivo activity of a-lactam antibiotics against methicillin-resistant Staphylococcus aureux J Infect Dis 1990;162:705-10. PO1 Fasching CE, Peterson LR, Moody JA, Sinn LM, Gerding DN. Treatment evaluation of experimental staphylococcal infections: comparison of p-lactam, lipopeptide, and glycopeptide antimicrobial therapy. J Lab Clin Med 1990;116:697-706. Franciolli M, Bille J, Glauszr MP, Moreillon P. /?-lactam-resis-

15

Journal of Antimicrobial Agents 9 (1997) I- 19

tance mechanisms of methicillin-resistant

Staphylococcus

au-

reus. J Infect Dis 1991;163:514-23.

WI Cantoni L, Wenger A, Glauser MP, Bille J. Comparative efficacy of amoxicillin-clavulanate, cloxacillin, and vancomycin against methicillin-sensitive and methicillin-resistant Staphylococcus aureus endocarditis in rats. J Infect Dis 1989;159:98993. combinaF331Hirano L, Bayer AS. /l-lactam-p-lactamase-inhibitor tions are active in experimental endocarditis caused by B-lactamase-producing oxacillin-resistant staphylococci. Antimicrob Agents Chemother 1991;35:685-90. b341 Chambers HF, Hackbart C, Drake TA, Rusnak MG, Sande MA. Methicillin-resistant Staphylococcus aureus endocarditis in rabbits: expression of resistance in vivo and in vitro. J Infect Dis 1984;149:894-903. 1851Chambers HF, Miller MH. Emergence of resistance to cephalothin and gentamicin during combination therapy of methicillin-resistant Staphylococcus aureus endocarditis in rabbits. J Infect Dis 1987;155:581-5. WI Chambers HF, Sachdeva M. Binding of beta-lactam antibiotics to penicillin-binding proteins in methicillin-resistant Staphylococcus aureus. J Infect Dis 1990;161:1170~6. P71 Catherall EJ, Gillon V, Hum S, Irwin R, Mizen L. Efficacy of ticarcillin-clavulanic acid for treatment of experimental Staphylococcus aureus endocarditis in rats. Antimicrob Agents Chemother 1992;36:458-62. [88] Washburn RG, Durack DT. Efficacy of ampicillin plus a p-lactamase inhibitor (CP-45899) in experimental endocarditis due to Staphylococcus aweus. J Infect Dis 1981;144:237-43. [89] Neu HC, Chin NX, Huang HB. In vitro activity and beta-lactamase stability of FK-037, a parenteral cephalosporin. Antimicrab Agents Chemother 1993;37:566-73. [90] Mine Y, Watanabe Y, Sakamoto H et al. In vitro antibacterial activity of FK037, a novel parenteral broad-spectrum cephalosporin. J Antibiot Tokyo 1993;46:71-87. [91] Mine Y et al. Excellent activity of FK037 a novel parenteral broad-spectrum cephalosporin against methicillin-resistant staphylococci. J Antibiot Tokyo 1993;46:99-119. [921 Nishino T, Otsuki M, Hatano K, Nishihara Y. In vitro and in vivo antibacterial activities of FK037, a new parenteral cephalosporin. Chemotherapy 1994;40:167-82. [931 Nakao M, Noji Y. Iwahi T, Yamazaki T. Antibacterial properties of SCE-2787, a new cephem antibiotic. J Antimicrob Chemother 1992;29:509-18. [941 Iwai T, Okonogi K, Yamazaki T et al. In vitro and in vivo activities of SCE-2787, a new parenteral cephalosporin with a broad antibacterial spectrum. Antimicrob Agents Chemother 1992;36:1358-66. P51 Fu KP, Foleno BD, Lafredo SC, Lococco JM, Isaacson DM. In vitro and in vivo antibacterial activities of FK-037. a novel parenteral broad-spectrum cephalosporin. Antimicrob Agents Chemother 1993;37:301-7. [961 Hanaki H, Akagi H, Masaru Y, Otani T, Hyodo A, Hiramatsu K. Tot-39, a novel parenteral broad-spectrum cephalosporin with excellent activity against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1995;39:1120-6. [971 Temansky RJ, Draheim, SE, Pike, AJ, Bell, FN, West, SJ, Jordan, CL et al. Discovery and structure-activity relationship of a series of I-carba-1-dithiacephems exhibiting activity against methicillin-resistant Staphylococcus aureus. J Med Chem 1993;36:1971-6. t981 Altamura M, Giannotti D, Perrotta E, Sbraci P, Pestellini V, Arcamone FM. Synthesis of new penem dithiocarbamates. Bioorg Med Chem Lett 1993;3:2159-64. [991 Jabes D et al. Activity of new penems against defined MRSA strains. Bioorg Med Chem Let 1993;3:2165-70.

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F.-J. Schmitt, M.E. Jones/International

[IOO] Pfaendeler HR, Wesiner F. Metzger K. Synthesis and antibacterial activity of (l’R,5R,6R)-2-tertbutyl-6-(I’-hydroxymethyl) oxapenem-3-carboxylic acid. Bioorg Med Chem Let 1993;3:221 l-8. K. In vitro and in vivo PO11 Asahi Y, Miyazaki S, Yamahuchi antibacterial activities of BO-2727, a new carbapenem. Antimicrab Agents Chemother 1995;39:1030&7. [102] Tateda-Suzuki E, Asasda K, Hiramatsu K. Evaluation of in vitro antimicrobial activity of BO-2727, a novel carbapenem, against methicillin-resistant Staphylococcus aureus and coagulase-negative stapyhlococci. Program and abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, Abstr. F5, 1994:30. PO31 Fu KP, Lafredo SC, Foleno B et al. In vitro and in vivo antibacterial activities of levofloxacin (I-ofloxacin), an optically active ofloxacin. Antimicrob Agents Chemother 1992;36:860-6. PO41 Peterson L, Quick J, Jensen B et al. Emergence of ciprofloxacin resistance in nosocomial methicillin-resistant Staphylococcus aureus isolates.Resistance during ciprofloxacin plus rifampin therapy for methicillin-resistant S. aureus colonization. Arch Intern Med 1990;150:215ll5. 11051Aboukasm AG. Buu-Hoi AY, El Solh N et al. Epidemiological studies of Staphylococcus aureus resistance to new quinolones in a university hospital. J Hosp Infect 1991;17:25533. StaphylococUW Rodriguez JN et al. Testing of quinolone-resistant cus aureus strains isolated in Brazil. Diag Microbial Infect Dis 1993;16:9916. uo71 Hori S, Ohshita Y, Utsui Y, Hiramatsu K. Sequential acquisition of norhoxacinand ofloxacin-resistance by methicillin-resistant and -susceptible Staphylococcus aureus. Antimicrob Agents Chemother 1993;37:2278-84. P, Tecson-Tumang UO81 Smith SM. Eng RHK, Bais P, Fan-Havard F. Epidemiology of ciprofloxacin-resistance among patients with methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 1990:26:567772. PO91 Blumberg HM, Rimland D, Carroll DJ, Terry P, Wachsmuth IK. Rapid development of ciprofloxacin resistance in methicillin-susceptible and methicillin-resistant Staphylococcus aureus. J Infect Dis 1991;163:1279-85, AL, Hollis RJ, Leme I. Janes RN. V]Ol Sader HS, Pignatori Oxacillin- and quinolone-resistant Staphylococcus aureus in Sao Paulo, Brazil: a multicentre molecular epidemiology study. Infect Control Hosp Epidemiol 1993:14:260&4. [1111 Aldridge KE, Gelfdnd MS, Schiro DD, Barg NL. The rapid emergence of fluoroquinolone-methicillin-resistant Staphylococcus aureus infections in a community hospital. An in vitro look at alternative antimicrobial agents. Diagn Microbial Infect Dis 1992;15:6OllS. [112] Aldrige KE, Jones RN, Barry AL, Gelfand MS. In vitro activity of various antimicrobial agents against Staphylococcus aureus isolates including fluoroquinoloneand oxacillin-resistant strains. Diagn Microbial Infect Dis 1992;15:517-21. 11131Cagni A, Chuard C, Vaudaux PE, Schrenzel J, Lew DP. Comparison of sparfloxacin, temafloxacin, and ciprofloxacin for prohylaxis and treatment of experimental foreign-body infection by methicillin-resistant Staphylococcus aureus. Antimicrab Agents Chemother 1995;39:1655560. 11141Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 1994;38:677-700. 11151Dworkin R, Modin G, Kunz S, Rich R, Zak 0, Sande M. Comparative efficacies of ciprofloxacin. pefloxcain, and vancomycin in combination with rifampin in a rat model of methicillin-resistant Staphylococcus aureus chronic osteomyelitis. Antimicrob Agents Chemother 1990;34: 1014-6. 11161Fresco MB, Melton JL. Stewart FP. Kulwich BA, Licata L.

Journal oj’ Atltirnicrobial Agents 9 (1997) 1~ 19 Barrett JF. In vivo efficacies of levofloxacin and ciprofloxacin in acute murine hematogenous pyelonephritis induced by methicillin-susceptible and -resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 1996;40:2529934. versus [I 171 Hessen MT. Pisakis PG, Kaye D. Oral temafloxacin vancomycin for therapy of experimental endocarditis caused by methicillin-resistant Stap/zylococcus aureus. Antimicrob Agents Chemother 1990;34:114335. an evolving national [1181 Jones RN. Fluoroquinolone-resistance. problem or just a problem for some physicians. Diagn Microbiol Infect Dis 1992; 15: 177-9. [I191 Kaatz GW, Barriere SL. Schaberg DR, Fekety R. The emergence of resistance to ciprofloxacin during treatment of experimental staphylococcal endocarditis. J Antimicrob Chemother 1987;20:75338. BJ. Kaatz GW, Seo SM. [1201 Kang SL. Rybak MJ, McGrath Pharmacodynamics of levofloxacin. ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant StaphJdococcus aureus in an in vitro infection model. Antimicrob Agents Chemother 1994;38:2702-9. JMT, Brumfitt W. Differing acu211 Maple PAC. Hamilton-Miller tivities of quinolones against ciprofloxacin-susceptible and ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1991;35:345550. [122] Mulligan ME et al. Ciprofloxacin for eradication of methicillinresistant Staphylococcus aureus colonization. Am J Med 1987;82 (Suppl 4a):21559. of once- or twice~1231Palmer SM, Rybak MJ. Pharmacodynamics daily levofloxacin versus vancomycin. with or without rifampin, against Staphylococcus aureus in an in vitro model with infected platelet-fibrin clots. Antimicrob Agents Chemother 1996:40:7Oll5. bacteria. Anu241 Piddock LJV. New quinolones and gram-positive timicrob Agents Chemother 1994;38:16339. F. Ciprofloxacin ther11251Smith SM. Eng RHK, Tecson-Tumang apy for methicillin-resistant Staphylococcus aureus infections or colonizations. Antimicrob Agents Chemother 1989;33: 181-4. clinical and U261 Wolfson JS, Hooper DC. The fluoroquinolones: laboratory considerations. Clin Microbial Rev 1992;14:1-7. ~1271Biedenbach DJ, Jones RN. In vitro evaluation of DV-775la, a new fluoroquinolone with an enhanced spectrum of activity against gram-positive aerobic organisms and anaerobes. Antimicrob Agents Chemother 1995;39:1636643. VW Tanaka M. Hoshino K. Ishida H, Sato K, Hayakawa I, Osada Y. Antimicrobial activity of DV-7751. a new fluoroquinolone. Antimicrob Agents Chemother 1993:37:2112-8. R. In vitro activity of ~1291Dahlhoff A, Petersen U. Endermann BAY 12-8039, a new 8-methoxyquinolone. Chemotherapy 1996;42:410~25. M, Tunewall G. Trimethoprim-sulu301 Bengtsson E, Evambom famethoxazole treatment in staphylococcal endocarditis and gram-negative septicemia. Stand J Infect Dis 1974;6:177-82. [I311 Elwell LP. Wilson HR, Knick VB, Keith BR. In vitro and in vivo efficacy of the combination trimethoprim-sulfamethoxazole against clinical isolates of methicillin-reistant Stuphylococcus aureus. Antimicrob Agents Chemother 1986:29:109224. [132] Gorgolas de M, Aviles P, Verdejo C, Fernandez-Guerrero ML. Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphldococcus aureus with trimethoprim-sulfamethoxazole and antibiotics that inhibit cell wall synthesis. Antimicrob Agents Chemother 1995;39:95337. [133] Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med 1992;117:390&8.

F.-J. Scchmit-_, M.E. Jones /International [134] Street AC, Durack

DT. Experience with trimethoprim-sulfamethoxazole in treatment of infective endocarditis. Rev Infect Dis 1988;10:915-21. [ 1351 Tamer MA, Bray JD. Trirnethoprim-sulfamethoxazole treatment of multi-antibiotic-resistant staphylococcus endocarditis and meningitis. Clin Pediatr 1982:21:125-6. [ 1361 Walsh TJ, Reboli AC et al. Randomized double blinded trial of rifampin or trimethoprim sulfamethoxazole against methicillinresistant Staphylococcus aureus colonization prevention at antimicrobial resistance and effects of host factors on outcome. Antimicrob Agents Chemother 1990:37:1334442. [I371 Yeldandi V, Strodtman R, Lentino JR. In vitro and in vivo studies of trimethoprim-sulfamethoxazole against multiple resistant Stuphylococcus aurws. J Antimicrob Chemother 1988:22:873-80. [138] Lawrence T. Totstein C, Bean R, Gorzynski EA. Amsterdam D. In vitro activities of rlmoplanin, selected glycopeptides, fluoroquinolones. and other antibiotics against clinical bloodstream isolates of Gram-positive cocci. Antimicrob Agents Chemother 1993;37:8966900. [I 391 Schaefler SD, Jones W, Perry L et al. Emergence of gentamicinand methicillin-resistant Strrphylococcus aureus strains in New York city hospitals. J Clin Microbial 1981:13:754-9. [I401 Darouiche R, Perkins B, Musher D, Hamill R. Tsai S. Levels of rifampin and ciprofloxacin .n nasal secretions: correlation with MIC90 and eradication of nasopharyngeal carriage of bacteria. J Infect Dis 1990;162:1124- 7. [I411 Dworkin RJ, Lee BL, Sandc MA. Chambers HF. Ciprofloxacin with rifampin: a predominantly oral regimen for right-sided Staphylococcus aureus endocarditis in intravenous drug abusers. Lancet 1989;i:1071-2. [I421 Karchner AW. Archer GL, Dismukes WE. Staphylococcus epidermidis causing prosthetic valve endocarditis: microbiologic and clinical observations guides to therapy. Ann Intern Med 1983;98:447-55. [143] Van der Auwera P, Meunier-Carpenter F, Klastersky J. Clinical study of combination therapy with oxacillin and rifampin for staphylococcal infections. Rev Infect Dis 1983;5 (Supp1):551522. [I441 Massanari RM, Donta ST. The efficacy of rifampin as adjunctive therapy in selected cases of staphylococcal endocarditis. Chest 1978;73:375-7. [l45] Ward TT, Winn RE, Hartstein AL, Sewell DL.Observations relating to an inter-hospital outbreak of methicillin-resistant Staphylococcus aureus: role of antimicrobial therapy in infection control. Infect Control 1981:2:453-9. [I461 Arathoon EG. Hamilton JR, Hench CE. Stevens DA. Efficacy of short courses of oral novobiocin-rifampin in eradicating carrier state of methicillin-resistant Staphylococcus aureus and in vitro killing studies of clinical isolates. Antimicrob Agents Chemother 1990:34:1655-9. [I471 Hackbarth CJ, Chambers HF, Sande MA. Serum bactericidal activity of rifampin in combination with other antimicrobial agents against Staphylococcus aureus. Antimicrob Agents Chemother 1986;29:61l-3. [I481 Henry NK, Rouse MS, Whitesell AL, McConnell ME, Wilson WR. Treatment of methicillin-resistant Stuphy/ococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med 1987;82 (Suppl 4a):73-5. [I491 Kaatz GW, Seo SM, Barriere SL. Albrecht LM, Rybak MJ. Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother 1989;33:1184-7. [I501 Bayer AS. Lam K. Efficacy of vancomycin plus rifampin in experimental aortic-valve rndocarditis due to methicillin-resistant Stap/zdococcus aureus: in-vitro-in-vivo correlations. J In-

Journal of Antimicrobial Agents 9 (1997) l-19

17

feet Dis 1985:151:157-65. [15l] Eng RH, Smith SM, Tillem M. Cherubin C. Rifampin-resistance. Development during therapy of methicillin-resistant Staphylococcus aureus. Arch Intern Med 1985;145:146-8. [l52] Segreti J, Gvazdinskas LC, Trenholme GM. In vitro activity of minocycline and rifampin against staphylococi. Diagn Microbiol Infect Dis 1989;12:253-5. [I531 Williams JD, Phillips 1. Rifampicin as an anti-staphylococcal agent. J Antimicrob Chemother 1984;13 (Suppl C):l-68. [154] Zinner SH, Lagast H, Klasterski J. Antistaphylococcal activity of rifampin with other antibiotics. J Infect Dis 1981;144:36571. 1551 Smith SM. Mangia A, Eng RHK et al. Clindamycin for colonization and infections by MRSA. Infection 1988:16:95-7. 1561 Reeves DS. Holt HA. Phillips I et al. Activity of clindamycin against Staphylococcus aureus and Staphylococcus epidermidis from four UK centres. J Antimicrob Chemother 1991;27:46974. 1571 Klainer AS. Clindamycin. Medical Clinics of North America 1987;71:1169-75. [I581 Kondo S, Linuma K, Yamamoto H, Maeda K, Umezawa H. Synthesis of I-N-((S)-4-amino-2-hydroxybutyryll-kanamycin B and -3’,4’-dideoxykanamycin B active against kanamycin-resistant bacteria. J Antibiot 1973;26:412-5. [159] Kindo S, Tamura A, Gomi S, Ikeda Y, Takiushi T. Mitsuhashi S. Structures of enzymatically modified products of arbekacin by methicillin-resistant Staphylococcus aureus. J Antibiot 1993;46:310-5. [160] Cafferkey MT, Hone R, Keane CT. Antimicrobial therapy of septicemia due to MRSA. Antimicrob Agents Chemother 1985;28:819923. [I611 Iwarson S, Fasth S, Olaison L et al. Adverse reactions to intravenous administration of fusidic acid. Stand J Infect Dis 1981;13:65-7. [I621 Lowbury JL, Cason JS, Jackson DM et al. Fucidin for staphyolococcal infection of burns. Lancet 1962;1:478-80. [I631 Amirak ID, Li AKC, Williams RJ et al. A fatal infection caused by MRSA acquiring resistance to gentamicin and fusidic acid during therapy. J Infect 1981;3:50-8. [I641 Besnier JM, Kanoun F, Martin C et al. Failure of a combination of vancomycin and fusidic acid in a patient with staphylococcal infection. J Antimicrob Chemother 1991;27:560-2. [l65] Portier H. A multicentre. open clinical trial of a new intravenous formulation of fusidic acid in severe staphylococcal infection. J Antimicrob Chemother 1990;25(Suppl B):39-44. [I661 Sum PE, Lee, VJ, Testa, RT, Hlavka. JJ, Ellestad. GA, Bloom, JD et al. Glycylcyclines: a new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 1994;37:184-8. [167] Testa RT, Petersen PJ, Jacobus NV, Sum PE, Li VJ. Tally FP. In vitro and in vivo antibacterial activities of the glycylcyclines. a new class of semi-synthetic tetracyclines. Antimicrob Agents Chemother 1993;37:2270-7. [168] Qadri SMH. Halim M. Ueno Y, Saldin H. Susceptibility of methicillin-resistant Staphylococcus aureus to minocycline and other antimicrobials. Chemotherapy 1994;40:2669. [169] Yuc JH. Dignani MC, Harris RL, Bradshaw MW, Williams TW. Minocycline as an alternative antistaphylococcal agent. Rev Infect Dis 1991;13:1023-4. [170] Chow JW, Hilf M, Yu VL. Synergistic interaction of antibiotics with nasal penetration to methicillin-sensitive and methicillinresistant Stc~pl~_vloeoccusaureus. J Antimicrob Chemother 1991;27:558-60. [l71] Lawlor MT. Sullivan MC, Levitz RE, Quintiliani R, Nightingale CH. Treatment of prosthetic valve endocarditis due to methicillin-resistant Staphylococcus aureus with minocycline. J Infect Dis 1990;161:812-4.

18 ~1721Nicolau

F.-J. Schmitz, M.E. Jones /International

DP, Freeman CD, Nightingale CH, Coe CJ, Quintiliani R. Minocycline versus vancomycin for treatment of experimental endocarditis caused by oxacillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1994;38:1515-8. [I731 Walsh TJ, Vlahov D, Hansen SL et al. Prospective microbiologic surveillance in control of nosocomial methicillin-resistant Staphylococcus aureus. Infect Control 1987;8:7-14. [I741 Scully BE, Briones F, Gu JW, Neu HC. Mupirocin treatment of nasal staphylococcal colonization. Arch Intern Med 1992;152:35336. [I751 Hooper DC, Wolfson JS, McHugh GL et al. Effects of novobiocin, coumermycin Al, clorobiocin and their analogues on Escherichia co/i DNA gyrase and bacterial growth. Antimicrob Agents Chemother 1982;22:662-71. CH, Fan ST, Lau KF. In vitro and in [I761 Lau WY, Teoh-Chan vivo study of fosfomycin in MRSA septicemia. J Hyg 1986;96:419-23. in the field of phosphonic [I771 Neumann M. Recent developments acid antibiotics. J Antimicrob Chemother 1984;14:309-11. P781 Aldridge KE, Schiro DD, Varner LM. In vitro antistaphylococcal activity and testing of RP 59500, a new streptogramin, by two methods. Antimicrob Agents Chemother 1992;36:854-5. [179] Aumercier M, Bouhallab S, Canmau ML. Le Goffic F. RP 59500:a proposed mechanism for its bactericidal activity. J Antimicrob Chemother 1992;30 (Suppl A):9-14. DH. Synergistic activity and fractional inhibitory 11801Bouanchaud concentration (FIG) index of components of RP 59500, a new semisynthetic streptogramin. J Antimicrob Chemother 1992;30 (Suppl A):9559. J, Shah S. In-vitro activity of RP [1811 Brumfitt W. Hamilton-Miller 59500, a new semisynthetic streptogramin antibiotic, against Gram-positive bacteria. J Antimicrob Chemother 1992;30 (Suppl A):122-77. 11821Chambers HF. Studies of RP 59500 in vitro and in a rabbit model of aortic valve endocarditis caused by methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 1992;3O(Suppl A):1 18-122. N, Chinali G, Cocito C. Review: The molecular U831 DiGiambattista basis of the inhibitory activities of type A and type B synergimycins and related antibiotics on ribosomes. J Antimicrob Chemother 1989;24:485-507. 11841Entenza JM, Drugeon H, Glauser MP, MoreiIIon P. Treatment of experimental endocarditis due to erythromycin-susceptible or -resistant methicillin-resistant Staphyloccocus aureus with RP 59500. Antimicrob Agents Chemother 1995;39:1419-24. 11851Fantin B, Leclercq R, Ottaviani M et al. In vivo activities and penetration of the two components of the streptogramin RP 59500 in cardiac vegetations of experimental endocarditis. Antimicrob Agents Chemother 1994;38:432-7. in11861Fass RJ. In vitro activity of RP 59500, a semisynthetic jectable pristinamycin, against staphylococci, streptococci, and enterococci. Antimicrob Agents Chemother 1991;35:553-9. R, Okubo T, Inoue K, Mitsuhashi S. 11871Inoue M. Okamoto Comparative in vitro activity of RP 59500 against clinical bacterial isolates. J Antimicrob Chemother 1992;30:45-51. of RP 59500 alone [I881 Kang LS, Rybak MJ. Pharmacodynamics and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model. Antimicrob Agents Chemother 1995;39:1505-11. P. Bacterial resistance to macrolide, S891 Leclercq R. Courvalin lincosamide and streptogramin antibiotics by target modification Antimicrob Agents Chemother 1991;35:1267-72. u901 Leclercq R, Nantas L, Soussy J, Duval J. Activity of RP 59500, a new parenteral semisynthetic streptogramin, against staphylococci with various mechanisms of resistance to macrolide-lincosamide-streptogramin antibiotics. J Antimicrob Chemother 1992;30 (Suppl A):67-75.

Journal of Antimicrobial Agents 9 (1997) l-19 [191] Neu HC, Chin NX; Gu JW. The in vitro activity of new streptogramins RP 59500, RP 57669, and RP 54476, alone and in combination. J Antimicrob Chemother 1992;30 (Suppl A):83394. [192] Thabaut A, Meyran M, Huerre M. Evolution and present situation of Staphylococcus aureus sensitivity to MLS in hospitals (197551983). J Antimicrob Chemother 1985;16 (Suppl A):205-6. [193] Ganguly AK, Szmulewicz S. Structure of everninomicin B. J Antibiot 1975:28:707-9. [194] Schlaes DM, Schlaes JH, Etter L, Hare RS, Miller GH. SCH 27899 (EVE), an everninomicin active against multiply-resistant enterococci and staphylococci. Abstract of 33rd ICAAC, New Orleans. No 460, 1993. K, Wadee C, Chahrour [I951 Urban C, Mariano N, Mosinka-Snipds R. Rahal JJ. Comparative in-vitro activity of SCH 27899, a everninomicin, novel and vancomycin. J Antimicrob Chemother 1996;37:361-4. VW Nakashio S, Iwasawa H, Dun FY, Kanemitsu K, Shimada J. Everninomicin, a new oligosaccharide antibiotic: its antimicrobial activity. post-antibiotic effect and synergistic bactericidal activity. Drugs Exp Clin Res 1995;21:7-16. u971 Casewell MW, Hill RLR. The carrier state: methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 1986;18 (Suppl A):ll12. 11981Boyce JM, Laundry M, Deetz TR, DuPont HL. Epidemiologic studies of an outbreak of nosocomial methicillin-resistant Staphylococcus aureus infections. Infect Control 1981;2: 110-6. B, Zaske D. An outbreak of infec[1991 Crossley K, Landesmann tions caused by strains of Staphylococcus aureus resistant to methicillin and aminoglycosides. J Infect Dis 1979;139:280-7. Fw Peacock JE, Moorman DR, Wenzel RP, Mandell GL. Methicillin-resistant Staphylococcus uureus: microbiological characantimicrobial susceptibility, and assessment of teristics, virulence of an epidemic strain. J Infect Dis 1981;144:575582. Wll Nobel WC, Williams REO, Jevons MP, Shooter RA. Some aspects of nasal carriage of staphylococci. J Clin Path 1964;17:79-83. of StaphyiococPO21 Ehrenkranz NJ. Person-to-person-transmission cus uureus: quantitative characterization of nasal carriers spreading infection. N Eng J Med 1964;271:225-30. Staphjdo~2031Lye WC, Leong SO, Lee EJC. Methicillin-resistant coccus aureus nasal carriage and infections in CAPD. Kidney Int 1993;43:1357762. ~2041Muder RR, Brennen C, Wagener MM et al. Methicillin-resistant staphylococcal colonization and infections in an long-term care facility. Ann Intern Med 1991;114:107-12. with m51 Mest DR, Wong DH, Shimoda KJ. Nasal colonization methicillin-resistant Staphylococcus aureus on admission to the surgical intensive care unit increases the risk of infection. Anaest Anal 1994;78:644-50. PO61 Pujol M, Pena C, Pallares R et al. Nosocomial Staphylococcus aureus bacteremia among nasal carriers of methicillin-resistant and methicillin-susceptible strains. Am J Med 1996;100:509- 16. [207] Hershow RC, Khayr WF, Smith NL. Comparison of clinical virulence of nosocomially acquired methicillin-resistant and methicillin-sensitive Staphylococcus aureus infections in a university hospital. Infect Control Hosp Epidemiol 1992;13:587793. [208] Hewitt H, Sanderson PJ. The effect of methicillin on skin lesions in guinea pigs caused by “methicillin-sensitive” and “methicillin-resistant” Staphylococcus aureus. J Med Microbial 1974;7:223-28. [209] Talon D, Rouget C, Cailleaux V et al. Nasal carriage of Staphylococcus aureus and cross contamination in a surgical care unit: efficiency of mupirocin ointment. J Hosp Infect 1995;30:39949.

F.-J. Schmitr. M.E. Jones /Internutional [210] Coello R, Garcia M, Arroyo P et al. Prospective study of infection, colonization and carriage of methicillin-resistant Staphylococcus aureus in 2.n outbreak affecting 990 patients. Eur J Clin Microbial Infect Dis 1994:13:74-81. [211] Guiguet M. Rekacewicz C, Leclerq B. Brun Y, Escudier B, Andermont A. Effectivener#s of simple measures to control an outbreak of nosocomial methicillin-resistant Staphylococcus aureus in an intensive care unit. Infect Control Hosp Epidemiol 1990;11:23-6. [212] Bitar CM, Mayhall CG, Lamb VA, Bradshaw TJ, Spadora AC, Dalton HP. Outbreak due to methicillin- and rifampicin-resistant Staphylococcus aurew : Epidemiology and eradication of the resistant strain from the hospital. Infect Control 1987:&l 523. [213] Murray-Leisure KA, Geib S, Graceley D et al. Control of epidemic methicillin-resistant Staphylococcus aurcus. Infect Control Hosp Epidemiol 1990;11:343-50. [214] Barrett ST. The value of nasal mupirocin in containing an outbreak of methicillin-resistant Staphylococcus aureus in an orthopaedic unit. J Hosp Infect 1990;15- 137-42. [215] Boyce JM. MRSA in hospitals and long-term care facilities: microbiology. epidemiology and preventive measures. Infect Control Hosp Epidemiol 1992;13:725-37. [216] Boyce JM. Strategies for controlling methicillin-resistant Sraphylococcus aureus in hospitals. J Chemother 1995;7 (Suppl 3):81-5. [217] Casewell MW, Hill RCR. Mupirocin (“pseudoamonic acid”) a promising new topical antimicrobial agent. J Antimicrob Chemother 1987;19:1-5. [218] Casewell MW, Hill RL. h4inimal dose requirements for nasal mupirocin and its role in the control of epidemic MRSA. J Hosp Infect 1991;19 (Suppl B):35-40. [219] Darouiche R, Wright C, Hamill R et al. Eradication of colonization by methicillin-resistant Staphylococcus aureus by using oral minocycline-rifampin and topical mupirocin. Antimicrob Agents Chemother 1991;35:1612. [220] Davies EA, Emmerson AR/I, Hogg GM, Patterson MF, Shields MD. An outbreak of infections with a MRSA in a special care baby unit: value of topical mupirocin and of traditional methods of infection control. J Hosp Infect 1987;10:120&8. [221] Doebbeling BN, Breneman DL, Neu HC et al. Elimination of Staphylococcus aureus nasal carriage in health care workers: analysis of six clinical trials with calcium mupirocin ointment. Clin Infect Dis 1993;17:466-74. [222] Doebbeling BN. Reagan DR, Pfaller MA, Houston AK, Hollis RJ, Wenzel RP. Long-tern efficacy of intranasal mupirocin ointment. Arch Inter Med 1994;154:1505%8. [223] Frank U, Lenz W, Damrath E, Kappstein I, Daschner FD. Nasal carriage of Sruphy/ococcus aureus treated with topical mupirocin (pseudomonic acid) in a children hospital. J Hosp Infect 1989;13:117-20. [224] Hill RL, Duckworth GJ, Casewell MW. Elimination of nasal carriage of MRSA with mupirocin during a hospital outbreak. J Antimicrob Chemother 1988:22:377-84. [225] Kaufmann CA et al. Attempts to eradicate methicillin-resistant

Journal of’ Antimicrobial Agents 9 (1997) I-19

[226]

[227]

[228]

[229]

[230]

[231]

[232]

[233]

[234]

[235] [236] [237]

[238]

[239] [240]

[241]

19

Staphylococcus nureus from a long-term care facility with the use of mupirocin ointment. Am J Med 1993;94:371-8. Layton MC, Patterson JE. Mupirocin resistance among consecutive isolates of oxacillin-resistant and borderline oxacillin-resistant Staphylococcus aureus at a university hospital. Antimicrob Agents Chemother 1994:38:1664&7. Maple PAC, Hamilton-Miller JMT. Brumfitt W. Comparison of the in vitro properties of the topical antimicrobials azelaic acid, nitrofurazone, silver sulphadiazine and mupirocin against methicillin-resistant Stuphldococ~us nureus. J Antimicrob Chemother 1992;29:661-8. Parras F. Guerrero M.C.. Bouza E et al. Comperative study of mupirocin and oral co-trimoxazole plus topical fusidic acid in eradication of nasal carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1995;39:175-9. Reagan DR, Doebbeling BN, Pfaller MA et al. Elimination of coincident Staphylococcus aureus nasal and hand carriage with intranasal application of mupirocin calcium ointment. Ann Intern Med 1991:114:101~6. Bryan CS, Wilson RS, Meade P, Sill LG. Topical antibiotic ointments for staphylococcal nasal carriers: survey of current practices and comparison of bacitracin and vancomycin ointments. Infect Control 198O;l: 153-6. Hughes J, Mellows G. Interaction of pseudomonic acid A with Escherichia coli B isoleucyl tRNA synthetase. Biochem J 1980;191:209%19. Farmer TH, Gilbart J, Elson SW. Biochemical basis of mupirocin resistance in strains of Staphylococcus aurws. J Antimicrob Chemother 1992;30:587-96. Capabianco JO. Doran CC, Goldstein RC. Mechanism of mupirocin transport to sensitive and resistant bacteria. Antimicrab Agents Chemother 1989;33:156-63. Rahman M. Connolly S, Nobel WC, Cookson B, Phillips I. Diversity of staphylococci showing high-level resistance to mupirocin. J Med Microbial 1990;33:97- 100. Rahman M, Noble WC, Cookson BD. Mupirocin-resistant Staphylococcus aureus. Lancet 1989;i:387. Slocombe B, Perry C. The antimicrobial activity of mupirocin an update on resistance. J Hosp Infect 1991;19 (B):19-25. Witte W. Klare I. Sensitivity to mupirocin of staphylococci isolated from colonized or infected patients in Germany. Eur J Clin Microbial Infect Dis 1993;12:476&8. Pearman JW, Christiansen KJ. Annedr DI et al. Control of methicillin-resistant Staphylococcus aureus (MRSA) in an Australian metropolitan teaching hospital complex. Med J Aust 1985;142:103-8. Poupard JA. Update on mupirocin resistance. J Chemother 1995;7 (Suppl 3):71-4. Rhinehart E, Shlaes DM. Keys TF et al. Nosocomial clonal dissemination of methicillin-resistant Staph~vlococcus aureus. Elucidation by plasmid analysis. Arch Intern Med 1987;147:521-4. Bradley JM. Noone P, Townsend DE, Grubb WB. Methicillinresistant Stuphylococcus aureus in a London hospital. Lancet 1985;i:l493-5.