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Glycopeptide antibiotics: evolving resistance, pharmacology and adverse event profile Expert Rev. Anti Infect. Ther. Early online, 1–14 (2015)
Karl Evans R Henson1, Miriam T Levine1, Eunice Ann H Wong1 and Donald P Levine*1,2 1 Department of Medicine, Division of Infectious Diseases, Detroit Medical Center and Wayne State University School of Medicine, 4201 St Antoine St, Detroit, MI 48201, USA 2 Department of Medicine, Division of General Internal Medicine, Detroit Receiving Hospital and University Health Center, Detroit, MI, USA *Author for correspondence: Tel.: +1 313 577 7935 Fax: +1 313 933 0645 [email protected]
The first glycopeptide antibiotic was vancomycin, isolated from the soil in the 1950s; since then, the class has expanded to include teicoplanin and the new semisynthetic glycopeptides dalbavancin, oritavancin and telavancin. They are bactericidal, active against most Gram-positive organisms, and in a concentration-dependent manner, inhibit cell wall synthesis. Resistance to vancomycin has emerged, especially among enterococci and Staphylococcus aureus through a variety of mechanisms. This emerging resistance to vancomycin makes proper dosing and monitoring of the area under the curve/MIC critically important. The chief adverse effect of vancomycin is nephrotoxicity, which is also intricately related to its dose. The efficacy of the semisynthetic glycopeptides has been demonstrated in skin and soft-tissue infections, but remains to be seen in serious methicillin-resistant Staphylococcus aureus infections. KEYWORDS: adverse events . dalbavancin . glycopeptides . oritavancin . pharmacodynamics . pharmacokinetics .
teicoplanin
.
telavancin . vancomycin
Introduction & historical perspective
Vancomycin, the first glycopeptide antibiotic (GPA), was discovered in the 1950s when a missionary in Borneo sent soil samples to his friend, an organic chemist working at Eli Lilly. The company had initiated a program to search for new antibacterials effective against penicillin-resistant staphylococci. A compound was isolated from the soil that was active against most Gram-positive bacteria. Compound O5865, dubbed ‘Mississippi mud’ because of the brown color of the solution, required purification via passage through an ion-exchange resin. The resulting drug was vancomycin [1], and it was intended for the use in penicillin-resistant staphylococci. However, with the approval of methicillin in 1958, followed soon after by cephalothin in 1964 [2,3], and because of the perceived toxicity profile of vancomycin, it soon became reserved for patients with serious b-lactam allergies or patients with infections caused by organisms resistant to the newer agents.
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MRSA developed as a result of sustained and widespread use of beta-lactam antibiotics. By the early 1990s, MRSA was acknowledged as an endemic nosocomial problem. Communityacquired MRSA strains were isolated soon after. This resistance trend brought vancomycin back to the forefront. While vancomycinresistant enterococci (VRE) caused problems in the early 1980s, it was not until 1997 when a lack of clinical response in a patient treated with vancomycin for S. aureus was documented and the first vancomycinintermediate strains (VISA) was isolated. In 2002, the first vancomycin-resistant S. aureus (VRSA) strain was isolated. Over the next several decades, more members of the glycopeptide class were discovered or synthesized, mainly driven by the need for antibiotics with activity against increasingly resistant Gram-positive bacteria [2]. Contributing to this renewed interest in glycopeptides was the ability in the 1980s to determine the chemical structures of these complex molecules. In fact, vancomycin’s structure was only fully
2015 Informa UK Ltd
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Review
Henson, Levine, Wong & Levine
Vancosamine
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Glucose
AA6 AA1
class, the glycopeptides are active against staphylococci, streptococci, Granulicatela spp. and Abiotrophia defectiva (formerly known as nutritionally variant streptococci), Listeria spp., Bacillus spp., Corynebacterium spp., Rhodococcus equi, Lactobacillus acidophilus, most Clostridium spp., and the majority of Gram-positive anaerobes. Most Enterococcus faecalis and some E. faecium remain susceptible to the GPAs. The rest of the members of the Lactobacillus genus, Clostridium ramosum, C. innocuum, Leuconostoc spp., Pediococcus spp. and Erysipelothrix rusopathiae are intrinsically resistant to this antibiotic class [4]. Vancomycin
Vancomycin (FIGURE 1) [5,6] was isolated from the actinomycete Streptomyces orientalis [1]. The components of the molecule are as follows: the heptapeptide core comAA7 posed of two chlorinated tyrosines, three AA5 phenylglycine systems, aspartic acid and N-methylleucine. The molecule becomes AA2–4 cyclic by means of two ether bonds and a carbon–carbon bond in various parts of the heptapeptide backbone. The disacchaFigure 1. The chemical structure of vancomycin [5,6]. Vancomycin is a complex molecule composed of a disaccharide (vancosamine and glucose) attached to a ride is composed of vancosamine and gluheptapeptide backbone. cose and is not a part of the cyclic AA1 and AA6: b-hydroxychlorotyrosine; AA2-4: Three phenylglycine systems; structure [6]. AA5: Aspartate amide; AA7: N-methylleucine. Vancomycin inhibits cell wall synthesis by forming a stable, noncovalent complex elucidated in 1982, roughly 20 years after its first discovery [3]. with the C-terminal D-Ala-D-Ala of murein monomers, nascent In the late 1980s, clinicians in Europe started to use teicoplanin peptidoglycan precursor units that emerge from the bacterial as an alternative to vancomycin; this antibiotic is not approved cytoplasm. These monomers normally attach to the growing for use in the USA. Apart from vancomycin and teicoplanin, the peptidoglycan molecule by transglycosylation followed by transcurrent members of the GPAs in clinical use today include the peptidation. The precursor-vancomycin noncovalent complex is youngest members of the class, the semisynthetic glycopeptides held together by five hydrogen bonds between the amino acids dalbavancin, oritavancin and telavancin. in vancomycin and the D-Ala-D-Ala residue. The complex Ristocetin, another glycopeptide, was released almost at the enters the cell membrane and causes a conformational change same time as vancomycin but because of hematologic toxicity was that blocks glycosyltransferase, resulting in inhibition of the quickly withdrawn from the market [3]. Avoparcin and actaplanin incorporation of the precursor molecules to the growing peptiare used in veterinary practice but not in humans. In this review, doglycan chain. This also prevents further transpeptidation and we will provide a brief overview of the chemistry and mechanism subsequent interruption of cell wall synthesis. The primary effect of action of the GPAs, an examination of the current antimicro- of this inhibition is in the late stages of cell wall synthesis in bial resistance trends, specifically in S. aureus and enterococci, dividing bacteria [4,7,8]. and an examination of the pharmacodynamics, pharmacokinetics and adverse effects of this peculiar class of antibiotics. Teicoplanin First described in 1978, teicoplanin (formerly teichomycin A2) Chemistry & mechanism of action is a GPA obtained by fermenting the actinomycete Actinoplanes The GPAs are tricyclic or tetracyclic compounds with a core teichomyceticus [9]. Its structure is similar to vancomycin, and it made up of seven amino acids (heptapeptide) to which are shares many chemical and microbiological properties with its bound two sugar moieties, giving rise to the name glycopeptide. older sibling, including its mechanism of action. It is a comThe GPAs are active only against Gram-positive bacteria. As a plex molecule composed of a backbone cyclic heptapeptide doi: 10.1586/14787210.2015.1068118
Expert Rev. Anti Infect. Ther.
Glycopeptide antibiotics
made up of aromatic amino acids, as well as two sugar moieties (D-mannose and N-acetyl-beta-D-glucosamine). It differs from vancomycin by the presence of a fatty acid moiety that allows the molecule greater tissue and cellular penetration [10].
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Lipoglycopeptides
There are three new lipoglycopeptides that are in clinical use today: telavancin, dalbavancin and oritavancin. The basic mechanism of action of these agents is the same as vancomycin. However, a feature common to all three lipoglycopeptides is the addition of a lipophilic side chain that increases the interaction with the bacterial cellular membrane by anchoring the compound to the lipid bilayer. This improves the molecule’s affinity for the terminal D-Ala-D-Ala, thereby enhancing its antimicrobial activity [11]. Telavancin, developed in 2005, is a semisynthetic derivative of vancomycin derived by the addition of a lipophilic decylaminoethyl substituent on the vancosamine amino group and a hydrophilic (phosphomethyl)aminoethyl moiety on one of the phenylglycine residues [3]. The hydrophilic side chain both enhances telavancin’s ability to distribute into tissues and its clearance, reducing any potential nephrotoxicity [11]. Dalbavancin is a derivative of the teicoplanin-like antibiotic A-40926, an agent produced by the actinomycete Nonomuria spp [11]. It was developed in the 1990s and approved for clinical use in 2014. The addition of a dimethylaminopropanolamine group via amidation of the C-terminal carboxyl moiety produced dalbavancin from teicoplanin. This modification resulted in a half-life of over 300 h [3]. Oritavancin (LY333328) was also discovered in the 1990s and is synthetically derived from a naturally occurring glycopeptide chloroeremomycin. A hydrophobic chlorophenyl-benzyl group is attached to the vancosamine amine, and there is an additional aminosugar on the phenylserine hydroxyl group [3]. These structural features account for oritavancin’s improved activity against VRE, including against vanA-producing strains. Because of oritavancin’s hydrophobic side chain and a high degree of protein binding its terminal half-life is over 300 h [11]. Resistance to glycopeptides
As in other classes of antibiotics, microbial resistance determines how we use vancomycin and the GPAs, especially in regard to S. aureus and the enterococci. Since vancomycin is the most widely used of all GPAs, most studies involve this antibiotic. Our discussion will follow the same course. Vancomycin-resistant enterococci & vancomycin-resistant S. aureus
Because of the frequent use of oral vancomycin for Clostridium difficile infections and iv. vancomycin for MRSA, enterococci soon developed resistance to vancomycin and teicoplanin. Uttley first reported this occurrence in E. faecium in 1988 [12] during a VRE outbreak in a hospital renal unit. Since then, various types of VRE, based on both phenotypic and genotypic changes, have been described [13]. High-level enterococcal GPA resistance informahealthcare.com
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occurs when the bacterium acquires and expresses operons that substitute a terminal D-lactate (D-Lac) or D-serine (D-Ser) for the terminal D-Ala in peptidoglycan precursors [14]. The D-lactate (D-Lac) replacement results in a 1000-fold decrease in vancomycin affinity because of the loss of one of the five hydrogen bonds needed for the drug to interact with the peptidoglycan precursor [15]. The D-serine (D-Ser) replacement affects vancomycin binding in a similar way but to a smaller degree. Another mechanism involves prevention or destruction of precursors that end in D-Ala by specific dipeptidases and carboxypeptidases [15]. There are seven operons or gene clusters that have been described (vanA, vanB, vanC, vanD, vanE, vanG and vanL) [16]. Among these, vanA and vanB are the most important clinically, especially since they are transferable via transposons. Enterococci with the vanA gene are resistant to both vancomycin and teicoplanin; exposure to either drug induces resistance. In contrast, vanB enterococci retain teicoplanin susceptibility and are resistant only to vancomycin [13]. While enterococci are not generally considered highly virulent bacteria, they are intrinsically resistant to multiple antibiotic classes and are able to acquire additional resistance mechanisms [13]. They then become reservoirs of antimicrobial resistance genes. In 1992, the conjugative transfer of vancomycin and other resistance genes from an E. faecalis to S. aureus was documented for the first time [17]. This transmissibility of vancomycin resistance genes to S. aureus was purely an in vitro phenomenon until the first report in 2002 of a S. aureus clinical isolate with a vancomycin MIC of 1024 mg/ml [18]. The isolate was from an infected catheter exit-site of a 40 year old diabetic woman receiving hemodialysis [19]. Since then, additional isolates have been found throughout the world [20,21]. Thus far, no deaths have been attributed to infection with these organisms. Expression of the vanA gene in S. aureus appears to come with a fitness cost to the organism [22] and the rarity of VRSA suggests that clonal spread does not occur with these isolates [14]. Using its three-tier antimicrobial resistance threat level (urgent > serious > concerning), the CDC has classified VRSA only as a ‘concerning’ threat [23]. The mechanism of resistance of enterococci and S. aureus to the other GPAs is mainly through the resistance operons discussed above. Teicoplanin retains activity against organisms with the vanB operon; strains expressing the vanA operon are highly resistant to teicoplanin [3]. Among the newer glycopeptide agents, only oritavancin retains efficacy against clinical strains that express both vanA and vanB gene clusters. VanA-producing strains are resistant to both dalbavancin and telavancin; these two antibiotics retain their efficacy against vanB-producing strains [3]. All three lipoglycopeptides have low potential for development of resistance; thus far, no clinically isolated strains exhibit resistance to the lipoglycopeptides. Vancomycin-intermediate S. aureus
The stepwise development of intermediate resistance (MIC 4–8 mg/ml) to vancomycin in S. aureus is the more common type [8,14]. The first VISA was isolated in Japan in 1997 and doi: 10.1586/14787210.2015.1068118
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Henson, Levine, Wong & Levine
had a vancomycin MIC of 8 mg/ml [24]. With vancomycin MICs in the intermediate range, clinicians are alerted to the likelihood of clinical failure when vancomycin is used. A more worrisome phenomenon is the increasing prevalence of heterogeneous vancomycin-intermediate S. aureus (hVISA). These strains have apparent vancomycin MICs in the susceptible range; only clinical failure with vancomycin despite susceptible-range MICs suggests the possibility of an hVISA infection [24]. hVISA is defined as a S. aureus isolate with a vancomycin MIC in the susceptible range (current breakpoint is £2 mg/ml) but where a proportion of the cells have MICs in the intermediate range [8]. The gold standard to detect these isolates is the modified population analysis profile [25], where the area under the curve (AUC) of the test strain is referenced to an hVISA control strain Mu3 [26]. This test is not widely used because it is labor-intensive and has not been standardized. Any process that interferes with the basic mechanisms of action of vancomycin, that is binding to terminal D-Ala-D-Ala residues decreases its potency [8]. Studies on the mechanisms that lead to hVISA/VISA have demonstrated a completely separate process from the development of VRSA. While there are many phenotypic and genotypic changes exhibited by VISA strains, these organisms are consistently found to have thicker cell walls than vancomycin-susceptible S. aureus (VSSA) strains. Most isolates also have reduced autolytic activity. The thickened cell wall reduces vancomycin access to its active site in the division septum of the cell [8]. This ‘gradual clogging of the antibiotic into the thickened staphylococcal cell wall’ [27] is the mechanism responsible for low-level vancomycin resistance in VISA. VISA develops from VSSA via sequential mutations, and hVISA forms as an intermediate between the two. Most VISA/hVISA species were detected only after a protracted course of infection with GPA failure [28–31]. Clonality between the VSSA parent strain and its subsequent resistant pair has been documented [31]. Risk factors for developing VISA/hVISA include prior MRSA infection or colonization, exposure to vancomycin, infections with high bacterial burden, and low serum vancomycin levels early in the treatment course [8]. Before 2006, the cutoff for vancomycin susceptibility was an MIC of £4 mg/ml. However, an epidemiological study conducted by the CDC [32] found that vancomycin was equally ineffective against MRSA strains with MICs of either 4 or 8 mg/ml. In the middle of growing evidence of vancomycin failure in infections with S. aureus with higher MICs, the Clinical and Laboratory Standards Institute (CLSI) revised the susceptibility breakpoint for vancomycin against S. aureus to £2 mg/ml [18]. While the great majority of MRSA strains are still susceptible to vancomycin in vitro, there are data demonstrating vancomycin’s decreasing efficacy in serious MRSA infections when the MICs are at the upper limit of this susceptibility cutoff [3]. In a meta-analysis of 48 studies by van Hal et al., a high vancomycin MIC (‡1.5 mg/ml by Etest) was significantly associated with high mortality rates [33], especially in bloodstream infections. This same study found that in patients who had VSSA infection, a vancomycin MIC ‡1.5 mg/ml was predictive doi: 10.1586/14787210.2015.1068118
of treatment failure even when a b-lactam antibiotic was used. Even with varying vancomycin MIC cutoffs (‡1–2 mg/ml), there is compelling evidence demonstrating the association of high vancomycin MIC with increased mortality rates in both MRSA and MSSA [34–37]. The issue, however, is far from decided. There is much discussion in the literature in the past few years about the role of the MIC testing methodology in vancomycin dosing (see section on Pharmacodynamics). Furthermore, not all investigators agree on the association between worse outcomes and high vancomycin MICs. A well-designed meta-analysis by Kalil et al. [38]., reviewing 38 MRSA BSI papers did not find a statistically significant difference in the risk of death between patients with vancomycin MIC >1.5 mg/ml and £1.5 mg/ml. The conflicting data underscore the need for further research with larger, more diverse populations. Given the increasing problem of antimicrobial resistance, especially in MRSA, some have started to question the use of vancomycin as a first-line agent [39,40]. With vancomycin’s perceived toxicity and narrow therapeutic index, its slow clearing of bacteremias, the rising prevalence of VISA and the emerging hVISA problem, and the availability of newer agents, vancomycin might be becoming obsolete. Nevertheless, some argue that vancomycin remains relevant given the scant data available for the newer agents [27,41]. The current Infectious Disease Society of America MRSA guidelines still identify vancomycin as the preferred firstline agent for the treatment of MRSA infections, with appropriate caveats [42]. In the middle of this debate, it is prudent to assume that vancomycin will retain its central role in the treatment of serious infections with Gram-positive organisms. Pharmacodynamics Vancomycin
It is critically important that we have a clear understanding of this drug’s pharmacodynamics since the dosing regimen is closely tied to the development of resistant bacterial strains (TABLE 1) [43]. Despite its lengthy history, few studies properly evaluate vancomycin’s pharmacodynamic properties, and the data available have not produced robust results to help predict patient outcomes [44]. Vancomycin is a slow bactericidal, concentration-independent antibiotic, that is, the rate of killing is primarily dependent on the time of concentration exceeding the organism’s MIC [44–46]. It also has a prolonged postantibiotic effect that is inversely affected by the size of the inoculum (i.e., the ‘inoculum effect’) [47]. Several pharmacodynamic parameters are proposed for monitoring vancomycin in the clinical setting, including the time vancomycin concentration remains above the MIC (t>MIC), the ratio of area under the serum drug concentrationversus-time curve to the MIC (AUC/MIC) and the ratio of the maximum serum drug concentration to the MIC (Cmax/MIC). Based on in vitro and animal models and limited human studies, the AUC/MIC appears to be the best predictor of vancomycin efficacy against S. aureus [43,44,46,48]. A retrospective study by Moise-Broder et al. [49] demonstrated that an AUC/MIC of ‡400 was associated with faster bacterial eradication in patients Expert Rev. Anti Infect. Ther.
Glycopeptide antibiotics
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Table 1. Pharmacokinetic parameters of vancomycin, teicoplanin, dalbavancin, telavancin, and oritavancin [10,62,64]. Parameter
Vancomycin
Teicoplanin
Dalbavancin
Telavancin
Oritavancin
Standard dose
15 mg/kg q12h
6 mg/kg q24 h
1 g on day 1, 500 mg on day 8
10 mg/kg q24 h
3 mg/kg x 1
Cmax (mg/l)
20–50
68–155
312
88
29
AUC (mg*h/l)
260
420–621
27103
858
146
Vd (L/kg)
0.3
0.9–1.6
0.11
0.1
0.65–1.92
Protein-binding (%)
10–55
88–94
93–98
90–93
86–90
Blister fluid:plasma concentration
NA
NA
0.60–1.11
0.79–0.82
0.185–0.195
Terminal t1/2 (h)
4–8
70–100
147–258
7–9
393
Renal excretion (%)
>80–90
48–61
42
72
30 mg/l for MRSA endocarditis and osteomyelitis, respectively [81]. An initial loading dose (6–12 mg/kg every 12 h for 3 doses) has been recommended to reach optimal serum trough level (10–15 mg/ml) promptly, followed by a maintenance dose of 6 mg/kg once daily [82]. Dalbavancin
Dalbavancin is available as lyophilized powder for iv. injection. A 1 g loading dose is followed by a 500 mg dose after 7 days. It is poorly absorbed from the gastrointestinal tract and is not given orally. Maximum plasma drug concentrations of 278.3–301 mg/l have been measured after a dose of 1 g. Dalbavancin is highly protein-bound (93–98%). Penetration into blister fluid correlates with plasma drug concentrations. It achieves greater blister fluid concentration than either telavancin or oritavancin [11]. Drug distribution into 40 different tissues after a 20 mg/kg dose was analyzed in a rat model: the highest concentrations were found in the kidney and liver after 24 h, and measurable concentrations were retained in brown fat, skin and skeletal muscle after 14 days [60,83]. Dalbavancin does not induce, inhibit or serve as substrate for CYP450 isoenzymes unlike telavancin [11,67]. Population pharmacokinetic studies in a cohort of 532 patients with skin soft tissue infection (502 patients) and catheter-related bloodstream infection (30 patients) showed a direct proportion between body surface area and creatinine clearance and dalbavancin clearance with a half-life of 8.5 days. Dalbavancin is eliminated both by informahealthcare.com
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renal (42%) and nonrenal routes, but no dose adjustments are needed in mild and moderate renal and hepatic insufficiency, or in end-stage renal disease with regular hemodialysis. Dosage adjustment is required in severe renal impairment with creatinine clearance 4 g/day) were associated with greater risk of nephrotoxicity although this was based on observational studies. Patients receiving higher doses of vancomycin also tended to develop nephrotoxicity more rapidly. Higher vancomycin trough levels (>15–20 mg/L but especially >20 mg/L), higher peak concentrations, and area under the time–concentration curve of vancomycin have also been proposed as risk factors. Likewise, prolonged duration of vancomycin therapy increases the risk for renal insufficiency [89,91]. In studies reviewed by Elyasi et al., treatment with vancomycin beyond 1 week increases the risk of vancomycin-associated nephrotoxicity from 6 to 21%; durations of therapy beyond 2 weeks are associated with nephrotoxicity rates as high as 30%. While not commonly used, continuous vancomycin infusion was associated with less nephrotoxicity than intermittent dosing. As expected, concomitant nephrotoxic agents were found to increase the incidence or nephrotoxicity by up to 35%. Treatment with additional nephrotoxic agents increases the incidence of vancomycin-induced nephrotoxicity and the risk of renal failure. Most studies cited in this review noted additive or even synergistic nephrotoxicity between vancomycin and aminoglycosides [89]. Patient characteristics also affect the risk of vancomycininduced nephrotoxicity. Critical illness such as sepsis, severe trauma, severe pancreatitis, major surgery and burns predispose patients to vancomycin-induced renal insufficiency as these patients are more vulnerable to renal failure. Baseline decubitus ulcer, malignancy, neutropenia and peritonitis are also associated with an increased risk of vancomycin-induced nephrotoxicity, as is baseline renal impairment. Interestingly, elderly patients are not at increased risk. Nephrotoxicity is also relatively uncommon in the pediatric population. This may be because children typically have fewer comorbidities, normal baseline renal function and less frequent use in combination with other nephrotoxins. There are little data on the impact of pregnancy upon the risk of vancomycin-induced nephrotoxicity; a small study also reviewed by Elyasi et al. suggests that at least in the second and third trimesters the risk of nephrotoxicity is unchanged. Nephrotoxicity is usually reversible, with a low incidence of residual damage so long as the drug is either discontinued or properly dose-adjusted if renal impairment develops. Renal impairment is rarely severe enough to require renal replacement doi: 10.1586/14787210.2015.1068118
therapy; in the review by van Hal et al., only 3% of nephrotoxic episodes were treated with short-term dialysis. Therapeutic drug monitoring and vigilant screening for vancomycin-associated nephrotoxicity can decrease the risk of this adverse event [90]. Teicoplanin may cause nephrotoxicity, but much less frequently than vancomcyin. A literature review by Svetitsky et al. found a relative risk of 0.44 (95% CI, 0.32–0.61) for 21 trials and 0.33 (95% CI, 0.22–0.50) for 17 trials comparing teicoplanin with vancomycin [92]. Severe nephrotoxicity was reported only in patients receiving vancomycin. A 2010 Cochrane review of 24 studies (2610 patients) similarly reported a relative risk of nephrotoxicity to be 0.55 (95% CI, 0.30–0.88) when comparing teicoplanin to vancomycin [88]. Red man syndrome
Red man syndrome (RMS) is the most common adverse drug reaction associated with vancomycin, occurring in 5–50% of hospitalized subjects and up to 90% of healthy control subjects [93]. RMS encompasses a spectrum of syndromes ranging from flushing, urticaria and/or pruritis to generalized erythema, intense pruritis and even hypotension. The pathophysiology involves vancomycin-induced mast cell degranulation and histamine release and is considered a pseudo-allergic drug reaction with no underlying immunological process [7,93]. It is enhanced by coadministration of opiates. RMS is easily prevented or at least diminished by reducing the infusion rate to 10 mg/min or slower and by premedication with diphenhydramine and ranitidine [7]. A multicenter retrospective study of 546 hospitalized patients aged 21 or younger identified Caucasian ethnicity, age ‡2 years, previous history of RMS, vancomycin dose ‡10 mg/kg, vancomycin concentration ‡5 mg/ml and antecedent use as risk factors for developing RMS. Interestingly, known genetic variations in histamine metabolism or receptors were not found to increase this risk [93]. In a systematic review by Svetitsky et al., the authors found a 5% rate of RMS among adults (the pediatric population was not assessed) and no cases among patients receiving teicoplanin [92]. A 2010 Cochrane review was in agreement with the premise that teicoplanin is less likely to cause RMS, citing a relative risk of 0.21 (95% CI, 0.08–0.59) [88]. Neutropenia
Vancomycin-induced neutropenia, defined as an absolute neutrophil count
Review
Glycopeptide antibiotics: evolving resistance, pharmacology and adverse event profile Expert Rev. Anti Infect. Ther. Early online, 1–14 (2015)
Karl Evans R Henson1, Miriam T Levine1, Eunice Ann H Wong1 and Donald P Levine*1,2 1 Department of Medicine, Division of Infectious Diseases, Detroit Medical Center and Wayne State University School of Medicine, 4201 St Antoine St, Detroit, MI 48201, USA 2 Department of Medicine, Division of General Internal Medicine, Detroit Receiving Hospital and University Health Center, Detroit, MI, USA *Author for correspondence: Tel.: +1 313 577 7935 Fax: +1 313 933 0645 [email protected]
The first glycopeptide antibiotic was vancomycin, isolated from the soil in the 1950s; since then, the class has expanded to include teicoplanin and the new semisynthetic glycopeptides dalbavancin, oritavancin and telavancin. They are bactericidal, active against most Gram-positive organisms, and in a concentration-dependent manner, inhibit cell wall synthesis. Resistance to vancomycin has emerged, especially among enterococci and Staphylococcus aureus through a variety of mechanisms. This emerging resistance to vancomycin makes proper dosing and monitoring of the area under the curve/MIC critically important. The chief adverse effect of vancomycin is nephrotoxicity, which is also intricately related to its dose. The efficacy of the semisynthetic glycopeptides has been demonstrated in skin and soft-tissue infections, but remains to be seen in serious methicillin-resistant Staphylococcus aureus infections. KEYWORDS: adverse events . dalbavancin . glycopeptides . oritavancin . pharmacodynamics . pharmacokinetics .
teicoplanin
.
telavancin . vancomycin
Introduction & historical perspective
Vancomycin, the first glycopeptide antibiotic (GPA), was discovered in the 1950s when a missionary in Borneo sent soil samples to his friend, an organic chemist working at Eli Lilly. The company had initiated a program to search for new antibacterials effective against penicillin-resistant staphylococci. A compound was isolated from the soil that was active against most Gram-positive bacteria. Compound O5865, dubbed ‘Mississippi mud’ because of the brown color of the solution, required purification via passage through an ion-exchange resin. The resulting drug was vancomycin [1], and it was intended for the use in penicillin-resistant staphylococci. However, with the approval of methicillin in 1958, followed soon after by cephalothin in 1964 [2,3], and because of the perceived toxicity profile of vancomycin, it soon became reserved for patients with serious b-lactam allergies or patients with infections caused by organisms resistant to the newer agents.
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MRSA developed as a result of sustained and widespread use of beta-lactam antibiotics. By the early 1990s, MRSA was acknowledged as an endemic nosocomial problem. Communityacquired MRSA strains were isolated soon after. This resistance trend brought vancomycin back to the forefront. While vancomycinresistant enterococci (VRE) caused problems in the early 1980s, it was not until 1997 when a lack of clinical response in a patient treated with vancomycin for S. aureus was documented and the first vancomycinintermediate strains (VISA) was isolated. In 2002, the first vancomycin-resistant S. aureus (VRSA) strain was isolated. Over the next several decades, more members of the glycopeptide class were discovered or synthesized, mainly driven by the need for antibiotics with activity against increasingly resistant Gram-positive bacteria [2]. Contributing to this renewed interest in glycopeptides was the ability in the 1980s to determine the chemical structures of these complex molecules. In fact, vancomycin’s structure was only fully
2015 Informa UK Ltd
ISSN 1478-7210
1
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Henson, Levine, Wong & Levine
Vancosamine
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Glucose
AA6 AA1
class, the glycopeptides are active against staphylococci, streptococci, Granulicatela spp. and Abiotrophia defectiva (formerly known as nutritionally variant streptococci), Listeria spp., Bacillus spp., Corynebacterium spp., Rhodococcus equi, Lactobacillus acidophilus, most Clostridium spp., and the majority of Gram-positive anaerobes. Most Enterococcus faecalis and some E. faecium remain susceptible to the GPAs. The rest of the members of the Lactobacillus genus, Clostridium ramosum, C. innocuum, Leuconostoc spp., Pediococcus spp. and Erysipelothrix rusopathiae are intrinsically resistant to this antibiotic class [4]. Vancomycin
Vancomycin (FIGURE 1) [5,6] was isolated from the actinomycete Streptomyces orientalis [1]. The components of the molecule are as follows: the heptapeptide core comAA7 posed of two chlorinated tyrosines, three AA5 phenylglycine systems, aspartic acid and N-methylleucine. The molecule becomes AA2–4 cyclic by means of two ether bonds and a carbon–carbon bond in various parts of the heptapeptide backbone. The disacchaFigure 1. The chemical structure of vancomycin [5,6]. Vancomycin is a complex molecule composed of a disaccharide (vancosamine and glucose) attached to a ride is composed of vancosamine and gluheptapeptide backbone. cose and is not a part of the cyclic AA1 and AA6: b-hydroxychlorotyrosine; AA2-4: Three phenylglycine systems; structure [6]. AA5: Aspartate amide; AA7: N-methylleucine. Vancomycin inhibits cell wall synthesis by forming a stable, noncovalent complex elucidated in 1982, roughly 20 years after its first discovery [3]. with the C-terminal D-Ala-D-Ala of murein monomers, nascent In the late 1980s, clinicians in Europe started to use teicoplanin peptidoglycan precursor units that emerge from the bacterial as an alternative to vancomycin; this antibiotic is not approved cytoplasm. These monomers normally attach to the growing for use in the USA. Apart from vancomycin and teicoplanin, the peptidoglycan molecule by transglycosylation followed by transcurrent members of the GPAs in clinical use today include the peptidation. The precursor-vancomycin noncovalent complex is youngest members of the class, the semisynthetic glycopeptides held together by five hydrogen bonds between the amino acids dalbavancin, oritavancin and telavancin. in vancomycin and the D-Ala-D-Ala residue. The complex Ristocetin, another glycopeptide, was released almost at the enters the cell membrane and causes a conformational change same time as vancomycin but because of hematologic toxicity was that blocks glycosyltransferase, resulting in inhibition of the quickly withdrawn from the market [3]. Avoparcin and actaplanin incorporation of the precursor molecules to the growing peptiare used in veterinary practice but not in humans. In this review, doglycan chain. This also prevents further transpeptidation and we will provide a brief overview of the chemistry and mechanism subsequent interruption of cell wall synthesis. The primary effect of action of the GPAs, an examination of the current antimicro- of this inhibition is in the late stages of cell wall synthesis in bial resistance trends, specifically in S. aureus and enterococci, dividing bacteria [4,7,8]. and an examination of the pharmacodynamics, pharmacokinetics and adverse effects of this peculiar class of antibiotics. Teicoplanin First described in 1978, teicoplanin (formerly teichomycin A2) Chemistry & mechanism of action is a GPA obtained by fermenting the actinomycete Actinoplanes The GPAs are tricyclic or tetracyclic compounds with a core teichomyceticus [9]. Its structure is similar to vancomycin, and it made up of seven amino acids (heptapeptide) to which are shares many chemical and microbiological properties with its bound two sugar moieties, giving rise to the name glycopeptide. older sibling, including its mechanism of action. It is a comThe GPAs are active only against Gram-positive bacteria. As a plex molecule composed of a backbone cyclic heptapeptide doi: 10.1586/14787210.2015.1068118
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made up of aromatic amino acids, as well as two sugar moieties (D-mannose and N-acetyl-beta-D-glucosamine). It differs from vancomycin by the presence of a fatty acid moiety that allows the molecule greater tissue and cellular penetration [10].
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Lipoglycopeptides
There are three new lipoglycopeptides that are in clinical use today: telavancin, dalbavancin and oritavancin. The basic mechanism of action of these agents is the same as vancomycin. However, a feature common to all three lipoglycopeptides is the addition of a lipophilic side chain that increases the interaction with the bacterial cellular membrane by anchoring the compound to the lipid bilayer. This improves the molecule’s affinity for the terminal D-Ala-D-Ala, thereby enhancing its antimicrobial activity [11]. Telavancin, developed in 2005, is a semisynthetic derivative of vancomycin derived by the addition of a lipophilic decylaminoethyl substituent on the vancosamine amino group and a hydrophilic (phosphomethyl)aminoethyl moiety on one of the phenylglycine residues [3]. The hydrophilic side chain both enhances telavancin’s ability to distribute into tissues and its clearance, reducing any potential nephrotoxicity [11]. Dalbavancin is a derivative of the teicoplanin-like antibiotic A-40926, an agent produced by the actinomycete Nonomuria spp [11]. It was developed in the 1990s and approved for clinical use in 2014. The addition of a dimethylaminopropanolamine group via amidation of the C-terminal carboxyl moiety produced dalbavancin from teicoplanin. This modification resulted in a half-life of over 300 h [3]. Oritavancin (LY333328) was also discovered in the 1990s and is synthetically derived from a naturally occurring glycopeptide chloroeremomycin. A hydrophobic chlorophenyl-benzyl group is attached to the vancosamine amine, and there is an additional aminosugar on the phenylserine hydroxyl group [3]. These structural features account for oritavancin’s improved activity against VRE, including against vanA-producing strains. Because of oritavancin’s hydrophobic side chain and a high degree of protein binding its terminal half-life is over 300 h [11]. Resistance to glycopeptides
As in other classes of antibiotics, microbial resistance determines how we use vancomycin and the GPAs, especially in regard to S. aureus and the enterococci. Since vancomycin is the most widely used of all GPAs, most studies involve this antibiotic. Our discussion will follow the same course. Vancomycin-resistant enterococci & vancomycin-resistant S. aureus
Because of the frequent use of oral vancomycin for Clostridium difficile infections and iv. vancomycin for MRSA, enterococci soon developed resistance to vancomycin and teicoplanin. Uttley first reported this occurrence in E. faecium in 1988 [12] during a VRE outbreak in a hospital renal unit. Since then, various types of VRE, based on both phenotypic and genotypic changes, have been described [13]. High-level enterococcal GPA resistance informahealthcare.com
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occurs when the bacterium acquires and expresses operons that substitute a terminal D-lactate (D-Lac) or D-serine (D-Ser) for the terminal D-Ala in peptidoglycan precursors [14]. The D-lactate (D-Lac) replacement results in a 1000-fold decrease in vancomycin affinity because of the loss of one of the five hydrogen bonds needed for the drug to interact with the peptidoglycan precursor [15]. The D-serine (D-Ser) replacement affects vancomycin binding in a similar way but to a smaller degree. Another mechanism involves prevention or destruction of precursors that end in D-Ala by specific dipeptidases and carboxypeptidases [15]. There are seven operons or gene clusters that have been described (vanA, vanB, vanC, vanD, vanE, vanG and vanL) [16]. Among these, vanA and vanB are the most important clinically, especially since they are transferable via transposons. Enterococci with the vanA gene are resistant to both vancomycin and teicoplanin; exposure to either drug induces resistance. In contrast, vanB enterococci retain teicoplanin susceptibility and are resistant only to vancomycin [13]. While enterococci are not generally considered highly virulent bacteria, they are intrinsically resistant to multiple antibiotic classes and are able to acquire additional resistance mechanisms [13]. They then become reservoirs of antimicrobial resistance genes. In 1992, the conjugative transfer of vancomycin and other resistance genes from an E. faecalis to S. aureus was documented for the first time [17]. This transmissibility of vancomycin resistance genes to S. aureus was purely an in vitro phenomenon until the first report in 2002 of a S. aureus clinical isolate with a vancomycin MIC of 1024 mg/ml [18]. The isolate was from an infected catheter exit-site of a 40 year old diabetic woman receiving hemodialysis [19]. Since then, additional isolates have been found throughout the world [20,21]. Thus far, no deaths have been attributed to infection with these organisms. Expression of the vanA gene in S. aureus appears to come with a fitness cost to the organism [22] and the rarity of VRSA suggests that clonal spread does not occur with these isolates [14]. Using its three-tier antimicrobial resistance threat level (urgent > serious > concerning), the CDC has classified VRSA only as a ‘concerning’ threat [23]. The mechanism of resistance of enterococci and S. aureus to the other GPAs is mainly through the resistance operons discussed above. Teicoplanin retains activity against organisms with the vanB operon; strains expressing the vanA operon are highly resistant to teicoplanin [3]. Among the newer glycopeptide agents, only oritavancin retains efficacy against clinical strains that express both vanA and vanB gene clusters. VanA-producing strains are resistant to both dalbavancin and telavancin; these two antibiotics retain their efficacy against vanB-producing strains [3]. All three lipoglycopeptides have low potential for development of resistance; thus far, no clinically isolated strains exhibit resistance to the lipoglycopeptides. Vancomycin-intermediate S. aureus
The stepwise development of intermediate resistance (MIC 4–8 mg/ml) to vancomycin in S. aureus is the more common type [8,14]. The first VISA was isolated in Japan in 1997 and doi: 10.1586/14787210.2015.1068118
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Henson, Levine, Wong & Levine
had a vancomycin MIC of 8 mg/ml [24]. With vancomycin MICs in the intermediate range, clinicians are alerted to the likelihood of clinical failure when vancomycin is used. A more worrisome phenomenon is the increasing prevalence of heterogeneous vancomycin-intermediate S. aureus (hVISA). These strains have apparent vancomycin MICs in the susceptible range; only clinical failure with vancomycin despite susceptible-range MICs suggests the possibility of an hVISA infection [24]. hVISA is defined as a S. aureus isolate with a vancomycin MIC in the susceptible range (current breakpoint is £2 mg/ml) but where a proportion of the cells have MICs in the intermediate range [8]. The gold standard to detect these isolates is the modified population analysis profile [25], where the area under the curve (AUC) of the test strain is referenced to an hVISA control strain Mu3 [26]. This test is not widely used because it is labor-intensive and has not been standardized. Any process that interferes with the basic mechanisms of action of vancomycin, that is binding to terminal D-Ala-D-Ala residues decreases its potency [8]. Studies on the mechanisms that lead to hVISA/VISA have demonstrated a completely separate process from the development of VRSA. While there are many phenotypic and genotypic changes exhibited by VISA strains, these organisms are consistently found to have thicker cell walls than vancomycin-susceptible S. aureus (VSSA) strains. Most isolates also have reduced autolytic activity. The thickened cell wall reduces vancomycin access to its active site in the division septum of the cell [8]. This ‘gradual clogging of the antibiotic into the thickened staphylococcal cell wall’ [27] is the mechanism responsible for low-level vancomycin resistance in VISA. VISA develops from VSSA via sequential mutations, and hVISA forms as an intermediate between the two. Most VISA/hVISA species were detected only after a protracted course of infection with GPA failure [28–31]. Clonality between the VSSA parent strain and its subsequent resistant pair has been documented [31]. Risk factors for developing VISA/hVISA include prior MRSA infection or colonization, exposure to vancomycin, infections with high bacterial burden, and low serum vancomycin levels early in the treatment course [8]. Before 2006, the cutoff for vancomycin susceptibility was an MIC of £4 mg/ml. However, an epidemiological study conducted by the CDC [32] found that vancomycin was equally ineffective against MRSA strains with MICs of either 4 or 8 mg/ml. In the middle of growing evidence of vancomycin failure in infections with S. aureus with higher MICs, the Clinical and Laboratory Standards Institute (CLSI) revised the susceptibility breakpoint for vancomycin against S. aureus to £2 mg/ml [18]. While the great majority of MRSA strains are still susceptible to vancomycin in vitro, there are data demonstrating vancomycin’s decreasing efficacy in serious MRSA infections when the MICs are at the upper limit of this susceptibility cutoff [3]. In a meta-analysis of 48 studies by van Hal et al., a high vancomycin MIC (‡1.5 mg/ml by Etest) was significantly associated with high mortality rates [33], especially in bloodstream infections. This same study found that in patients who had VSSA infection, a vancomycin MIC ‡1.5 mg/ml was predictive doi: 10.1586/14787210.2015.1068118
of treatment failure even when a b-lactam antibiotic was used. Even with varying vancomycin MIC cutoffs (‡1–2 mg/ml), there is compelling evidence demonstrating the association of high vancomycin MIC with increased mortality rates in both MRSA and MSSA [34–37]. The issue, however, is far from decided. There is much discussion in the literature in the past few years about the role of the MIC testing methodology in vancomycin dosing (see section on Pharmacodynamics). Furthermore, not all investigators agree on the association between worse outcomes and high vancomycin MICs. A well-designed meta-analysis by Kalil et al. [38]., reviewing 38 MRSA BSI papers did not find a statistically significant difference in the risk of death between patients with vancomycin MIC >1.5 mg/ml and £1.5 mg/ml. The conflicting data underscore the need for further research with larger, more diverse populations. Given the increasing problem of antimicrobial resistance, especially in MRSA, some have started to question the use of vancomycin as a first-line agent [39,40]. With vancomycin’s perceived toxicity and narrow therapeutic index, its slow clearing of bacteremias, the rising prevalence of VISA and the emerging hVISA problem, and the availability of newer agents, vancomycin might be becoming obsolete. Nevertheless, some argue that vancomycin remains relevant given the scant data available for the newer agents [27,41]. The current Infectious Disease Society of America MRSA guidelines still identify vancomycin as the preferred firstline agent for the treatment of MRSA infections, with appropriate caveats [42]. In the middle of this debate, it is prudent to assume that vancomycin will retain its central role in the treatment of serious infections with Gram-positive organisms. Pharmacodynamics Vancomycin
It is critically important that we have a clear understanding of this drug’s pharmacodynamics since the dosing regimen is closely tied to the development of resistant bacterial strains (TABLE 1) [43]. Despite its lengthy history, few studies properly evaluate vancomycin’s pharmacodynamic properties, and the data available have not produced robust results to help predict patient outcomes [44]. Vancomycin is a slow bactericidal, concentration-independent antibiotic, that is, the rate of killing is primarily dependent on the time of concentration exceeding the organism’s MIC [44–46]. It also has a prolonged postantibiotic effect that is inversely affected by the size of the inoculum (i.e., the ‘inoculum effect’) [47]. Several pharmacodynamic parameters are proposed for monitoring vancomycin in the clinical setting, including the time vancomycin concentration remains above the MIC (t>MIC), the ratio of area under the serum drug concentrationversus-time curve to the MIC (AUC/MIC) and the ratio of the maximum serum drug concentration to the MIC (Cmax/MIC). Based on in vitro and animal models and limited human studies, the AUC/MIC appears to be the best predictor of vancomycin efficacy against S. aureus [43,44,46,48]. A retrospective study by Moise-Broder et al. [49] demonstrated that an AUC/MIC of ‡400 was associated with faster bacterial eradication in patients Expert Rev. Anti Infect. Ther.
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Table 1. Pharmacokinetic parameters of vancomycin, teicoplanin, dalbavancin, telavancin, and oritavancin [10,62,64]. Parameter
Vancomycin
Teicoplanin
Dalbavancin
Telavancin
Oritavancin
Standard dose
15 mg/kg q12h
6 mg/kg q24 h
1 g on day 1, 500 mg on day 8
10 mg/kg q24 h
3 mg/kg x 1
Cmax (mg/l)
20–50
68–155
312
88
29
AUC (mg*h/l)
260
420–621
27103
858
146
Vd (L/kg)
0.3
0.9–1.6
0.11
0.1
0.65–1.92
Protein-binding (%)
10–55
88–94
93–98
90–93
86–90
Blister fluid:plasma concentration
NA
NA
0.60–1.11
0.79–0.82
0.185–0.195
Terminal t1/2 (h)
4–8
70–100
147–258
7–9
393
Renal excretion (%)
>80–90
48–61
42
72
30 mg/l for MRSA endocarditis and osteomyelitis, respectively [81]. An initial loading dose (6–12 mg/kg every 12 h for 3 doses) has been recommended to reach optimal serum trough level (10–15 mg/ml) promptly, followed by a maintenance dose of 6 mg/kg once daily [82]. Dalbavancin
Dalbavancin is available as lyophilized powder for iv. injection. A 1 g loading dose is followed by a 500 mg dose after 7 days. It is poorly absorbed from the gastrointestinal tract and is not given orally. Maximum plasma drug concentrations of 278.3–301 mg/l have been measured after a dose of 1 g. Dalbavancin is highly protein-bound (93–98%). Penetration into blister fluid correlates with plasma drug concentrations. It achieves greater blister fluid concentration than either telavancin or oritavancin [11]. Drug distribution into 40 different tissues after a 20 mg/kg dose was analyzed in a rat model: the highest concentrations were found in the kidney and liver after 24 h, and measurable concentrations were retained in brown fat, skin and skeletal muscle after 14 days [60,83]. Dalbavancin does not induce, inhibit or serve as substrate for CYP450 isoenzymes unlike telavancin [11,67]. Population pharmacokinetic studies in a cohort of 532 patients with skin soft tissue infection (502 patients) and catheter-related bloodstream infection (30 patients) showed a direct proportion between body surface area and creatinine clearance and dalbavancin clearance with a half-life of 8.5 days. Dalbavancin is eliminated both by informahealthcare.com
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renal (42%) and nonrenal routes, but no dose adjustments are needed in mild and moderate renal and hepatic insufficiency, or in end-stage renal disease with regular hemodialysis. Dosage adjustment is required in severe renal impairment with creatinine clearance 4 g/day) were associated with greater risk of nephrotoxicity although this was based on observational studies. Patients receiving higher doses of vancomycin also tended to develop nephrotoxicity more rapidly. Higher vancomycin trough levels (>15–20 mg/L but especially >20 mg/L), higher peak concentrations, and area under the time–concentration curve of vancomycin have also been proposed as risk factors. Likewise, prolonged duration of vancomycin therapy increases the risk for renal insufficiency [89,91]. In studies reviewed by Elyasi et al., treatment with vancomycin beyond 1 week increases the risk of vancomycin-associated nephrotoxicity from 6 to 21%; durations of therapy beyond 2 weeks are associated with nephrotoxicity rates as high as 30%. While not commonly used, continuous vancomycin infusion was associated with less nephrotoxicity than intermittent dosing. As expected, concomitant nephrotoxic agents were found to increase the incidence or nephrotoxicity by up to 35%. Treatment with additional nephrotoxic agents increases the incidence of vancomycin-induced nephrotoxicity and the risk of renal failure. Most studies cited in this review noted additive or even synergistic nephrotoxicity between vancomycin and aminoglycosides [89]. Patient characteristics also affect the risk of vancomycininduced nephrotoxicity. Critical illness such as sepsis, severe trauma, severe pancreatitis, major surgery and burns predispose patients to vancomycin-induced renal insufficiency as these patients are more vulnerable to renal failure. Baseline decubitus ulcer, malignancy, neutropenia and peritonitis are also associated with an increased risk of vancomycin-induced nephrotoxicity, as is baseline renal impairment. Interestingly, elderly patients are not at increased risk. Nephrotoxicity is also relatively uncommon in the pediatric population. This may be because children typically have fewer comorbidities, normal baseline renal function and less frequent use in combination with other nephrotoxins. There are little data on the impact of pregnancy upon the risk of vancomycin-induced nephrotoxicity; a small study also reviewed by Elyasi et al. suggests that at least in the second and third trimesters the risk of nephrotoxicity is unchanged. Nephrotoxicity is usually reversible, with a low incidence of residual damage so long as the drug is either discontinued or properly dose-adjusted if renal impairment develops. Renal impairment is rarely severe enough to require renal replacement doi: 10.1586/14787210.2015.1068118
therapy; in the review by van Hal et al., only 3% of nephrotoxic episodes were treated with short-term dialysis. Therapeutic drug monitoring and vigilant screening for vancomycin-associated nephrotoxicity can decrease the risk of this adverse event [90]. Teicoplanin may cause nephrotoxicity, but much less frequently than vancomcyin. A literature review by Svetitsky et al. found a relative risk of 0.44 (95% CI, 0.32–0.61) for 21 trials and 0.33 (95% CI, 0.22–0.50) for 17 trials comparing teicoplanin with vancomycin [92]. Severe nephrotoxicity was reported only in patients receiving vancomycin. A 2010 Cochrane review of 24 studies (2610 patients) similarly reported a relative risk of nephrotoxicity to be 0.55 (95% CI, 0.30–0.88) when comparing teicoplanin to vancomycin [88]. Red man syndrome
Red man syndrome (RMS) is the most common adverse drug reaction associated with vancomycin, occurring in 5–50% of hospitalized subjects and up to 90% of healthy control subjects [93]. RMS encompasses a spectrum of syndromes ranging from flushing, urticaria and/or pruritis to generalized erythema, intense pruritis and even hypotension. The pathophysiology involves vancomycin-induced mast cell degranulation and histamine release and is considered a pseudo-allergic drug reaction with no underlying immunological process [7,93]. It is enhanced by coadministration of opiates. RMS is easily prevented or at least diminished by reducing the infusion rate to 10 mg/min or slower and by premedication with diphenhydramine and ranitidine [7]. A multicenter retrospective study of 546 hospitalized patients aged 21 or younger identified Caucasian ethnicity, age ‡2 years, previous history of RMS, vancomycin dose ‡10 mg/kg, vancomycin concentration ‡5 mg/ml and antecedent use as risk factors for developing RMS. Interestingly, known genetic variations in histamine metabolism or receptors were not found to increase this risk [93]. In a systematic review by Svetitsky et al., the authors found a 5% rate of RMS among adults (the pediatric population was not assessed) and no cases among patients receiving teicoplanin [92]. A 2010 Cochrane review was in agreement with the premise that teicoplanin is less likely to cause RMS, citing a relative risk of 0.21 (95% CI, 0.08–0.59) [88]. Neutropenia
Vancomycin-induced neutropenia, defined as an absolute neutrophil count
