Glycopeptides (Dalbavancin, Oritavancin, Teicoplanin, Vancomycin)

Updated January, 2009

N. Virgincar, MSc, MD, Dip RCPath

Specialist Registrar in Medical Microbiology

Alasdair MacGowan, BMed Biol(Hon), M.D., FRCP, FRCPath

Professor of Clinical Microbiology and Antimicrobial Therapeutics

Bristol Centre for Antimicrobial Research & Evaluation

Department of Medical Microbiology

University of Bristol & North Bristol NHS Trust

Southmead Hospital

Westbury-on-Trym

Bristol BS10 5NB

UK

Tel: +44(0)117 959 5651/2

Fax: +44(0)117 959 3154

e mail: alasdair.macgowan@north bristol.swest.nhs.uk

CLASS

               The glycopeptides are an expanding group of structurally complex anti Gram positive antibacterials, representatives of which have been used in human and veterinary medicine since the 1950s. Vancomycin and ristocetin were the first available, however ristocetin was associated with bone marrow and platelet toxicity, and was quickly withdrawn. Teicoplanin entered clinical use in Europe in the late 1980s and is now widely used as an alternative to vancomycin. It is not available in the USA. Other glycopeptides such as avoparcin and actaplanin have been used in veterinary practice.

               A semisynthetic derivative of vancomycin oritavancin (LY 333328) has been undergoing clinical development for some time while an amide derivative of teicoplanin dalbavancin (B1 397) is also in clinical development.

               Ramoplanin, a lipoglycodepsipeptide has a similar microbiological spectrum to the glycopeptides but is not discussed here (73).

Vancomycin

               Vancomycin was isolated by Eli Lilly and Company in 1956 from a soil sample from Borneo containing a newly discovered actinomycete, Nocardia orientalis (124). In vitro studies showed the compound to have significant in vitro potency against all staphylococcal strains tested. Animal studies showed the level of toxicity to be relatively low, and the drug was approved for use in man 1958 (5). Initial lots of vancomycin contained large amounts of impurities, and it was termed “Mississippi Mud” because of its brown discoloration. The licensing of methicillin two years later, which was as effective as vancomycin against penicillin-resistant staphylococci resulted in the decline of vancomycin use. In the 1980s, methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci and Enterococci emerged as therapeutic problems, which renewed clinical interest in vancomycin. Increased usage has been accompanied by emergence of resistance first in Enterococci and subsequently in Staphylococci, threatening the future utility of vancomycin and similar glycopeptides.

Jorgenson L, et al.  Vancomycin disposition and penetration into ventricular fluid of the central nervous system following intravenous therapy in patients with cerebrospinal devices.  Pediatr Neurosurg 2007;43:449-455.

Chemical Structure

               Chemical structure of vancomycin was confirmed in 1978. Vancomycin is a large, complex glycopeptide with a molecular weight of 1449. It is supplied commercially as a hydrochloride salt and is most soluble at pH 3 to 5. Solubility decreases with increasing pH, and vancomycin is unstable in alkaline solutions. Vancomycin powder is generally reconstituted with sterile water and diluted with dextrose or saline to a final concentration of 2.5 to 5.0 grams per litre.

ANTIMICROBIAL ACTIVITY

               The antibacterial spectrum of vancomycin is limited to Gram-positive organisms. Bacteria inhibited by concentrations of 4mg/L or less are considered susceptible, in North America and Europe (213, 156, 183a, 217). Vancomycin does not have significant activity against mycobacteria, fungi, Bacteroides spp or Gram-negative bacteria except Flavobacterium meningosepticum and some Neisseria spp (127, 154). Vancomycin is slowly bactericidal against sensitive bacteria, and there is no correlation between vancomycin concentrations in the range 2-50mg/L and killing of S. aureus (1, 101). Enterococci are inhibited but not killed by clinically achievable concentrations. Vancomycin has a number of persistent antibiotic effects. A post antibiotic effect has been shown in vitro and in animals (118, 36). Sub MIC drug concentrations prolonged the PAE (135). Vancomycin’s antibacterial effect in time-kill curves is much reduced by increasing the inoculum from 10⁶ to 10⁸ cfu/ml. (11, 160). Both methicillin-sensitive and resistant strains of S. aureus and most strains of coagulase-negative staphylococci have vancomycin MICs in the range 0.25 to 4.0 mg/L. The first report of a clinically significant coagulase-negative staphylococcus resistant isolate was in 1987 (172). Some strains of Staphylococcus haemolyticus and S. epidermidis with reduced susceptibility to vancomycin have also been reported (59, 30). As mentioned later in the chapter, the first S. aureus isolate with an MIC >4mg/L to vancomycin appeared in Japan in 1996 from a wound infection in a child receiving vancomycin for MRSA wound infection (82). In addition, some strains of S. aureus are deficient in autolysins and are tolerant to the bactericidal activity of vancomycin (70,169).

               Vancomycin-aminoglycoside combinations were synergistic against most methicillin-susceptible and resistant strains of S. aureus by the time-kill curve method (203) and also in animal models (12). However, some controversy surrounds the efficacy of the combination of vancomycin and rifampin. When used against coagulase-negative staphylococci, vancomycin and rifampin are often synergistic and rarely demonstrate antagonism (50, 112). But, in S. aureus, vancomycin-rifampin synergy is found inconsistently, and antagonism has been reported (202).

               In animal models of clinical infection of methicillin-resistant S. aureus (MRSA) endocarditis, the response to combination therapy has varied. In an experimental model of MRSA endocarditis (12), found vancomycin-rifampin to be more effective in eradicating organisms from the valve and causing clinical cure than vancomycin alone. Similar data was reported in a rabbit endocarditis model (60) and a chronic MRSA bone infection model (81). However, in a randomized trial of vancomycin alone versus vancomycin-rifampin for treatment of MRSA endocarditis in humans (108) found slow clinical response in both groups, and no advantage, to combination treatment. Vancomycin has also been shown to increase the bactericidal activity of linezolid in in vitro pharmacokinetic models (4) and quinupristin/dalfopristin in in vitro models and animal infective endocarditis (93, 140).

               The combination of vancomycin and an aminoglycoside is bactericidal against enterococci unless high level aminoglycoside resistance is present (79, 201).

               Streptococci, including viridans species, anaerobic and microaerophilic strains, and penicillin-sensitive and resistant pneumococci are susceptible to vancomycin. Most strains of Listeria monocytogenes are inhibited by clinically achievable levels of vancomycin (114), but therapeutic failures have also been reported (48, 10).

               Nondiphtheroid corynebacteria including C. jeikeium are susceptible in vitro (86). Vancomycin-resistant isolates of opportunistic pathogens like Lactobacillus, Leuconostoc, Lactobacillus and Pediococcus are frequently isolated (164, 184).

               The anaerobic spectrum of vancomycin includes anaerobic and microaerophilic streptococcus, and clostridia species, including both C. perfringens and C. difficile. The susceptibility of actinomycetes is variable (106), and Gram-negative anaerobes such as Bacteroides species are resistant. Vancomycin has no activity against Enterobacteriaceae, rickettsiae, chlamydia and mycobacteria.

Mariani-Kurkdjian P. et.al.  Monitoring serum vancomycin concentrations in the treatment of Staphylococcus infections in children. Arch Pediatr. 2008 Oct 8. [Epub ahead of print]

MECHANISM OF ACTION AND RESISTANCE

               Vancomycin acts on the second stage of cell wall synthesis in dividing organisms. It inhibits formation of peptidoglycans, the major structural polymer of the bacterial cell wall. Vancomycin inhibits transpeptidation, by binding to the D-alanyl-D-alanine residues at the free carboxyl end of the pentapeptide, and prevents elongation of the peptidoglycan backbone (142, 206, 175). Vancomycin also alters the permeability of cytoplasmic membranes of protoplasts and may impair RNA synthesis (90, 91). These multiple mechanisms of action may partially account for the low incidence of resistance to vancomycin in most of Gram-positive bacteria.

               Acquired resistance to vancomycin was unusual until the late 1980s, when first reports of enterococci resistance to glycopeptides began to occur in UK (190) and other European countries. This increase in resistance coincided with a significant rise in the use of vancomycin to treat MRSA and coagulase-negative staphylococcal infections as well as C. difficile colitis in many countries. The prevalence of vancomycin-resistant enterococci isolated from intensive care units in the USA increased from 0.4% in 1989 to 13.6% in 1993 (26). In the UK 3.0% of E. faecalis and 26% E. faecium isolated from blood are vancomycin resistant (218). This pattern of increased resistance has caused concern because of the concurrent resistance to multiple antibiotics especially in E. faecium and the potential transfer of vancomycin resistance to other Gram-positive bacteria (103, 150, 134a). Most vancomycin-resistant enterococcal isolates have been E. faecium, but glycopeptide resistance has also been seen in E. faecalis, E. gallinarum, E. casseliflavus, E. avium, E. durans, E hirae, and E. raffinosus.

               There are several recognized phenotypes of vancomycin resistance in enterococci, VanA, VanB, VanC, VanD, VanE, VanG, VanH, VanT, VanX, VanY, VanXY (8, 58, 143, 29, 65, 192). VanA and VanB resistance phenotypes were described primarily in E. faecalis and E. faecium. VanA is the most common phenotype. VanA resistant strains possess inducible, high level resistance to vancomycin and teicoplanin. Normally, glycopeptides inhibit cell wall synthesis by forming complexes with the terminal D-alanine residues of peptidoglycan precursors. VanA resistance is mediated by production of a ligase that results in synthesis of cell wall precursors that end in the depsipeptide D-alanyl-lactate rather than the dipeptide D-alanyl-D-alanine, the target for vancomycin (8). The VanA gene is located on a transposon (Tn 1546) which often resides on a plasmid (9). VanA resistance is transferred by plasmids to susceptible enterococci as well as to other Gram-positive organisms. VanB strains were believed to have lower levels of resistance to vancomycin (MICs, 32-64 μg/ml) and lower MICs to teicoplanin. It is now known that resistance to vancomycin in these isolates may range from 4 -≥1000μg/ml (67). The vanB cluster is often located on the host chromosome. However, it can also occur on plasmids, and, even when it is chromosomal, this gene cluster has been transferable from one strain of enterococci to another as part of large mobile elements (153). VanC resistance phenotypes were described in E. gallinarum, E. casseliflavus and E. flavescence, which demonstrates intrinsic, low-level vancomycin resistance (MIC 4-32mg/L) and are lower MICs to teicoplanin. The vanC gene is chromosomal, constitutive and nontransferable (8,197). The vanD gene described in E. faecium is located on the chromosome and is not transferable. The strain was inhibited by vancomycin 64mg/L and teicoplanin at 4μg/ml (143). The vanE resistance gene described in E. faecalis shows low level of vancomycin resistance (MIC, 16mg/L) and susceptible to teicoplanin (MIC, 0.5mg/L) (58). VanG has also been described in E. faecalis and is inducible by vancomycin conferring low level vancomycin resistance (MIC 16mg/L) and does not produce raised MICs to teicoplanin (126). In addition Enterococci need to remove D-Ala from growing precursors (VanY), degrade D-Ala-D-Ala (Van X) or both (Van XY). There is also a two component regulatory system (VanS-VanR) resulting in induction by either vancomycin (VanB, C, E, G phenotype) or vancomycin and teicoplanin (VanA phenotype) (192).

               In 1997, the first clinical strain of S. aureus with reduced susceptibility to vancomycin (Mu50) and teicoplanin (VISA) was reported from Japan (84) followed by two additional cases from United States (25). In 1997, a resistance phenotype of hetero-resistance to vancomycin (Mu3)(hVISA) was isolated in Japan (82). VISA and hVISA have been described from many countries all over the world though VISA (Mu50 like) strains remain rare. The incidence of hVISA is unknown because of variability in detection techniques and their sensitivity and specificity. Using the most reliable methodology – population analysis – profiles then the true incidence of hVISA is probably <5%. There are a number of definitions of vancomycin reduced susceptibility in S. aureus which makes discussion difficult. NCCLS and the European break point committees regard S. aureus strains with vancomycin MIC ≤ 4mg/L as susceptible. NCCLS regards strains with MICs of 8 or 16mg/L as intermediate and ≥ 32mg/L as resistant. EUCAST regards strains of 8mg/L as intermediate and those with MIC ≥16mg/L as resistant. Most recently several strains of S. aureus have been described in the USA where VanA gene cluster appears to have moved by conjugative transfer into S. aureus from Enterococci (27,28). While some of these strains have high vancomycin MIC ≥ 32mg/L, others do not. This is thought to be related to the stability of the resistance genes post transfer. The mechanism of intermediate resistance in S. aureus (VISA) is unknown but these isolates have lower growth rates and thicker cell walls (179). Hanaki et al (77) reported that hVISA produced three to five-fold greater quantities of penicillin-binding proteins 2 and 2’ and increased quantities of cell wall precursors. Also amidation of glutamine residues in cell-wall muropeptides, which reduces the cross-linking within the cell wall and thereby reduce the number of intracellular vancomycin target molecules was shown (78). Finan et al (57) observed a marked decrease or no PBP4 activity on clinically derived VISA which again reduces cross-linking and susceptibility.

               Disc diffusion tests have been shown to be unreliable for detection of VRSA, VISA or hVISA (188). The first screening method for VISA was described by Hiramatsu et al (84) which was based on simplified population analysis. It involves inoculating 10µL of a 10⁸ CFU/ml on brain heart infusion agar (BHIA) containing 4ug of vancomycin per ml. Growth at 24h was considered potential VISA. Subsequently other methods have been used to determine MIC like, macro Etest, broth dilution, agar dilution and MicroScan, but population analysis profiling (14) has been proposed as the most precise method of determining heteroresistance (111). Wootton et al (216) have modified this method a step further and calculated the area under the population analysis curve and compared it to Mu3 as a control. The resulting ratios were 0.90-1.3 for hVISA and >1.3 for VISA. However, Centers for Disease Control and Prevention has adopted three criteria to identify VISA strains: broth microdilution MIC of 8-16mg/L, Etest MIC of >6mg/L and growth on BHIA screen plates containing 6mg/L vancomycin at 24h (187). This method will detect VISA but not hVISA which is not really recognized in the USA as a microbiological or clinical entity.

               A glycopeptide tolerant phenotype has also been described in clinical S. aureus isolates in which the MICs remain ≤ 4mg/L but MBC are raised. The clinical significance of these strains is unknown.

PHARMACOKINETICS

               Vancomycin is administered intravenously or orally. Intramuscular administration is not recommended as it causes severe pain. Systemic absorption of the oral form is minimal and serum levels are negligible even in anephric patients (21). However, the coexistence of bowel inflammation and renal failure may very rarely result in potentially toxic concentration when vancomycin is given orally (182). When taken orally, vancomycin is excreted in stool in high concentrations that far exceed the MIC for C. difficile (40). The significance of these observations are however unclear as much of the vancomycin will be bound and the free fraction (microbiologically active) is unknown.

               Systemic infections are treated with vancomycin administered by slow (60 min or 1mg/min) intravenous therapy to avoid infusion related side effects. In subjects with normal kidney function, multiple 15mg/Kg i.v doses of vancomycin produce the following mean plasma concentration: 18-26mg/L two hours after infusion, and 8mg/L eleven hours after infusion (Data on file). Distribution of vancomycin is a complex process consistent with two or three compartment pharmacokinetic model. An initial rapid distribution phase of about ten minutes is followed by an intermediate half-life of approximately one hour. The elimination half-life varies between three to eleven hours in patients with normal renal function (161, 128). Vancomycin has a volume of distribution of about 0.3L/kg, a total clearance of 0.06 L/hr/kg of which renal excretion accounts for 80-90%. The calculated AUC is about 250-300mg.hr/L and protein binding (albumin) around 50%. The pharmacokinetic parameters are different in obese patients as these patients have larger volume of distribution and increased rates of glomerular filtration. With multiple dosing, levels above 75% of those in serum are attainable in ascitic, pericardial, and synovial fluid, 50% in pleural fluid, and 30-50% in bile (122). Vancomycin does not significantly penetrate the cerebrospinal fluid (CSF) in the absence of meningeal inflammation. The degree of vancomycin penetration of the CSF increases in direct proportion to the severity of meningeal inflammation, but is unpredictable, with reported ranges of 1-37% of the serum levels (34,76,196). Higher doses of 15mg/Kg every 6 h have been used to treat patients with meningitis (95) or some physicians have chosen to administer the drug by the intrathecal route. Following intra-peritoneal instillation of vancomycin, 54-65% of the dose is detectable in the serum (137). Penetration into bone is more variable even in patients with osteomyelitis, but adequate cancellous and cortical levels were obtained (71). The lung penetration of vancomycin is controversial with a range of different findings. This is probably related to different methodologies used (38,158). Employing lung tissue homogenates tissue vancomycin concentrations in some patients were undetectable (38). In contrast when epithelial lining fluid (ELF) and alveolar macrophages (AM) in patients undergoing bronchial alveolar lavage were studied, ELF concentrations were 2.4mg/L and AM levels 45.2mg/L 12 hours after a standard dose giving serum concentrations of 5 10mg/L.

               Vancomycin is excreted primarily unchanged by the kidneys by glomerular filtration, 80-90% of an administered dose appears in urine within 24 hours (75). As renal function declines, elimination half-life of vancomycin increases and in anephric patients may exceed seven days (128).

Jorgenson L, et al.  Vancomycin disposition and penetration into ventricular fluid of the central nervous system following intravenous therapy in patients with cerebrospinal devices.  Pediatr Neurosurg 2007;43:449-455.DOSAGE

               In non elderly adult patients with normal renal function, 1g (15mg/Kg) every 12h is the usual dose of vancomycin. Peak serum levels with a dose of 1g every 12h is usually between 20-40mg/L and trough levels are between 5-10mg/L. These are considered desirable concentrations to treat Gram-positive infections, but convincing data is lacking. In elderly patients the elimination half-life of vancomycin was prolonged (12.1h) compared to that of young male patients (7.2h) receiving the same dose (130). Vancomycin dosing in the elderly usually required dose modification.

               In children with normal renal function, fixed dosage can be based on age as follows: <1 week, 15 mg/Kg every 12h; 8-30 days, 15 mg/L every 8h; >30 days, 10mg/Kg every 6h (171). Vancomycin doses in premature infants are based on gestational age as follows: <27 weeks, 27 mg/Kg every 36h; 27-30 weeks, 24mg/Kg every 24h; 31-36 weeks, 18mg/Kg every 24h, >37 weeks, 22.5mg/Kg every 12h (87). Regardless of the dosing regimen, vancomycin dose should be adjusted according to the serum levels of the drug, as there is significant inter individual pharmacokinetic variation in these age groups.

               In burns patients and intravenous drug abusers, the half-life is shorter and dose requirements are higher (165).

               Vancomycin is virtually completely eliminated by the kidney, and since vancomycin elimination correlates directly with creatinine clearance, the dosage can be based on creatinine clearance rather than on a simple determination of serum creatinine level (129). Creatinine clearance can be estimated by means of the following formula (31): CrCl (males) = [Wt (Kg) x (140-age)] / [72 x Scr (mg/dl)]; CrCl (females) = 0.85 x CrCl (males). A number of nomograms have been developed by North American specialists to determine vancomycin dose based on estimates of renal function from creatinine clearance (121,127). In Moellering’s method, vancomycin is dosed daily according to creatinine clearance value; however, by Matzke’s method the dose of the vancomycin remains constant at about 15mg/Kg but the dosing interval increases with declining renal function. There have been no good quality evaluations of these normograms in improving clinical outcomes and reducing toxicity and simpler approaches may be justified.

               Very little vancomycin is cleared from the body by haemodialysis or peritoneal dialysis (110, 119). Patients on haemodialysis should be given 1g i.v weekly. Vancomycin dose can be repeated if necessary by monitoring serum vancomycin levels. Hemodialysis with the newer, more-permeable, high-flux membranes or continuous a-v and v-v hemodialysis results in more rapid vancomycin clearance and more frequent dosing is necessary (149). Continuous hemofiltration removes large amounts of vancomycin and monitoring of serum levels is necessary (13a). Patients on CAPD can receive a loading dose of 30mg/Kg IP, followed by 1.5 mg/Kg in each peritoneal exchange or 7 mg/Kg once daily. If the i.v route is chosen, a loading dose of 15mg/Kg, followed by an additional dose of 15mg/Kg every seven days depending on serum vancomycin levels (23).

               In recent times, administration of vancomycin 2.0 – 2.5g/day by continuous infusion has become practice in some countries. In addition sometimes vancomycin is infused to achieve a desired steady state concentration often in the range 10-15mg/L. The exact role of this form of administration needs to be established, but it is comparable to standard dosing in efficacy and tolerance, and may be more cost effective (88,219).

Ingram PR, et al. Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy. J Antimicrob Chemother. 2008 Mar 10

               For patients on continuous renal replacement, dosages should be modified (Table 1).

Table 1:  Dosing During Continuous Renal Replacement Therapy

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD

or CVVHDF which combine dialysis with fluid removal.

Note: Recommended loading dose is 15-20mg/kg

Hall RG 2nd, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. 2008 Jun;121(6):515-8.

ADVERSE EFFECTS

               Adverse events were more common in the past, but now the modern purified formulation of vancomycin has an improved safety profile.

               Red-man syndrome is the most frequently reported dose and infusion rate related event associated with vancomycin. It occurs 10-20 minutes after the start of infusion. Patients usually complain of pruritus and flushing of skin over the upper part of the body. Hypotension and musculoskeletal pain is also reported. Polk et al (146) found that this syndrome was a result of non-immunologically mediated, vancomycin–induced histamine release. Symptoms resolve within 20 min of the infusion being stopped but may persist for several hours (34). These events can be prevented by administering vancomycin over at least 60 minutes in dilute solution and is not a contraindication for future use of the antibiotic (55, 125). Life-threatening allergic reactions although rare, have been reported (34, 54). So, when hypotension and urticarial rash develops, hypersensitivity should be considered.

               The incidence of nephrotoxicity reported was as high as 25% in the initial clinical trials (3, 215), but these studies were complicated by the number of confounding variables such as concomitant use of nephrotoxic drugs, hypotension and heart failure. In later studies of patients receiving vancomycin alone, the rate of reversible nephrotoxicity was found to be 0-5% (180a, 54). However, the risk of nephrotoxicity of aminoglycosides is enhanced by vancomycin when the two are given together (166). Goetz et al (66) performed a meta-analysis of studies published between 1966 and 1991 of adult patients receiving vancomycin plus an aminoglycoside or either drug alone. They concluded that the incidence of nephrotoxicity with combination therapy is 13.3% greater than with vancomycin alone and 4.3% greater than with aminoglycoside alone. In a retrospective case review of >200 patients with proven Gram-positive bacteraemia patients who developed nephrotoxicity had higher vancomycin levels before the onset of toxicity (220) and a retrospective review of cancer patients receiving vancomycin associated troughs of >15mg/L with greater toxicity (97). The balance of evidence suggests that vancomycin can cause renal impairment. Vancomycin is eliminated by glomerular filtration, as renal function declines vancomycin levels increase, so it may be important to monitor serum levels of the drug but dose adjustment is central.

               Vancomycin associated ototoxicity like tinnitus, vertigo and hearing loss have been reported, but these were associated with high serum levels (>40mg/L) of the drug or concurrent use of ototoxic drugs or conditions such as meningitis that can cause hearing loss (61, 180a, 189). Importantly, a review of the literature by Brummett et al (20) concluded that the ototoxicity of vancomycin has been overrated, and very few cases of ototoxicity due to vancomycin have occurred.
Forouzesh A, Moise PA, Sakoulas G. Vancomycin Ototoxicity: A Re-Evaluation in an Era of Increasing Doses. Antimicrob Agents Chemother. 2008 Nov 10. [Epub ahead of print]

               Vancomycin associated neutropenia has been reported after patients have been treated for several weeks. Reversal of neutropenia occurs after stopping the antibiotic (18, 54, 205). There is no clear relationship between serum levels and neutropenia. Thrombocytopenia have also been reported in patients receiving vancomycin (198).

Narita, M. Vancomycin-Induced Neutropenia. 

               Phlebitis occurs commonly when vancomycin is infused through peripheral veins. Drug fever and immunologically mediated rashes have also been reported (54, 180a). Cases of severe hypotension and cardiac arrest after bolus administration of vancomycin appear in the literature (65,123). Diarrhea, nausea, vomiting and abnormal liver function tests have also been reported in clinical trials involving vancomycin (207).

MONITORING REQUIREMENTS

               Monitoring serum vancomycin concentrations is well entrenched but perhaps unjustified in clinical practice. When vancomycin was first used in the 1950’s, due to impure drug formulations, hearing loss was noted in a patient with renal dysfunction who had serum vancomycin concentration of 80-95µg/ml (61), the authors suggested monitoring serum concentrations to maintain them below 40mg/L to prevent drug toxicities. Since then vancomycin serum concentrations are measured routinely to avoid toxic concentrations and to maintain therapeutic levels. The utility of routine vancomycin therapeutic monitoring has been questioned since the early 1990s (24).

               The two forms of toxicities which could be avoided by monitoring serum vancomycin concentrations are nephrotoxicity and ototoxicity. There are reports of reversible ototoxicity associated with serum drug concentrations of greater than 40mg/L and often pre-existing renal impairment but the relationship between vancomycin use and ototoxicity is unclear (see above). Reversible nephrotoxicity has been reported in 5% of treated cases (52,54,85,189), but these findings were from uncontrolled observational studies and should be considered as evidence of a weak association between vancomycin and toxicity.

               Cantu et al (24) have suggested that vancomycin should be dosed on the basis of patient’s ages, weight and estimated renal function. Subsequently, a study by Saunders (170) showed that peaks were below 40mg/L when troughs were less than 15mg/L, and suggested monitoring only trough concentrations, and that levels of 10-12mg/L be considered early signs of accumulation and may need dose modifications. Two prospective studies of the impact of therapeutic drug monitoring (TDM) on nephrotoxicity have been published. A randomized trial in haematology patients indicated reduced nephrotoxicity in the TDM group and a cohort study in non neutropenic, non ICU patients support this finding (45, 204). The therapeutic trough levels of 5-10mg/L or 5-15mg/L and peak of 20-30mg/L (34,56,62,117, 167) currently recommended are not based on controlled trials in which serum concentrations have been related to clinical response. However the initial vancomycin dose should be selected using guidelines based on age and renal function. Some believe the best approach should be based on population pharmacokinetics and clearance (98, 129, 152, 167). In general, serum concentrations should be monitored after 4-5 days of therapy in non-renal patients and earlier if patient is receiving other nephrotoxic drugs (56, 117).

Guideline:  Rybak M, et al.  Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.  Am J Health-Syst Pharm 2009;66:82-98.

Clinical Indications

               Vancomycin is used in the parenteral form to treat serious infections caused by Gram-positive organisms. It is main stay for intravenous treatment of infections caused by methicillin resistant S. aureus (MRSA). It is also used to treat Gram-positive infections in patients who are unable to tolerate beta-lactam antibiotics but this may not represent best practice. Vancomycin was used to treat infections caused by methicillin-sensitive S. aureus (MSSA) prior to the discovery of penicillinase-resistant penicillins. Later studies showed that the success rate of vancomycin treatment of MSSA endocarditis is 60-75% (3) and also, the duration of bacteremia was prolonged when vancomycin was used to treat MSSA compared to beta-lactams (108).

Lodise TP, Lomaestro B, et al.  Larger Vancomycin Doses (>=4 grams/day) are Associated with an Increased Incidence of Nephrotoxicity.   Antimicrob Agents Chemother. 2008;52:1330-1336.

               If vancomycin is used alone to treat MRSA endocarditis clinical response is slow and mortality was increased in MSSA pneumonia with bacteraemia when cloxacillin and vancomycin was compared (107). Combination therapy has been used to improve the efficacy of vancomycin and the addition of aminoglycosides, fusidic acid, or dalfopristin/quinupristin, or rifampicin should be considered (200).

               Coagulase-negative staphylococci are the most common causes of infection of prosthetic devices like cardiac valves, artificial hips, CSF shunts and vascular grafts. The combination of vancomycin, rifampicin and an aminoglycoside is recommended for the treatment of prosthetic valve endocarditis caused by methicillin-resistant coagulase-negative staphylococci (50,94).

Stryjewski ME et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis. 2008 Jun 1;46(11):1683-93.

               Vancomycin can also be used to treat endocarditis caused by susceptible strains of enterococci in penicillin-allergic patients, but it must be used in combination with an aminoglycoside. It is the drug of choice for infections caused by resistant organisms like Corynebacterium spp (68,86).

               Vancomycin has been used to treat CNS shunt infections caused by susceptible organisms. However, removal of the device and intrathecal administration of the drug is generally needed for cure (69,76).

               Vancomycin is used for treatment of pseudomembranous colitis caused by C. difficile. Oral administration of 125 to 250mg results in luminal levels of 500-2000 mg/L, which is high above the MIC for C difficile [0.2 mg/L] (49). Coagulase negative staphylococci and other Gram-positive organisms, is the most common cause of infections in neutropenic patients, due to the use of more intensive chemotherapy regimens and long-term indwelling central venous catheters. Vancomycin is used for treatment of proven Gram-positive infections but the use of vancomycin in the initial empirical treatment of febrile neutropenic patients is controversial. Several randomized trials showed no decrease in morbidity or mortality when vancomycin was not used as part of initial therapy (51,155,163).

               Vancomycin is useful for the prevention of bacterial endocarditis in high risk, penicillin-allergic patients undergoing dental, oral or upper respiratory tract procedures and American Heart Association also recommends vancomycin in combination with gentamicin for gastro-intestinal and genitourinary procedures. Vancomycin is also used for surgical prophylaxis when prosthetic materials are being implanted into patients known or suspected of being colonized with MRSA. Operations which may be considered for vancomycin prophylaxis are vascular graft, prosthetic joint and neurosurgical implants.

Teicoplanin

               Teicoplanin (teichomycin A2) is a glycopeptide antibiotic which was obtained by fermenting the actinomycete Actinoplanes teichomyceticus. Teicoplanin was first described in 1978 and has a structure similar to that of vancomycin (139). Teicoplanin shares many chemical and microbiological properties with vancomycin, but offers advantage over vancomycin in that, it has longer elimination half life, can be administered by intramuscular injection, however resistance is much more common in coagulase negative Staphylococci and recommended doses may be too low for more severe infection. Teicoplanin is not approved for use in the United States but has been extensively used in Europe since 1988.

Structure and Mechanism of Action

               Teicoplanin is a complex of six analogues. The core aglycone is a linear heptapeptide of oxidatively linked aromatic amino acids. It bears sugars like D-mannose, N-acetyl-b-D-glucosamine and an acyl (fatty acid) moiety (19). The fatty acid component causes teicoplanin to be more lipophilic, resulting in greater tissue and cellular penetration (138). The manufactured form of teicoplanin is the sodium salt and sufficient sodium chloride to yield an isotonic solution (pH 7.5). It remains stable in solution for 48 hours at room temperature and for 7 days at 4 °C (162).

               Like other glycopeptides, teicoplanin inhibits cell wall synthesis in susceptible bacteria. It inhibits polymerisation of peptidoglycan in bacterial cell walls by binding non-specifically to saturate the outer layers of the bacterial peptidoglycan. It then binds to the terminal amino acyl- D-alanyl-D-alanine precursor, which fits into a cleft in the teicoplanin molecule (157, 180). Teicoplanin is not active against Gram-negative bacteria. The outer lipid membrane of Gram-negative bacteria prevents access of the large polar molecules such as teicoplanin penetrating to the peptidoglycan layer (89).

ANTIMICROBIAL ACTIVITY AND RESISTANCE

               Teicoplanin has slower bactericidal activity against Gram-positive organisms than vancomycin (9a, 48a). Bacterial killing by teicoplanin occurs in growing not resting cells (133, 145, 194).

               Activity against both methicillin-susceptible and resistant Staphylococcus aureus (MRSA) is comparable to that of vancomycin, with a mean MIC₉₀ of 0.2 to 1.5 mg/L but the susceptibility of coagulase-negative staphylococci is more variable with MICs of 2 to 4 mg/L (174). Aldridge (2) reported MIC₉₀ for teicoplanin of 16mg/L or more for Staphylococcus epidermidis, S. haemolyticus, S. hominis, S. warneri and S. xylosus. Staphylococcus saprophyticus is fully susceptible to teicoplanin (159). More recent data from the UK and Ireland where teicoplanin is widely used in clinical practice indicates 35% of oxacillin resistant coagulase negative Staphylococci and 23% oxacillin susceptible coagulase negative Staphylococci from blood cultures are teicoplanin resistant (MIC>4mg/L) (218).

               In vitro, teicoplanin is more potent than vancomycin against most streptococcal species, including Streptococcus pneumoniae, with MIC₅₀ and MIC₉₀ in the 0.06-0.12 and 0.12-0.25 mg/L respectively, compared with values of 0.25-0.5 and 0.5-1mg/L for vancomycin (181). MIC₉₀ values for enterococci range from 0.2 to 3.1mg/L, versus 1.56 to 4.0mg/L for vancomycin (174). Teicoplanin is only moderately bactericidal against Enterococcus faecalis (136).

               Teicoplanin is active against other aerobic and anaerobic Gram-positive bacteria. Corynebacteria, Clostridia (including C. difficile), Bacillus spp, Listeria monocytogenes, and Propionibacterium acnes are inhibited by low concentrations of teicoplanin with mean MIC₉₀0.3 - 0.8 mg/L (11, 15, 132, 134, 144). It is not active against Gram-negative bacteria, Mycobacterium spp and fungi. Teicoplanin is synergistic with aminoglycosides for around half the enterococcal and staphylococcal strains (44). At equivalent concentrations, the postantibiotic effect of teicoplanin exceeds that of vancomycin for MRSA and E. faecalis (35). The clinical importance of this phenomenon is not clear. Lactobacillus spp, Pediococcus spp and Leuconostoc spp are inherently teicoplanin resistant. Acquired resistance to the glycopeptides in enterococcus species was first reported in 1988 (102, 190). Various patterns of resistance (VanA, VanB, VanC, VanD, VanE and VanG) to both vancomycin and teicoplanin are now well documented (see above). Enterococci with the VanA phenotype have transferable plasmid-mediated resistance to both vancomycin and teicoplanin. VanB inducible resistance and VanC constitutive resistance to vancomycin but teicoplanin MIC ≤2mg/L. Inducible resistance to teicoplanin has been reported in an isolate of E. faecium with the VanS phenotype (80), and VanD confirms resistance to both teicoplanin and vancomycin.

               Wilson et al (207) first reported S. haemolyticus resistant to teicoplanin (MIC 16 mg/L) following cardiac surgery. Kaatz et al (92) reported development of constitutive, non-plasmid mediated resistance in serial isolated of S. aureus from a patient being treated for endocarditis. Vancomycin-intermediate S. aureus (VISA) with MIC of 8mg/L and treatment failure have been reported. In VISA strains, over production of PBP2 and PBP2’ with thickening of the bacterial cell wall is seen, limiting access of the antibiotic to its target site (83). These strains have higher MICs to teicoplanin (MIC 8-32mg/L than vancomycin (MIC 8mg/L).

PHARMACOKINETICS

               Teicoplanin is poorly absorbed from the gastrointestinal tract of healthy volunteers (22) but can be administered by either intravenous or intramuscular route. Teicoplanin is not recommended for oral administration for the treatment of systemic infections, however, it can be given orally for the treatment of pseudomembranous colitis (162). Unlike vancomycin intravenous injections can be given as bolus over 5 minutes. Intravenous administration of 3 and 6 mg/kg in healthy volunteers results in peak plasma levels of 53.5 and 111.8mg/L, respectively, with concentrations of 2.1 and 4.2 mg/L at 24 h (195). By the intramuscular route, a dose of 6mg/Kg i.m, was associated with a peak serum concentration of 12mg/L after 4 hours (7). Systemic availability after i.m. administration approaches 100% and clearance is similar to that of the intravenous route. After intravenous administration, teicoplanin has an elimination half-life of up to 170h in patients with normal kidney function. This prolonged half-life is likely due to its high degree of protein binding (90%) (138). Therapeutic levels have been found in the heart (210) and blister and peritoneal fluid (212). Teicoplanin does not penetrate cerebrospinal fluid well even in the presence of inflamed meninges (183), but intraventricular administration has been used. Teicoplanin pharmacokinetics is best described by a three compartment model with the elimination serum half life being 80 170h depending on the sampling protocol. Teicoplanin is 90% protein bound and has a volume of distribution of 0.9 1.6L/kg and total plasma clearance of 0.01 (L/hr/kg). 80% of teicoplanin is renally excreted and the AUC (mg/L.hr) is 500 600 after a 6mg/kg 24 hourly dose.

               Teicoplanin is excreted almost completely by the kidneys, 80% of the dose being recovered in urine and 3% in stool in 16 days (22), without significant metabolism. Teicoplanin is excreted almost entirely by glomerular filtration, with minimal renal secretion. Elimination half-life is prolonged in patients with renal insufficiency, and dosage adjustments are necessary as renal function declines. Clearance of teicoplanin declines as renal function decreases and is correlated linearly with creatinine clearance (53, 99). Lam and colleagues designed a dosage nanogram based on the relationship between teicoplanin clearance and creatinine clearance and an average desired steady-state concentration of 20mg/L (99). Teicoplanin is not removed by haemodialysis. Measurements of serum concentration helps in determining the appropriate dose and dosing interval in severe infections and renal impairment.

DOSAGE

               Due to its prolonged terminal half-life, teicoplanin can be administered intravenously or intramuscularly every 24 hours. Occasionally, a 48 hour or 3 times per week dosing is used in non hospitalized patients. Unlike vancomycin, dosage adjustments are made on the basis of the severity of infection as well as renal function. To achieve adequate serum levels rapidly, a loading dose of 400mg (6 mg/kg) 12-hourly on the first day is essential. This dose is usually dissolved in 100ml of infusion fluid and administered as a 30-min i.v. infusion. For less serious infections such as those involving the urinary tract, and skin and soft tissue, a lower dose of the usual 200mg (3 mg/kg) daily may be used. Treatment of serious Gram-positive infections such as septicemia, infective endocarditis, and osteomyelitis requires a higher loading dose of 400 to 800 mg (6-12 mg/kg) every 12h for two to three doses, followed by a maintenance dose of 400 to 800 mg (16, 174). There is no established range for therapeutic serum concentrations of teicoplanin, but it has been suggested that trough levels of at least 10 mg/L are necessary for treatment of severe infections (207). However others have shown that therapy for endocarditis with teicoplanin as a single agent has been problematic, and maintenance of trough levels of >20 is recommended (115, 151). MacGowan et al (116) reviewed 92 patients with S. aureus bacteremia using a multivariate analysis to relate age, weight, dose, loading dose, combination therapy and serum concentrations to outcome and has shown that only trough concentrations and age were significantly related to outcome.

               In patients with renal failure, it is suggested giving a normal dosage regimen until the fourth day (120). Then, for creatinine clearance between 40-60mL/min half the normal dose of teicoplanin once every day should be given. If creatinine clearance is below 40mL/min, maintenance doses of 1/3 the normal dose is given (162). Alternatively, higher maintenance doses (6mg/kg) can be given at less frequent intervals (every 2-3 days). Nomograms and serum drug monitoring may be useful in determining the appropriate dose of teicoplanin in critically ill patients with renal failure.

               Teicoplanin is not removed by haemodialysis. Patients on hemodialysis are generally treated with a loading dose of 800mg followed by 400mg weekly (13). Peritoneal dialysis eliminates very little teicoplanin. Patients with Gram-positive peritonitis can be successfully treated by giving teicoplanin intraperitoneally. The UK data sheet recommends 20mg/L per bag in the first week, 20mg/L per alternate bag in the second week and 20mg/L in the overnight bag in the third week (120).

               Oral teicoplanin may be an effective alternative treatment for colitis caused by C. difficile. In small studies, no dosage regimen has been established for therapy of C. difficile colitis, but doses of 100 to 400mg/day for 10 days have been used effectively (47).

               Teicoplanin can be used in the treatment of pediatric patients. A dose of 10mg/Kg iv for children and 6mg/Kg for neonates once-daily is appropriate (105, 141, 185).

Intravenous drug abusers have highly variable renal clearance of teicoplanin (168). In severe infections the dosage has to be adjusted according to the serum levels.

               Potel et al. (148) found that terminal half-life of teicoplanin was not significantly affected by the extent of the burn, but the trough concentrations were. Patients with burns excreted teicoplanin more quickly and less predictably than other patients.

               Neurosurgical shunt infections by staphylococci can be treated with intraventricular teicoplanin. A dose of 20mg in 5-10ml, every 1-2 days for adults and 5mg in 2-4ml per day for children, a similar volume of cerebrospinal fluid first being aspirated has been used (39).

ADVERSE EFFECTS

               Teicoplanin is generally well tolerated by intramuscular or intravenous use. Clinical trials and postmarketing experience in Europe indicate that one or more adverse events were experienced by 10.3% of 3377 patients treated with teicoplanin (43). The most common adverse events were hypersensitivity (2.6%), abnormal liver function (1.7%), fever (0.8%), local intolerance (1.6%), abnormal renal function (0.7%) and ototoxicity (0.3%). Thrombophlebitis during intravenous administration is common at higher doses of teicoplanin, and pain with intramuscular injection is minimal. In a meta-analysis of 11 comparative clinical trials, adverse events occurred significantly more often with vancomycin (21.9%) than with teicoplanin (13.9%) (214).

               In humans nephrotoxicity is less common with teicoplanin than with vancomycin when administered with an aminoglycoside. At a dose of 6mg/Kg/day, clinical trials show a lower incidence of nephrotoxicity with teicoplanin plus an aminoglycoside than with vancomycin plus an aminoglycoside (123, 189). However, in comparative US trials of vancomycin and teicoplanin (n=823 patients), both agents had equivalent nephrotoxicity (203).

               The incidence of ototoxicity associated with teicoplanin is extremely low. Greenberg, 1990 reported a few patients who developed tinnitus or a mild loss of high-frequency hearing, but these patients received 15mg per Kg per day of teicoplanin and the trough serum levels in these patients was 41mg/L.

               Patients developing red man syndrome with intravenous vancomycin tolerate teicoplanin well (147, 178). However allergic cross-reactivity may occur between vancomycin and teicoplanin (74). Since uncertainty exists about cross-reactivity and because of its long half-life, teicoplanin should probably not be administered to patients with serious hypersensitivity reactions to vancomycin. Thrombocytopenia due to teicoplanin use have been reported (186) which is more likely with high prolonged doses and is associated with trough serum concentrations of >60mg/L (13% vs 5%; (207). A number of other adverse events have been reported in clinical trials, the most common being rash, diarrhoea, nausea and vomiting.

Clinical Indications

               Teicoplanin can be used an alternative to vancomycin in the treatment of many Gram-positive infections, but its use is limited to a greater degree than vancomycin by bacterial resistance, especially in coagulase negative Staphylococci. It can be used as empirical treatment, in immunocompromised patients and in bacteremias secondary to invasive devices like intravascular catheters, which are usually caused by coagulase-negative staphylococci. It is a safe alternative for prophylaxis and therapy of infections in patients with serious allergic reactions to beta-lactam antibiotics.

               Two large, open, multicenter studies have evaluated the efficacy of teicoplanin in the treatment of a variety of Gram-positive infections including bone and joint, skin and soft tissue, lung and endocarditis. In these studies, clinical efficacy was 87 to 92% and bacteriologic efficacy was 79 to 85% (100, 109). Teicoplanin has been used effectively in the treatment of staphylococcal, streptococcal and enterococcal endocarditis when combined with an aminoglycoside (151). However, substantial failure rates have been seen in the treatment of S. aureus endocarditis and intravenous drug abusers, especially when lower doses of the drug are used (63, 168). This problem may be partially overcome by using higher maintenance doses (12-30mg/kg/day) or by addition of aminoglycosides (207). Treatment is given for 4-6 weeks. Randomized trials have failed to show any difference in efficacy of teicoplanin at a daily dose of 6mg/Kg/day and vancomycin either as monotherapy in immunocompromised (193) or in combination with other antibiotics in febrile neutropenic patients with suspected vascular catheter infections (32, 96, 177). Teicoplanin is also an effective treatment for Gram-positive bacteremia.

               Lewis et al (109) reported a cure rate of 96% in skin and soft tissue infections with Gram-positive organisms using a daily dose of 400mg teicoplanin. In septic arthritis and osteomyelitis a dose of 12mg/kg/day may be needed (104).

               Oral teicoplanin is a possible alternative for treatment of C. difficile colititis. Teicoplanin 100mg twice-daily orally for 10 days appeared to be equally effective to vancomycin (46). However more comparative studies are needed before recommendations can be made about the utility of teicoplanin in the treatment of C. difficile colitis.

               Teicoplanin can be used for prophylaxis of endocarditis in penicillin-allergic patients or when vancomycin or other antibiotics are not tolerated (176). Wall et al (199) used a single dose of 400mg teicoplanin in orthopedic surgical wound prophylaxis and found it to be as effective as two doses of cefuroxime. However, in cardiac surgery flucloxacillin and tobramycin was found to be superior to teicoplanin (210). Teicoplanin has been used in the treatment of pediatric patients with septicaemia, lung infections, skin and soft tissue, bone and joint infections and in patients with neutropenia and fever with high clinical response rate (42, 141).

               Teicoplanin is suitable for outpatient treatment of some community-acquired Gram-positive skin and soft tissue infections (42), or initially hospitalized patients subsequently treated as outpatients for acute and chronic osteomyelitis (37, 104).

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Oritavancin

               Oritavancin is a semisynthetic carbohydrate-modified parenteral glycopeptide antibiotic which is currently in phase III clinical studies. Oritavancin has activity comparable to that of vancomycin and teicoplanin, but retains activity against glycopeptide-resistant pathogens (14).

Structure and Mechanism of Action

               Oritavancin is a semisynthetic glycopeptide antibiotic derivative of A82846B, a natural product analog of vancomycin obtained by monoalkylation at the disaccharide amino function (8). Oritavancin inhibits cell wall synthesis, its lipophilic side chain helps in membrane anchoring and stabilizing the dimmer in the most favourable position, and so interacting with the growing peptidoglycan chain (2). Oritavancin also inhibits the transglycosylation step of cell wall biosynthesis (3, 17).

ANTIMICROBIAL ACTIVITY AND RESISTANCE

               Oritavancin, like other glycopeptides, has activity only against Gram-positive bacteria. In vitro studies showed MIC₉₀ values of 2 and 4 mg/L for methicillin-sensitive and methicillin-resistant S aureus respectively, but was less active against methicillin-sensitive and resistant S. epidermidis with MIC₉₀ values of 4 and 8 mg/L respectively (15).

               Oritavancin has in vitro potency against VanA enterococci with MIC₉₀ of 1ug/ml (6) and its MIC₉₀ against penicillin-sensitive and resistant S. pneumoniae is 0.008mg/L and 0.03mg/L respectively (9, 19, 20). The activity of oritavancin against anaerobic Gram-positive bacteria is good with MIC₉₀ of 0.5mg/L for Peptococcus species, MIC₉₀ of 0.032mg/L for Propionibacterium acnes, MIC₉₀ of 2.0mg/L for Clostridium difficile and MIC₉₀ of 1.0mg/L for Clostridium perfringens (21).

               Broth microdilution and time-kill curves showed oritavancin to be bactericidal against MRSA and VRE. Bactericidal activity against VRE was concentration dependent at 4-fold the MIC value (18, 25).

               The combination of oritavancin and gentamicin exhibits synergistic bactericidal activity against most strains of vancomycin-sensitive and resistant enterococci, MRSA and GISA in vitro (1, 13, 16, 18, 24). Also combination of oritavancin and ampicillin is synergistic against vancomycin resistant E. faecium (5).

               Zeckel et al (23) assessed the in vitro activity of 1,479 nosocomial Gram-positive pathogens, collected from 18 centres in 12 countries, the MIC₅₀ and MIC₉₀ for oritavancin of these Gram-positive isolates is as show in Table 2.

               Moderate level resistance to oritavancin (MIC≤16mg/L) can develop in vanA and vanB resistant enterococci by a single step mutation. This is as a result of mutation in the vanS_B sensor gene, overproduction of VanH, VanA and VanX proteins for D-alanyl-D-lactate synthesis and D-alanyl-D-alanine hydrolysis, mutation in D-alanyl-D-alanine ligase, and expression of the vanZ gene of the vanA cluster (4). Spontaneous stable resistance to oritavancin occurs in 10^-7 vancomycin-resistant E. faecium isolates (16).

               Oritavancin exhibits in vitro concentration-dependent postantibiotic effect durations of 2.4-7.7 hours (MRSA) and 18.7 hours for vancomycin-resistant E. faecium (18).

PHARMACOKINETICS

               Chien et al., 1998 (7) studied the pharmacokinetics in eight healthy male volunteers after intravenous administration of single dose of 0.5 to 3mg/kg of oritavancin. C max increased linearly with dose (range 13.1 to 23.6mg/L). Changes in plasma clearance (range 0.0547-0.138 ml/min/kg), volume of distribution at steady state (Vss, 0.65-1.92 L/kg), and terminal disposition half-life (t_1/2, 132-356 hrs) were dose independent over the range studied. The excretion of the drug in urine in 336 hrs was less than 6%.

               Fetterly et al., 2003 (10) found that after a single dose of 800mg in eight subjects and after multiple dosing of 200mg/day i.v. for 3 days in eight subjects, the mean±SD C_max, t1/2, AUC_0-24 and AUC_0-t (AUC from time zero until the last measurable concentration) were 137±29mg/L, 204±162, 1111±316 mg/L/hour, and 2267±762mg/L.hour respectively. Similarly values for multiple doses were 46± 11mg/L, 151±39 hrs, 457±99 mg/L/hour, and 1146±277mg/L.hour. Protein binding is 90%.

CLINICAL TRIALS AND ADVERSE EFFECTS

               Oritavancin is in phase III clinical trials. Two phase III trials (published in abstract form) have been conducted in humans. In the first double-blind, randomized, parallel-group trial for skin and soft tissue infections, 517 adult patients received 1.5 and 3.0 mg/Kg/day of oritavancin intravenously for 3-7 days or vancomycin 10-15mg/Kg twice/day intravenously for 3-7 days followed by oral cephalexin 500-1000mg twice/day to complete 10-14 days of therapy. In the first follow-up visit (day 28+/- 7) respective success rates were 76%, 76% and 80% in 384 clinically and 256 bacteriologically evaluable patients. The overall adverse events were not significantly different among the three groups but tremors, pulmonary embolism or thrombosis were seen in the oritavancin group (22).

               In the second trial of similar design, patients were randomized (2:1) to receive intravenous oritavancin 200mg/day for 3-7 days followed by oral placebo, or i.v. vancomycin 15mg/Kg twice/day for 3-7 days followed by oral cephalexin 1000mg twice/day. Both regimens were given for a total of 10-14 days. A total of 1246 patients received study drugs of which 1000 were clinically evaluable. The clinical cure rates were 79% and 76% for oritavancin and vancomycin-cephalexin group respectively and in the bacteriologically evaluable (686) patients the bacteriologic eradication rates were 75% and 73% for oritavancin and vancomycin-cephalexin respectively (11).

               No published data is available in humans on efficacy, tolerability and the effect of oritavancin on bacterial ecology like skin and fecal flora. Also the experience to date with the development of resistance in the laboratory setting is regarded by some as worrisome (12). Based on the results of phase III clinical trials, submission of a New Drug Application to the United States Food and Drug Administration is expected in 2004.

Table 2. MICs of Oritavancin for some Gram-positive Isolates (23).

REFERENCES

1. Aeschlimann JR, Allen GP, Hershberger E, Rybak MJ. Activities of LY33328 and vancomycin administered alone or in combination with gentamicin against three strains of vancomycin-intermediate S. aureus in an in vitro pharmacodynamic infection model. Antimicrob Agents Chemother 2000; 44: 2991-2998. [PubMed]

2. Allen NE, LeTourneau DL, Hobbs JN. The role of hydrophobic side chains as determinants of antibacterial activity of semisynthetic glycopeptide antibiotics. J Antibiot 1997; 50: 677-684. [PubMed]

3. Allen Ne, Nicas TI. Mechanism of action of oritavancin and related glycopeptide antibiotics. FEMS Microbiol Rev 2003; 26: 511-532. [PubMed]

4. Arthur M, Depardieu F, Reynolds P, Courvalin P. Moderate-level resistance to glycopeptide LY33328 mediated by genes of the vanA and vanB clusters in enterococci. Antimicrob Agents Chemother 1999; 43: 1875-1880. [PubMed]

5. Baltch Al, Smith RP, Ritz WJ, Bopp LH. Comparison of inhibitory and bactericidal activities and postantibiotic effects of LY333328 and ampicillin used singly and in combination against vancomycin-resistant Enteroccus faecium. Antimicrob Agents Chemother 1998; 42: 2564-2568. [PubMed]

6. Biavasco F, Vignaroli C, Lupidi R, Manso E, Facinelli B, Varaldo PE. Antimicrob Agents Chemother 1997; 41: 2165-2172. [PubMed]

7. Chien J, Allerheiligen S, Phillips D, Cerimele B, Thomasson HR. Safety and pharmacokinetics of single intravenous doses of LY33328 diphosphate (glycopeptide) in healthy men [abstr]. In: Program and abstracts of the 38th interscience conference on antimicrobial agents and chemotherapy, San Diego, CA, September 24-27, 1998. Washington, DC: American Society for Microbiology, 1998:A-55. [PubMed]

8. Cooper RD, Snyder NJ, Zweifel MJ, Staszak MA, Wilkie SC, Nicas TI, Mullen DL, Butler TF, Rodriguez MJ, Huff BE, Thompson RC. Reductive alkylation of glycopeptide antibiotics: synthesis and antibacterial activities. J Antibiot (Tokyo) 1996; 49: 575-81. [PubMed]

9. Fasola E, Spangler SK, Ednie LM, Jacobs MR, Bajaksouzian S, Appelbaum PC. Comparative activities of azithromycin and LY333328, a new glycopeptide, against penicillin-susceptible and resistant pneumococci. Antimicrob Agents Chemother 1996; 40: 2661-26663. [PubMed]

10. Fetterly GJ, Ong C, Bhavnani SM et al. Characterization of oritavancin (ORI) pharmacokinetics (PK) in plasma and blister fluid in normal healthy volunteers. In: Program and abstracts of the 43rd interscience conference on antimicrobial agents and chemotherapy, Chicago, Il, September 14-17, 2003, Washington, DC: American Society for Microbiology, 2003: A-18. [PubMed]

11. Giamarellou H, O’Riordan W, Harris H, Owen S, Porter S, Loutit J. Phase 3 trial comparing 3-7 days of oritavancin vs. 10-14 days of vancomycin/cephalexin in the treatment of patients with complicated skin and skin structure infections (CSSI). In: Program and abstracts of the 43rd interscience conference on antimicrobial agents and chemotherapy, Chicago, IL, September 14-17, 2003. Washington. DC: American Society of Microbiology, 2003: L-739a. [PubMed]

12. Guay DR. Oritavancin and Tigecycline: Investigational antimicrobials for multidrug-resistant bacteria. Pharmacotherapy 2004; 24: 58-68. [PubMed]

13. Hershberger E, Aeschlimann JR, Moldovan T, Rybak MJ. Evaluation of bactericidal activities of LY333328, vancomycin, teicoplanin, ampicillin-sulbactam, trovafloxacin and RP59500 alone or in combination with rifampin or gentamicin against different strains of vancomycin-intermediate Staphylococcus aureus by time-kill curve methods. Antimicrob Agents Chemother 1999; 43: 717-721. [PubMed]

14. Hunter PA. Clinical implications of antimicrobial resistance, London, UK. IDDB Meeting Report 2001 February 28. [PubMed]

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16. Lefort A, Saleh-Mghir A, Garry L, Carbon C, Fantin B. Activity of LY333328 combination with gentamicin in vitro and in rabbit experimental endocarditis due to vancomycin-susceptible or resistant Enterococcus faecalis. Antimicrob Agents Chemother 2000; 44: 3017-3021. [PubMed]

17. Malabarba A, Ciabatti R. Glycopeptide derivatives. Curr Med Chem 2001; 8: 1759-1773. [PubMed]

18. Mercier RC, Houlihan HH, Rybak MJ. Pharmacodynamic evaluation of a new glycopeptide, LY333328, and in vitro activity against S. aureus and E. faecium. Antimicrob Agents Chemother 1997; 41: 1307-1312. [PubMed]

19. Patel R, Rouse MS, Piper KE, Cockerill FRRD, Steckelberg JM. In vitro activity of LY333328 against vancomycin-resistant enterococci, methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae. Diagn Microbiol Infect Dis 1998; 30: 89-92. [PubMed]

20. Rubio MC, Goni P, Vergara Y, Seral C, Garcia C, Gomez LUSP, Gomez LUSR. Susceptibility of penicillin-resistant and penicillin-susceptible S. pneumoniae to newer antimicrobial agents. Chemother 1999; 11: 191-194. [PubMed]

21. Sillerstrom E, Wahlund E, Nord CE. In vitro activity of LY333328 against anaerobic Gram-positive bacteria. J Chemother 1999; 11: 90-92. [PubMed]

22. Wasilewski M, Disch D, McGill J, Harris H, O’Riordan W, Zeckel M. Equivalence of shorter course therapy with oritavancin vs vancomycin/cephalexin in complicated ski/skin structure infections (CSSI) [late-breaking abstr]. In: Program and abstracts of the 41st interscience conference on antimicrobial agents and chemotherapy, Chicago. IL, December 16-19, 2001. Washington, DC: American Society for Microbiology, 2001. [PubMed]

23. Zeckel Ml, Preston DA, Allen BS. In vitro activities of LY333328 and comparative agents against nosocomial Gram-positive pathogens collected in a 1997 global surveillance study. Antimicrob Agents Chemother 2000; 44: 1370-1374. [PubMed]

24. Zelenitsky SA, Booker B, Laing N, Karlowsky JA, Hoban DJ, Zhanel GG. Synergy of an investigational glycopeptide, Ly33328, with once-daily gentamicin against Enterococcus faecium in a multiple-dose, in vitro pharmacodynamic model. Antimicrob Agents Chemother 1999; 4: 592-597. [PubMed]

25. Zelenitsky SA, Karlowsky JA, Zhanel GG, Hoban DJ, Nicas T. Time-kill curves for a semisynthetic glycopeptide, LY333328, against vancomycin-susceptible and vancomycin-resistant E. faecium strains. Antimicrob Agents Chemother 1997; 41: 1407-1408. [PubMed]

Dalbavancin

               Dalbavancin (BI 397) is a semisynthetic glycopeptide antibiotic. It was designed to be an improved alternative to vancomycin. In vitro studies has shown it to be active against clinically important Gram-positive bacteria. It has undergone phase II trials in US (8). The long half life of dalbavancin may allow once weekly dosing regime and the preclinical and clinical studies to date has not shown significant dose limiting side effects.

Structure and Mechanism of Action

               Dalbavancin is a semisynthetic antibiotic, [di-(3-demethylaminopropyl)amide, N-alkylated at the aminoglucoronyl moiety] derived from the parent compound A-40926 (7,9). Dalbavancin inhibits bacterial cell wall biosynthesis by forming a complex with the C-terminal D-alanyl-D-alanine of growing peptidoglycan chains (4).

Review Article:  Lentino JR, Narita M, Yu VL.  New Antimicrobial Agents as Therapy for Resistant Gram-Positive Cocci.

ANTIMICROBIAL ACTIVITY

               In-vitro dalbavancin is more active than teicoplanin and vancomycin against all tested staphylococci (Table 3). Against streptococci it is as active as teicoplanin and four to eight times more active than vancomycin. Dalbavancin is effective against vancomycin-susceptible (Van-S) and resistant (Van-B) strains, but poorly active against Van-A strains (2). Dalbavancin showed potent activity against Gram-positive anaerobes and fastidious aerobes including Actinomyces spp, Propionibacterium spp, and Clostridium species excluding C.clostridioforme. Dalbavancin has variable activity against Lactobacillus spp. The activity against corynebacteria was equivalent to that of vancomycin (5). In-vivo, a single daily dose of dalbavancin was equal to or more active than twice daily doses of teicoplanin and vancomycin against staphylococci in experimental endocarditis in rats and septicaemia in immunocompetent mice (2).

PHARMACOKINETICS

               In animal study following iv administration of a single 20mg/kg dose of dalbavancin in rats, plasma concentration averaged 333.1+/- 32.1 mg/L at 3min after administration and 0.43+/- 0.03 mg/L at 120h. The pharmacokinetics of dalbavancin can be described by a two-compartment model, with the half-life of the initial and terminal disposition phases were 0.48 and 14h (2). Bernareggi et al (1) after a single 10mg/Kg subcutaneous dose in rats, found high and prolonged levels in the blood with Cmax value of 132mg/L, a Tmax of 3 min and a Cmin of 0.7mg/L at 96h. Slow kidney and faecal elimination was seen.

               In the phase I study, 4 healthy volunteers received a single dose of 70,140,220 and 360mg iv infusion and in the multiple dose section, eight subjects received 70mg/day for seven days. Cmax and AUC increased in proportion to the dose and the terminal half-life was 174h (10). In a phase I study, dalbavancin up to 1120 mg/day or 500mg twice a day as a loading dose, followed by 100 mg as a maintenance dose for 6 days was well tolerated, no ototoxicity was observed. Dalbavancin has a long elimination half-life of 9-12 days in humans (6). Dalbavancin is >90% protein bound (3).

CLINICAL TRIALS AND ADVERSE EVENTS

               In a randomized, controlled, open-label, phase II trial once-weekly dalbavancin was compared to standard antimicrobial therapy for skin and soft-tissue infections. Adults received 1100mg as a single i.v infusion, 1000mg i.v and then 500mg i.v one week later, or a prospectively defined standard of care treatment. The plasma concentration of >30mg/L were maintained for 1 week after a single 1100 mg dose, and the concentration remained >20mg/L for 20 days in patients who received 1000 mg on day 1 and 500 mg on day 8. Clinical success rate was 94.1%, 61.5% and 76.2% for patients treated with 2 doses of dalbavancin, one dose of dalbavancin and standard of care regimen respectively (8).

               Phase III studies are under way to evaluate the efficacy and safety of dalbavancin in the treatment of skin and soft tissue infections caused by Gram-positive bacteria.

Table 3. In-Vitro Activity of BI 397 Against Staphylococci, Streptococci and Enterococci (2).

REFERENCES

1. Bernareggi A, Danese A, Cavenadhi L. Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses. Antimicrob Agents Chemother 1988; 32: 246-249. [PubMed]

2. Candiani G, Abbondi M, Borgonovi M, Romano G, Parenti F. In-vitro and in-vivo antibacterial activity of BI 397, a new semi-synthetic glycopeptide antibiotic. J Antimicrob Chemother 1999; 44: 179-192. [PubMed]

3. Cavaleri M, Cooper A, Nutley MA, Stogniew M. Protein binding of dalbavancin using isothermal titration microcalorimetry (abstract A-1385). Interscience Conference On Antimicrobial Agents and Chemotherapy 2002; 42: 18 [PubMed]

4. Ciabatti R, Malabarba A. Semisynthetic Glycopeptides: Chemistry, structure-activity relationships and prospects. FARMACO 1997; 52: 313-321. [PubMed]

5. Goldstein EJ, Citron DM, Merriam CV, Warren Y, Tyrrell K, Fernandez HT. In-vitro activities of dalbavancin and nine comparator agents against anaerobic Gram-positive species and corynebacteria. Antimicrob Agents Chemother 2003; 47: 1968-1971. [PubMed]

6. Leighton A, White R, Chaudhari U, Van Saders C, Baylor M, Perry m, Henkel T, Kelly e, Campbell KCM. Stringent audiology assessment in a healthy volunteer study with glycopeptide dalbavancin. Interscience Conference On Antimicrobial Agents and Chemotherapy 2001; 41: Abs 2192. [PubMed]

7. Pavlov AY, Preobrazhenskaya MN, Malabarba A, Ciabatti R. J Antibiot (Tokyo) 1998; 51: 525-527. [PubMed]

8. Seltzer E, Dorr MB, Goldstein BP, Perry M, Dowell JA, Henkel T and the dalbavancin skin and soft-tissue study group. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clinical Infectious Diseases 2003; 37: 1298-1303. [PubMed]

9. Selva E, Goldstein BP, Ferrari P, Pallanza R, Riva E, Berti M, Borghi A, Beretta G, Scotti R, Romano G et al. J Antibiot (Tokyo) 1988; 41: 1243-1252. [PubMed]

10. White RJ, Brown GL, Cavelero M, Romano G. V-glycopeptide: Phase 1 single and multiple-dose placebo controlled intravenous safety, pharmacokinetic and pharmacodynamic study in healthy subjects. Interscience Conference on Antimicrobial Agents and Chemotherapy 2000; 40: Abs 2196. [PubMed]