The WorldWide Intensivist: A brief review of Teicoplanin

Teicoplanin

Critical Points


Dose: Usually 6mg/kg/day, after two loading doses 12hr apart (each 6mg/kg)

Headlines

Many Gram-positive bacteria that were sensitive to simple penicillins are now resistant. In the past, the best treatment for these nasty bacteria was vancomycin, which unfortunately has significant side effects. Teicoplanin is a less toxic replacement for vancomycin in most situations where resistant organisms are encountered.
In several clinical circumstances, empiric treatment with teicoplanin is extremely effective. The best established of these circumstances is neutropaenic sepsis.
Carefully selected patients may also benefit from teicoplanin prophylaxis.
In appropriate doses, teicoplanin is usually as cost-effective as vancomycin, with less toxicity.
In a few special circumstances, vancomycin may still be the drug of choice, despite its extra toxicity.
The looming spectre of vancomycin (and/or teicoplanin) resistance should encourage us to be careful and not use either drug recklessly.

When to use it

Sensitive organisms

Teicoplanin is mainly used in moderate to severe infections with Gram-positive organisms. It is not effective against Gram-negatives. It is important to remember that in Gram-positive infections that are known to be sensitive to simples agent such as penicillin or cloxacillin, these are the drugs of choice. As is always the case, the correct drug should be given for the correct duration, to minimise resistance. The following microorganisms are usually or frequently sensitive to teicoplanin:

Staphyloccus aureus
Staphylococcus epidermidis
Streptococci
Enterococci (although resistance is now emerging!)
Clostridium species including Clostridium difficile
Peptostreptococci
Other less frequent pathogens such as Corynebacteria, and Propionibacterium.

There is a small number of organisms that are inherently resistant to teicoplanin. These are usually not pathogenic, or not often encountered, but include:

Erysipelothrix
Leuconostoc, Pediococcus and some Lactobacilli.

Far more important is acquired resistance . This has recently emerged as a substantial problem in Enterocci . Organisms that are resistant to teicoplanin are also often resistant to Vancomycin, and vice versa. Some organisms may be sensitive to teicoplanin, and resistant to vancomycin, or the reverse may occur. If vancomycin and teicoplanin resistance is present, then there may be no effective treatment for the patient, apart from some experimental agents that are not yet readily available.

Clinical Effectiveness

Dosing details are considered below. The conventional dose is 6mg/kg/day (400mg/day in a 70kg adult) following one or more loading doses, all given intravenously. The only reason for oral administration would be Clostridium difficile-induced enterocolitis, as the drug is very poorly absorbed orally.

Teicoplanin is extremely useful in the following clinical situations:

Severe lower respiratory tract infections with presumed or documented Gram-positive infection
Skin and/or soft-tissue infection
Infection where "methicillin-resistant Staphylococcus aureus" (MRSA) is documented or suspected
Severe Enterococcal infections, especially intra-abdominal infections such as peritonitis (usually in combination with other agents)
Neutropaenic sepsis
Infective endocarditis due to a variety of organisms, including "Staphylococcus epidermidis" and Staphylococcus aureus
Bone or joint infection caused by Gram-positives

The drug may also be useful in:

Antibiotic prophylaxis related to surgery or intravenous catheter insertion. This use has recently been reviewed for orthopaedic surgery [ Periti P et al. J Antimicrob Chemother 1998 Mar;41(3):329-40 ]
Empiric therapy following failure of other antibiotic treatment for presumed Gram-positive infection
Pseudomembranous enterocolitis (although many would regard metronidazole as the agent of choice)

Patients with the following infections may require higher than conventional doses (ie over 6mg/kg/day, following loading dose(s)):

Monotherapy of infective endocarditis due to Staphylococcus aureus
Infections in intravenous drug abusers
Paediatric patients, especially neonates

It is clearly not appropriate to use intravenous or intramuscular teicoplanin if:

The patient has known hypersensitivity to the agent;
The microorganism is known to be resistant to teicoplanin;
The drug is used to treat Cl. difficile enterocolitis;
Central nervous system infection is present, as central nervous system penetration is poor. In isolated cases, the agent has been given intrathecally.

Teicoplanin toxicity (again)

Side-effects and Toxicity

Side effects are relatively uncommon, and the side-effect profile is favourable, especially when compared with vancomycin. Side effects include:

Allergic reactions in 2.6% (rashes are said to be more common with higher doses) Anaphylactoid reactions (the "red man syndrome") that occur fairly frequently with rapid vancomycin administration are rarely if ever seen with teicoplanin. On rare occasions, cross-reactivity may occur between vancomycin and teicoplanin. It is suggested that if a reaction has ocurred to teicoplanin, then substitution of vancomycin is unwise.
Local intolerance in 1.7%
Fever in 0.8%
Ototoxicity in 0.3%
Alterations in liver and renal function are uncommon but have been reported
Thrombocytopaenia has rarely been reported [ Int J Antimicrob Agents 1998 May;10(2):143-52 ]
While vancomycin in the recommended dilution is reported to be toxic to the endothelium, this is not true for teicoplanin. See Robibaro et al [ Adv Exp Med Biol 1998;431:833-8 ]

Pharmacology

Teicoplanin is actually a group of at least six bulky glycopeptides, all with very similar activities. The main components are termed A2-1 to A2-5, and A3-1.

Absorption

The drug may be given intravenously (IV) or intramuscularly (IM), but is poorly absorbed orally. Peak blood concentrations after IV administration are achieved after half an hour. Given IM, levels peak at about four hours. For best antimicrobial effect, authorities recommend that the levels remain above 10mg/Litre. This is usually achieved with the following dosage regimen (in a 70kg adult):

400mg STAT
400mg after 12 hours
Thereafter, 400mg daily

It is NOT necessary to monitor serum levels unless there is severe renal dysfunction.

Distribution

The volume of distribution is normally between 0.8 L/kg and 1.6 L/kg. Protein binding is high (90% in serum, mainly to albumin), and good levels (up to three times serum peak levels) are achieved in heart muscle. Penetration into fat and cerebrospinal fluid is poor. Bone penetration of teicoplanin is good (better than vancomycin) [ Drago L, et al. Drugs Exp Clin Res 1998;24(4):185-90 ] The vitreous humour is poorly penetrated [ Eye 1998;12 ( Pt 2):252-5 ]

Elimination

The body doesn't metabolise teicoplanin substantially (only 3%) - it is mainly excreted in the urine. Metabolites have little antibacterial activity. The terminal half life is long , about one week (155-168 hours) and increases as renal function declines. There are minor differences in the handling of the five main components of teicoplanin, of no clinical significance.

With renal dysfunction:

Give the normal dose until day 4
Thereafter, if the creatinine clearance (CC) is 40 to 60ml/min, give half the normal dose daily
or if the CC is under 40ml/min, give one third of the normal dose, and monitor levels regularly throughout therapy.

Higher doses (12mg/kg/day) are indicated with:

Monotherapy of Staphylococcus aureus infective endocarditis (rather add an aminoglycoside for two weeks)!
infections in intravenous drug abusers (the clearance is greater, for reasons that are unclear)
bone and joint infections.

Drug interactions

Teicoplanin is well-tolerated when co-administered with aminoglycosides. Nephrotoxicity with the combination is far less frequent than is the case where equivalent doses of vancomycin are co-administered with aminoglycosides.

Do NOT allow teicoplanin to mix with concurrently administered ciprofloxacin lactate as precipitation occurs.

How it Works

Teicoplanin inhibits formation of cell walls in Gram-positive bacteria. It does this by interfering with formation of links in the cell wall (transglycosylation), acting on amino acyl-D-alanyl-D-alanine residues. In "sensitive" organisms, it inhibits bacterial growth at levels under 8mg/Litre, killing these organisms at higher concentrations. If the organisms are exposed to the agent for longer periods of time, then killing occurs more effectively! In some (but possibly not all) bacterial populations, a post-antibiotic effect has been seen, this lasting for up to over four hours.

Mechanisms of Bacterial Resistance

Despite the increasing prevalence of glycopeptide resistance, a recent large study still showed that most Gram-positive clinical isolates are sensitive [ Int J Antimicrob Agents 1998 Nov;10(4):271-7 ]. Resistance to teicoplanin often implies resistance to vancomycin and vice versa. Glycopeptide resistance has been divided into:

VanA found in Enterococcus faecalis and E faecium, and transmitted from one enterococcus to the next by a transposon ("jumping gene") called Tn1546, and shows up as high-level resistance to both teicoplanin and vancomycin.
Tn1546 is rather complex, containing several separate genes, with complex functions and confusing names. The gene product of "vanS" in the presence of vancomycin turns on "vanR", which in turn stimulates production of vanA, vanX, vanY and vanZ, as well as van H. vanH makes D-lactate, which is then incorporated into the cell wall in place of D-alanine, preventing the action of glycopeptides. Even more cunningly, the vanX and vanY genes prevent normal incorporation of D-alanine into the cell wall (otherwise the glycopeptides could still act)! vanZ appears to mediate teicoplanin resistance, but we're not sure how. There is evidence that vanH,A and X are present in the organisms that produce glycopeptides - resistance mechanisms may have originally come from them!! [ Antimicrob Agents Chemother 1998 Sep;42(9):2215-20 ]
Inducible VanB resistance, with resistance to vancomycin but full susceptibility to teicoplanin! The mechanism is distinct from vanA resistance. Some vanB variants may even be dependent on the presence of vancomycin for growth, although removal of the drug may be not result in cure! [ Antimicrob Agents Chemother 1999 Jan;43(1):41-7 ]
Built in (constitutive) resistance to vancomycin but not teicoplanin, found in E gallinarium and E casseliflavus, termed VanC. VanC has been subtyped into C1..C3.
VanD has also been described.
Resistance to teicoplanin with susceptibility to vancomycin, seen in some strains of Staphylococcus epidermidis and S. haemolyticus.

It is thought by some that administration of the drug avoparcin to livestock and birds as an antibiotic growth promoter is one reason for the rise in antimicrobial resistance in Enterococci. A recent article from the New England Journal of Medicine supports this, finding glycopeptide resistance commonly present in turkeys given avoparcin. Avoparcin acts at the same site as teicoplanin and vancomycin, and has been temporarily banned in Europe because of these suspicions. See a recent article in the New Scientist.

Of extreme concern is the recent emergence of decreased sensitivity of Staphylococcus aureus to vancomycin. This resistance is not related to the VanA..VanC genes, but we continue to worry that S aureus might just acquire for example the VanA gene. Amazingly enough, scientists have been rash (mad?) enough to experimentally transfer VanA into S. aureus!

There are several investigational drugs that may eventually become clinically useful with teicoplanin resistance, however these are not yet available. They include streptogramins (quinupristin/dalfopristin), some fluoroquinolones (clinafloxacin, grepafloxacin, moxifloxacin, gatifloxacin, and trovafloxacin) as well as everninomicin derivatives (SCH27899), ketolides, and oxazolidinones (linezolid), [ Jones RN et al, Diagn Microbiol Infect Dis 1999 Feb;33(2):101-12 ], and possibly the glycopeptide LY333328.

A Comparison with Vancomycin

Relatively few studies have compared clinical efficacy of vancomycin with that of teicoplanin. The following general conclusions appear to hold:

Teicoplanin is less toxic than vancomycin
Administration is more convenient
Overall costs are similar

Recent Studies

Bucaneve G et al [ Pharmacoeconomics 1999 Jan;15(1):85-95 ] compared vancomycin and teicoplanin for febrile neutropaenia and claimed little difference in final cost, with higher price of teicoplanin offset by fewer adverse effects and ease of use. (n=527)
Vazquez L et al found similar results [ Haematologica 1999 Mar;84(3):231-6 ] comparing the two drugs as second-line empiric therapy for neutropaenic sepsis. (n=66)
Nucci M et al. [ Oncol Rep 1998 Sep-Oct;5(5):1205-9 ] showed little difference between the two drugs in febrile neutropaenia. (n=99)
Pittet and Harding [ J Infect 1998 Sep;37(2):127-35 ]have recently reviewed the use of the two agents in infective endocarditis, emphasizing that there are no randomised controlled trials comparing them in this situation. Outcome is similar using either drug.

Teicoplanin in combination

Synergy may occur with:

Imipenem
aminoglycosides
Some penicillins

For treatment of infective endocarditis caused by Staphylococcus aureus, the addition of an aminoglycoside is highly recommended.

References

A CDC review of glycopeptide resistance is worth reading.
Campoli-Richards DM et al. Drugs 1990 40:449-86.
A thorough review.
Brogden RN & Peters DH. Drugs 1994 47:823-54.
A reappraisal, with updates on use and pharmacokinetics.

Disclaimer

Information on this page is provided for teaching purposes. You should not make a clinical treatment decision based on information contained in this page without consulting other references including the package insert of the drug, textbooks and where relevant, expert opinion. We cannot be held responsible for any errors you make in administering drugs mentioned on this page, nor for use of any erroneous information contained on this page.