ONE-YEAR EXPERIENCE WITH TIGECYCLINE IN TREATING SERIOUS INFECTIONS IN SEVERELY BURNED PATIENTS

INTRODUCTION

Tigecycline is a relatively new semi-synthetic antibiotic from the glycylcycline class of antibiotics, a group derived from lipophilic tetracyclines (1). In 2005 it was first used in the USA, while in Europe it has been used since April 2006. Tigecycline is derived from Minocycline by adding isobutyl-glycyl-amide lateral chain in the 9^th position on the D circle; it represents higher potency and reduction of bacterial resistance mechanism (particularly efflux and protection of ribosome) (2). Similarly, like the previous tetracycline generation, tigecycline inhibits proteosynthesis by binding to 30S subunit of the bacterial ribosome; this binding prevents tRNA access to the ribosome, inhibiting incorporation of the amino acids to the peptide chains (3, 4). The most common indication for tigecycline treatment is soft tissue infections and infections of the intra-abdominal area. It is a broad spectrum antibiotic which has effect on many strains of gram positive and gram negative bacteria (5, 6). Like other tetracyclines, tigecycline is also a typical agent of bacteriostatic antibiotics (value of the bactericidal concentration MBC90 is 32 times higher than the value MIC) (7, 8). Tigecycline is a back-up antibiotic, indicated mainly for mixed infections caused by certain pathogens. Formula of the chemical structure is shown in Fig. 1, pharmacokinetic properties are in Table 1. Table 2 shows the side effect associated with tigecycline administration. Tigecycline is not recommended for children and adolescents 18 years and younger, pregnant and lactating women (9, 10).

MATERIAL AND METHODS

Over one year tigecycline was used in the treatment of 11 severely burned patients (10 males and 1 female). The average extent of burned areas in patients in the group was 35% TBSA (24 – 75%) and their age was 42.5 (24–67 years of age). In seven patients of the group inhalation trauma was bronchoscopically confirmed. The average length of hospitalization was 48 days (35 –149 days), average length of hospitalization during the initiation of tigecycline therapy was 43 days (19–67 days). Identification of the infection complication source (see Table 2) was completed in the microbiology laboratory with the use of commercial set (ENTEROtest 24 Lachema, API BioMérieux, BBL crystal Becton Dickinsen). MIC was established with the use of E-test. None of the patients from the group died.

RESULTS

Tigecycline was used August 9^th, 2008 through August 8^th, 2009 in eleven patients. The most common indication for initiation of treatment by this antibiotic was a combined infection of skin and subcutis (in the area of burned, necro-ectomized, harvested or transplanted area). In Table 2 we show particular bacteria whose isolation from the clinical material led to the indication of tigecycline therapy.

In one case tigecycline was used to treat ventilator pneumonia, where the germ was Klebsiella pneumoniae ESBL. We choose tigecycline due to the fact that the patient suffered lower respiratory tract infection as well as skin infection and was newly diagnosed with an allergy to Cerbapenem. The therapy lasted 12 days and was successful.

In the remaining ten patients the indication for tigecycline was complicated infection of soft tissues with mixed bacterial flora. In these patients the clinical response to therapy was very good, and the treatment led to eradication of bacteria from the infection site.

Average treatment time with tigecycline was 10.6 days and was always influenced by the severity of infection and the patient’s response.

In all patients the clinical response was satisfactory, leading to the elimination of pathogens sensitive to this medication. The most common bacterial pathogen was coagulase-negative staphylococcus (9 times in total), Klebsiella pneumoniae ESBL (7 times in total), Escherichia coli 4 times (of which Escherichia coliwith ESBL production in 3 cases), Enterococcus faecalis (1 time), Enterobacter cloacae (1 time). (Table 3.)

Glycylcyclines are structurally similar to the TTC group of antibiotics and therefore can have similar side effects. However, we did not find side effects associated with tigecycline in any patients in our group. This may of course be due to the small number of patients in our group. The most common side effects in a much larger group of patients are listed in Table 2 (2).

DISCUSSION

Every burned area is sterile immediately after the injury; however, it quickly becomes colonized and consequently is initially infected mainly by gram-positive bacteria, which can be replaced by gram-negative pathogens during the course of hospitalization (12). The most frequently isolated pathogens in severely burned patients include coagulase-negative staphylococci, enterococci, Bacillus sp. In the case of coagulase-negative staphylococcus its pathogenicity is open to question in many cases. However, in the context of severe burn trauma associated with lack of skin cover as a significant mechanical barrier, and due to the specific immunosuppression, coagulase-negative staphylococcus presents a real threat to our patients (12, 13). The gram-negative spectrum is most frequently represented by Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Acinetobacter calcoaceticus - baumannii. Apart from pseudomonades, all isolated bacteria are theoretically sensitive to tigecycline.

In recent years multiresistant strains tend to be the dominant infection in severely burned patients. The alarming component is an increasing number of ESBL strains in our patients, particularly in Klebsiella pneumoniae and Escherichia coli. In these cases the antibiotic treatment is often difficult and frequently requires several types of antibiotics. Tigecycline can be conveniently used as a monotherapy in these infections. Tigecycline is also an alternative to patients with hypersensitivity to the beta-lactam antibiotics (14). The introduction of tigecycline into clinical practice may decrease the pressure nowadays on such frequently used antibiotics as chinolones and carbapenems (15).

Tigecycline indications may in the future be broadened to include respiratory track infections, as is the case today in the USA. The use of tigecycline in these infections is supported by data describing very good penetration of the antibiotic into the pulmonary tissue; indication also corresponds to the wide spectrum of bacteria coverage, which involves the most common causative agent of pneumonia including atypical agents (7).

Very often tigecycline use is related to cases of sepsis. All patients in our group had clinical symptoms that satisfied criteria for sepsis.

CONCLUSION

Due to the fact that infection complications are an increasingly significant cause of death in severely burned patients, early indication and correct choice of antibiotic plays a significant role in the treatment of these patients. From the point of view of infection complications in burned patients tigecycline – with its high efficiency, low toxicity and low frequency of side effects – presents a very interesting alternative to the antibiotics used at present. Even though it is registered only for complicated intra-abdominal infections and infections of soft tissues in the Czech Republic, progressive studies of successful antibiotic treatment by tigecycline that come up even in the Czech Republic will certainly widen the indication for other types of infections (16).

Abbreviations used: TBSA (total body surface area), AUC (area under the curve), MBC (minimal bactericidal concentration), MIC (minimal inhibitory concentration), ESBL (extended spectrum beta-lactamases)

Address for correspondence:

B. Lipový, M.D.
Department of Burns and Reconstructive Surgery
Faculty Hospital Brno
Jihlavská 20
625 00 Brno
Czech Republic
E-mail: b.lipovy@seznam.cz