Annals of Burns and Fire Disasters - vol. XI - n. 2 - June 1998

TREATMENT OF SERIOUS INFECTIOUS COMPLICATIONS IN BURNED PATIENTS WITH-EMIPENEM/CILASTATIN

Lesseva M., Hadjiiskî 0.

Center for Burns and Plastic Surgery, Pirogov Medical Institute, Sofia, Bulgaria

SUMMARY. Systemic antibiotics are inevitable in the treatment of infectious complications in Burns and one of their unfavourable sequels is the selection of multiresistant nosocomial strains. This means that numerous antimicrobial agents cannot be used and a search has to be made for new alternatives. The aim of the present study is to present our clinical experience with the use of Imipencm/Cilastatin in the treatment of severe infections in patients with extensive deep Burns. Twenty patients were included, fifteen during the last year. The results presented of in vitro susceptibility tests to Imipenem characterize it as the most effective of all available antimicrobial agents against bacterial pathogens in Burns. Some P. aeruginosa strains were relatively more resistant to Irnipenern. The results of the treatment were evaluated as very good (80.0%) and good (20.0%), while in 75.0% of the cases the symptoms of infection initially resolved before the 36th hour. Candida superinfection appeared in 35.0% of the patients after several different antibiotic courses. The good clinical and bacteriological results of our study indicate that Imipencm/Cilastatin is a correct choice in empirical treatment and in proved serious cases, including mixed infections, with multiresistant bacterial pathogens. However, its use must be strictly controlled in order to restrict growth of resistant strains.

Introduction

Infectious complications are the leading cause of morbidity and mortality in patients with severe burns who have survived the early phase of hypovolaemic shock. The burned patient is particularly susceptible to infectious complications secondary to loss of a first line of defence against microbial invasion, presence of devitalized tissue that provides a favourable environment for microbial growth, and alterations in the specific and non-specific components of the immune system following thermal injury. That is why Burn patients are susceptible not only to Burn wound infection but also to pulmonary infection, urinary tract infection, intravascular infection, septicaemia, etc., and the use of systemic antibiotics is inevitable. Prolonged courses of antibiotic combinations, some of which begin empirically, result in the selection of multidrug-resistant nosocomial strains, mainly Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter spp. Widespread use of third-generation cephalosporins in nosocomial infections has been accompanied by the development of beta-lactamasemediated resistance. Another cause of concern is the rapid development of resistance in Acinetobacter spp. to most of the earlier beta-lactams, aminoglycosides, third-generation cephalosporins, and quinolons, as this organism has become an increasingly important pathogen in recent years. Obviously, new alternatives in antimicrobial therapy are needed, especially for empirical use, when a broad spectrum of antibacterial activity and good tolerance are of great importance. Third-generation cephalosporins, combined or not with aminoglycosides, are often ineffective. Quinolons reveal a relatively broad antibacterial spectrum which however excludes anaerobes, and certain species such as Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcusfaecalis rapidly develop resistance to them. Micro-organisms respond to betalactamase inhibitors (sulbactam, clavulanic acid) by producing TEM betalactamases resistant to them as well as by "over-production" of chromosomal beta lactamases.' This determines the growing interest in the group of carbapenems - exclusively broad spectrum antibiotics, stable to almost all serine betalactamases and shown to be very effective in clinical practice!
Imipenem/Cilastatin was the first carbapenern to be marketed, approximately ten years ago, since when there has been little development of resistance to the drug.' It is active against most gram-negative aerobic and anaerobic pathogens, including Enterobacter spp., Serratia spp., Pseudonionas aeruginosa, Acinetobacter spp., Bacteroides fragilis and Fusobacterium spp,, as also (unlike thirdgeneration cephalosporins) against gram-positive organisms - coagulase-positive and -negative staphylococci, streptococci from different serogroups, and Clostridium spp. Imipenem/Cilastatin is usually effective against most of the other antibiotic nosocomial strains.` Only Stenotrophomonas maltophilia, some strains of Pseudomonas aeruginosa, methicillin-resistant staphylococci and Enterococcus faecium are primaryresistant to this drug. Imipenern/Cilastatin induces a postantibiotic effect in tests against gram-positive and -negative pathogens! Clinical trials in surgical infections, severe pulmonary infections, septic conditions and other infections reveal the high in vivo efficacy of Imipenem/Cilastatin (over 80% success).""' In cases of severe infection, caused by multidrug-resistant Pseudomonas aeruginosa strains, synergistic combinations of Imipenern/Cilastatin with aminoglycosides are recommended."," D. Chankova and E. Savov," by means of chess fitration, established a good synergistic in vitro effect of Imipenern/Cilastatin combined with Amikacin against multidrug-resistant strains in 98% of cases.
The broad antibacterial spectrum, together with the good pharmacokinetic properties and low toxicity, are a premise for Imipenem/Cilastatin to be used as an empirical monotherapy in serious infections," including mixed lifethreatening difficult-to-treat bacterial infections.
The aim of the present study is to present our clinical experience with Imipenem/Cilastatin in the treatment of serious infections in patients with large and deep Burns.

Materials and methods

During the five-year study period (1993-1997) we followed up 20 patients (17 adults and 3 children), treated with Imipenern/Cilastatin in the intensive care units of the Sofia Burns Centre. The ages ranged from 10 months to 61 years and the total Burn surface area from 12 to 60%. The in vitro susceptibility testing to Imipenem of all the 1197 bacterial strains isolated in the last year of the period was performed with the single disk diffusion method of KirbyBauer, using disks with 10 mkg per disk Imipenem (BBL), on Mueller-Hinton agar. (During the previous years, in vitro testing to Imipenem was not done regularly.)
The criteria we observed for Imipenem/Cilastatin treatment were as follows: data for life-threatening systemic infection, and variously localized severe bacterial infection caused by multidrug-resistant nosocomial strains or unsuccessfully treated with other antibiotics. The usual daily intravenous dosage was 0.5 g q6h for adults and 15 mg/kg q6h for children.
The clinical results were evaluated according to the evolution of the clinical symptoms and laboratory data for infection, the extent and rate of their resolution, and any adverse events.
The bacteriological results were evaluated in relation to the irradication of the bacterial pathogens, the requisite time for this, the development, if any, of Imipenem-resistant strains, fungal super-infection, and/or gut dysbacteriosis.
The total result of the treatment was categorized according to the following criteria:

1. very good - clinical cure and bacteriological eradication of all pathogens

2. good - clinical cure but persistence of some bacterial pathogens, causing clinically insignificant infectious complications or merely contamination

3. satisfactory - clinical improvement (without definitive cure), persistence of bacterial pathogens

4. unsatisfactory - persistence of clinical symptoms, with or without persistence of bacterial pathogens

Results

The in vitro susceptibility of bacterial pathogens in Burns to Imipenem during the last year, compared with susceptibility to some other antimicrobials commonly used in the Burn Centre, is presented in Table I.

The leading pathogens are staphylococci, followed by Pseudomonas aeruginosa and Acinetobacter spp. and others with considerably lower rates such as Serratia spp. and Enterobacter spp. Not long ago Proteus mirabilis was fourth in frequency" but at present it is in sixth place. It is obvious that the rates of the strains sensitive to Imipenem, among all the gram-negative bacterial species, are higher than to any other antimicrobial agent (between 88.4%, for Pseudomonas aeruginosa, and 100%). With regard to grampositive organisms, except for MRS, 14% of enterococci showed resistance to Imipenem. Our results revealed higher rates of sensitivity of glucose non-fermentative gramnegative bacteria to Imipenem than the rates in hospitals both in Bulgaria (where 5/45 strains of Acinetobacter spp. and 16/18 strains Pseudontonas aeruginosa were resistant to Imipenem)' and abroad.
Five of the 20 patients treated with Imipenem/Cilastatin were involved during the initial four years of the studyperiod and the other 15 patients only in the last year. The drug was given as monotherapy in 17 cases (85.0%) and in combination with Amikacin (during the initial 3-5 days) in 3 cases (15.0%) (Table II).

Eleven patients (55.0%) received previous therapy with other antibiotics. Infectious complications were caused by a single pathogen in ten cases (50.0%), while the infection was mixed in six cases (30.0%) and remained unknown in four patients (20.0%). All the patients had clinical signs of systemic infection, bacteriologically confirmed in 14 patients (70.0%), which was accompanied by local infection (Burn wound, lungs, urinary tract, etc.).
The aetiology of the infectious complication, treated with Imipenem/Cilastatin, is presented in Fig. 1 and Table III

Fig. 1 - Rates of bacterial pathogens, isolated from the Imipenem/ Cilastatin treated burned patients.

The pathogens isolated were the following: Acinetobacter spp., 8 patients; Pseudomonas aeruginosa, 6; Serratia spp., 3; Enterobacter spp., 3; Citrobacter spp. and methicillin-resistant staphylococci (MRS), one patient each (the sum is more than 20 because of the cases with mixed infection). Most frequently they caused bacteraernia, except for Pseudomonas aeruginosa, which predominated in Burn wound infections.
The clinical results show a cure of the infectious complications in all the patients. Only one 55-year-old male with 35% TBSA Burns died, but the death was not attributable either to infection or to the antibiotic treatment. Initial resolution of the local and systemic signs of infection occurred between 18 and 48 h after the first dose of the drug (Fig. 2): in 6 patients (30.0%) between 18 and 24 h, in 9 patients (45.0%) between 24 and 36 h, and in the remaining 5 patients after about 48 h. The antibiotic courses lasted on average from five to seven days. Adverse events, probably connected with the treatment, were found in 7 patients (35.0%), e.g. Candida spp. superinfection, but antimycotic treatment was necessary in only four cases (candidosis resolved spontaneously in the other patients on discontinuation of the antibiotic treatment).

Fig. 2 - Distribution of patients according to beginning of resolution of infectious symptoms.

Table II presents the bacteriological results of the treatment. Nineteen of the isolated strains were sensitive in vitro to Imipenern (86.4%); two strains, respectively from Burn wound exudation and tracheal lavage, revealed intermediate susceptibility (9.1%). Only a strain of Pseudomonas aeruginosa (4.5%) from a blood culture was resistant to Imipenem, although treatment with this drug was clinically and bacteriologically successful. Irradication of all the pathogens was achieved in 18 cases (16 patients) (81.8%). In four cases (18.2%) the pathogens causing the main infectious complication (bacteraemia, lung infection) were successfully irradicated, while Pseudomonas aeruginosa persisted in the Burn wounds (3 strains) or tracheal secretion (1 strain). After treatment no cases of persisting pathogens were found. In all the cases with Candida superinfection there had been previous antibiotic therapy. Four patients (20.0%) developed resistance to Imipenem strains 5-10 days after commencing treatment (three strains of Pseudonionas aeruginosa and one of MRSA from Burn wound exudations). Similar results have been published by Colardyn and Edwards.
The overall results of the Imipenem/Cilastatin treatment were evaluated as very good (16 patients - 80.0%) and good (4 patients - 20.0%) (Table V).

Discussion

Correct antibiotic treatment depends on several prerequisites, one of the most important of which is the bacterial aetiology of the infectious complications. At present, the characteristic nosocomial pathogens in the Sofia Burns Centre belong to three bacterial species selected over the years. In our study, staphylococei, with the exception of MRS strains, were highly sensitive to a great number of antimicrobials, including Imipenem. Pseudomonas aeruginosa and Acinetobacter spp., on the contrary, were resistant to most of the available antimicrobial agents but demonstrated high in vitro susceptibility to Imipenem, i.e., 88.4% of the Pseudomonas aeruginosa strains and 97.1% of the Acinetobacter spp. strains. Pseudomonas aeruginosa showed such susceptibility only to ceftazidime (80.5%), while less than 50% of the strains were sensitive to the other drugs. Imipenem was often the only drug effective against Acinetobacter spp., with significantly higher activity than ciprofloxacin, the second most effective agent (55.4%). Similar results have been published by other authors. The demonstrated antibacterial spectrum of activity distinguishes Imipenem as the most effective of all the available antimicrobial drugs against the nosocomial strains present in the Sofia Burns Centre (with the limitations mentioned) and as the best choice for the empirical treatment of some very severe and life-threatening infections, as also found by other researchers.
Imipenem/Cilastatin has been used in several cases during the last six or seven years for the treatment of lifethreatening infections caused by multiresistant nosocomial strains in patients with severe Burns. In recent years a trend has been observed of growing resistance, especially of gram-negative organisms, to most of the available antibiotics, including third-generation cephalosporins and new quinolons.'," For this reason antibiotics like Imipenem/Cilastatin, which used to be kept in reserve for difficult-to-treat infections, are used more and more often, which is well demonstrated by the fact that 15 out of the 20 patients have been treated with this drug in the last year. These patients were treated in the intensive care units of the Centre for deep extensive burns, with complications due to severe systemic infections, which in 70.0% of the cases were accompanied by local infections (urinary tract, Burn wound, pulmonary infection, etc.). The isolated pathogens were multidrug-resistant strains, mainly Acinetobacter spp. and Pseudomonas aeruginosa and, rarely, Enterobacter spp., Serratia spp. or others. All of them were susceptible in vitro to Imipenem, except for two intermediate strains of Pseudomonas aeruginosa and a resistant strain. In three of the sixteen patients with mixed infection, Imipenem/Cilastatin was combined with Amikacin to obtain a synergistic effect" but in most of the cases (15%) we preferred monotherapy.
The results of Imipenem/Cilastatin treatment were very good and good in all the patients. The symptoms of infection began to resolve by the 36th hour after commencement of treatment in 75.0% of the cases and by the 48th hour in all cases, which gave us the opportunity to apply the drug in shorter courses (mean period 5-7 days, maximum 10). There was an interesting case of bacteraemia and lower respiratory tract infection, caused by a Pseudomonas aeruginosa strain that was resistant to all the tested antibacterial agents, including Imipenem. Nevertheless, Imipenem/Cilastatin treatment gave excellent clinical and bacteriological results. Clearly, in some cases, there is a distinction between the in vitro and in vivo effects of Imipenern/Cilastatin, which encourages us to apply the drug in other similar cases.
The only observed adverse event was the development of Candida super-infection in 35.0% of the patients, all of whom had gone through long-term treatment with other antimicrobials. This complication resolved spontaneously in about half the patients.
Some strains of Pseudomonas aeruginosa that persisted after treatment in four patients showed themselves to be comparatively more stable to Imipenern/Cilastatin treatment (from the bacteriological point of view). In three of these cases the strains contaminated the Burn wounds, without causing infection, and in the fourth, in which there was lower respiratory tract infection, the strain probably originated from the throat flora and contaminated the tracheal swab, as the patient recovered without modification of the antimicrobial treatment. Imipenem/Cilastatin therapy led to the development of Imipenem-resistant strains in four patients, three being Pseudomonas aeruginosa. The time of their appearance (5-10 days after termination of the antibiotic treatment) was enough long to obtain the results of the susceptibility tests, on the basis of which the antimicrobial therapy could be irnodified.

Conclusion

The good clinical and bacteriological results of the treatment with Imipenem/Cilastatin of serious infectious complications in patients with deep extensive Burns demonstrate that this drug could be successfully used both in the empirical treatment of severely ill patients and in bacteriologically proved cases of serious mixed infections with multiple localizations. Imipenern/Cilastatin must however be applied under strict control, otherwise its intensive use in uncertain indications could lead to the development of resistant strains and to their further diffusion in the wards.

RESUME. L'emploi des antibiotiques systémiques est inévitable dans le traitement des complications infectieuses dans les patients brûlés, mais une conséquence défavorable est la sélection de souches nosocomiales multirésistantes. Par conséquence, il faut éviter l'emploi de beaucoup d'agents antimicrobiens et chercher de nouvelles alternatives. Le but de cette étude est de présenter l'expérience des Auteurs avec l'emploi clinique de Imipenem/Cilastatin dans le traitement des infections sévères dans les patients atteints de brûlures profondes et étendues. L'étude concernait 20 patients, dont 15 ont été traités en 1996. Les résultats des tests de la susceptibilité in vitro à l'Imipenem le caractérisent comme le plus efficace de tous les agents antimicrobiens disponibles contre les pathogènes bactériens dans les brûlures. Certaines souches de Pseudomonas aeruginosa ont montré une résistance relativement majeure à l'Imipenem. Les résultats du traitement ont été jugés très bons dans 80% des cas et bons dans 20%, tandis que dans 75% des cas les symptômes de l'infection se sont résolus avant 36 heures. Une superinfection due à Candida s'est manifestée chez 35,0% des patients après divers traitements antibiotiques. Les bons résultats cliniques et bactériologiques de ces recherches montrent que Imipenem/Cilastatin est un choix justifié dans le traitement empirique et dans le traitement des infection graves confirmées, y compris les infections mixtes, avec l'emploi des pathogènes bactériens multirésistants. Il faut cependant contrôler rigoureusement cet emploi pour limiter la diffusion de souches résistantes.

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