Mariscal-Sistiaga F, Lenguas-Portero F, Galvan-Guijo B., Ahon-Elizaide J.M., Gomez-Tello V., Herruz-Cabrera R.*, Garcia Torres V.

SUMMARY. During 1990, 20 cases of nosocomial pneumonia in critical bum patients were treated in the Critical Bum Unit of the La Paz Hospital in Madrid. Fourteen of these patients were cured while four of them experienced a clinical improvement. The pathogen microorganism was eliminated in ten cases, and five controls were always negative, coinciding with clinical improvements and cures. No adverse effects were perceived. We conclude that azthreonam, in association with vancomycin and teichoplanin, is a very effective drug for treatment of nosocomial pneumonia in severe bum patiens, for which tolerance, both local and systemic, is excellent.

Azthreonarn is a monobactalamic antibiotic with a specific activity spectrum with respect to all aerobic gram-negative bacteria, including Pseudomonas aeruginosa. It achieves very similar minimum inhibitor concentrations (MIC) and minimum bactericidal concentrations (MBQ. It acts by fixation to certain proteins in the bacterial membrane, the inhibition pro-ducing elongation and lysis of the bacterium; it also extends its bactericidal action to granulocyte phagocyted micro-organisms, improving phagocytosis.
It shows a high degree of resistance to lytic enzymes (beta-lactamases) present in the periplasmic space of gram-negative bacteria, both with regard to chromosomic and plasmidic resistance. It does not induce production of beta-lactamases.
Azthreonam penetrates the organic tissues and liquids, where it reaches far higher concentrations than the MIC of the main Enterobacteriaceae. This antibiotic enjoys very good tolerance, with few side effects necessitating interruption of its administration. Azthreonam is indicated in treatment of infections of the urinary, gynaco-obstetrical and lower respiratory tract, the abdomen, bones, joints, skin and soft tissue, in non-complicated gonorrhoea and septicaemia, and in post-surgical infection when the infections are caused by gram-negative aerobic bacteria (1). A critical bum patient is one whose bum extent, depth, mechanism and site and/or previous pathology presents a serious life threatening risk requiring admission to special Burn Units (2). The bum patient behaves like an immunodeficient patient (3, 4). The loss of the outer limit of the body, the skin, which constitutes an effective barrier against most microorganisms (5), the stress brought on by repeated surgical operations (6), the plasma and blood transfusions (7), and the metabolic alterations suffered lead to a Temporary Secondary Immunodeficiency Syndrome (8). All this favours development of septic complications (infections of the lower respiratory tract, septicaemia, urinary infections, infections of the skin, etc.), which become the fundamental cause of death (9), even in the presence of appropriate local and systemic treatments, by causing the failure of all antimicrobial therapy attempts (10, 11).

During 1990-91, 20 seriously burned patients with nosocomial pneumonia (two also with concomitant urinary infection) were admitted to the Serious Bums Unit of the Hospital La Paz in Madrid and studied prospectively. They were treated with azthreonam (2g/6h intravenously): 6 on monotherapy and 14 on associated therapy (12 with vancomycin, I with cephalothin, and I with vancomycin and amphotericin B). In cases where vancomycin was the associated antibiotic, the patients' plasmatic levels were monitored in order to adjust the dose and to avoid renal damage.
In accordance with established inclusion criteria, patients of both sexes were admitted suffering from nosocomial pneumonia, the aetiology of which was known or suspected to be caused by gram-negative micro-organisms requiring antibiotic treatment for a minimum period of 5 days. Burn patients with associated urinary infection were also admitted.
Exclusion criteria eliminated from the study patients under 14 years of age, patients with terminal disease which prevented completion of the treatment cycle, patients who in the opinion of the investigators could not be evaluated, patients suffering from established renal failure, patients whose infection was caused by micro-organisrns resistant to the antibiotic, patients with a history of anaphylactic reaction to the antibiotic studied or to other betalactamic antibiotics, women during lactation and granulocytopenic patients (neutrophils <1000/mm').
Assessment of the bum area extent was made by the rule of nines (12) and the infection criteria were those of the Centers for Disease Control (13). Analytical, radiological and bacteriological controls were carried out every three days, with the exception of certain cases in which some intervals were shortened for justifiable reasons.
Clinical controls were carried out on a daily basis, and were continued for a period of two weeks after patient discharge.

Cure: remission of clinical and radiological manifestations caused by the infectious disease.
Improvement: favourable clinical and radiological response, with persistence of some clinical manifestations related to the infectious disease. Failure: absence of a response, with persistence of clinical and radiological manifestations of equal intensity.

Elimination of causative micro-organism: sterilization of cultures obtained from the infection site.
Selection: emergence of a new pathogen agent different from the original one, at the same or another infection site, during the treatment period, or during the immediate post-treatment period, together with clinical manifestations thereof.
Failure: persistence of the same pathogen agent during treatment.

Out of the 20 patients treated, 14 (70%) were male, and 6 (30%) female, with ages ranging from 16 to 73 years (mean 42.9 years). Of these patients, 9 had suffered no known previous pathology, 4 had a psychiatric case history (2 were drug addicts), 3 suffered from chronic alcoholism, 3 from obesity, I from arterial hypertension, I from epilepsy, I from toxic syndrome, I from diabetes mellitus, and one was HIV positive; several of these pathologies were concomitant in some patients. On admission, we observed in addition to the bums 6 smoke inhalation syndromes, 2 polytraumatisms, I bronchoaspiration, I diabetic decompensation, and I arsenic intoxication. Table I illustrates the injury mechanisms. The percentage of body area burned varied between 25% and 85% (mean 53.75%). By depth the injuries were: 11 superficial dermic, 19 deep dermic and 16. subdermic. These involved various anatomical sites, depending on the case.
The prevailing micro-organisms were: It Pseudomonas aeruginosa, 2 Acinetobacter, 2 Staphylococcus aureus, I Escherichia coli, I Pseudomonas cepacia, and I Candida Albicans, in pneumonia cases, and 1 Escheriqhia coli and I Proteus mirabilis, in concomitant urinary infections.
Thirteen patients required prolonged mechanical ventilation for more than 7 days.
From the clinical point of view, 14 cures (70%) were achieved, 4 (20%) improvements and 1 (5%) failure, while in I case (5%) the result could not be evaluated. There were 3 deaths, one of them secondary to the infectious process, and two caused by problems alien to the infection.

Bacteriologically speaking, there were 10 (50%) negative results and 4 (20%) selections (Candida albicans, Staphylococcus aureus, Acinetobacter and Pseudomonas aeruginosa resistant to azthreonam). Cultures were negative in 5 (25%) patients, and one patient could not be evaluated because of death before the successive bacteriological control.
No adverse effects were observed.

The prevailing germs Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter and Escherichia coli isolated in our patients do not differ from those isolated in most serious Burn Units (14, 15).
The clinical results obtained (14 cures and 4 improvements) mean that azthreonarn was effective in 90% of the pathologies treated. With regard to bacteriological results, we must point out that the 5 cases with negative cultures corresponded to patients in whom the samples were taken during azthreonam treatment. Since clinical success was achieved in these patients, we consider that this bacteriological group must be linked to that of negative results. This corresponds to 15 (75%) bacteriological successes.
It is to be expected that prolonged use of azthreonam in monotherapy may select Staphylococcus, as was the case in two of our patients, since the antimicrobial spectrum is limited, being effective only against. gram-negative germs (1).

The good bacteriological and clinical results obtained in our study and the importance of preserving renal function intact suggested to us the use of azthreonam in the treatment of nosocomial pneumonia in patients with serious burns, rather than other potentially nephrotoxic antimicrobial agents.
In view of the selection of germs observed, and taking into account that the antimicrobial spectrum of azthreonam is limited to gram-negative microorganisms, we consider that this antibiotic should be administered in association with other efficient agents against Staphylococcus (vancomycin, teichoplanin, etc.).
Azthreonarn is a very active drug against gramnegative pathogens that cause nosocomial pneumonia in critical bum patients, with an excellent local and systemic tolerance.

RESUME. Pendant 1990, 20 cas de pneumonie nosocomiale chez des grand brûles ont été treités dans le Centre des Brûlés de l'Hôpital La Paz, Madrid. De ces patients 14 ont guéri et 4 ont eu une amélioration clinique. Le micro-organisme pathogène a été éliminé en 10 cas, et 5 contrôles ont été toujours négatifs, en correspondance d'améliorations et guérisons cliniques. Les auteurs D'ont pas observé d'effets défavorables, Ils concluent que fazthreonam, en association avec la vancomycine et la teicoplanine, est un médicament très efficace pour le traitement de la pneumonie nosocomiale chez les grands brûlés et pour lequel il y a une excellente tolérance locale et systémique.

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