THE ROLE OF AZTREONAM IN THE CONTROL OF GRAM. NEGATIVE BURN WOUND INFECTION

Kamel A.H.(1), El Megeed E.A.(2)

(1) Plastic and Reconstructive Surgery Unit, Assiut University Hospital, Assiut, Egypt Microbiology
(2) Department, Assiut University, Assiut

SUMMARY. This study was conducted on 68 patients with mixed second- and third-degree burns and/or raw areas admitted to the Burn Unit of Assiut University Hospital and the Assiut Burn Centre (Egypt). The purpose was to study the effect of topically applied Aztreonarn alone and in conjunction with its systemic administration in the control of gram-negative burn wound infection. The results were compared with those of a control group of 57 patients with gram-negative infection who received a classic method of dressing. Assessment was performed on clinical and bacteriological bases. It is concluded that the use of Aztreonam, as a topical dressing is very helpful in the control of gram-negative mixed second- and third-degree degree burn wound infection, particularly if due to Pseudomonas, and that in the presence of high fever over 38.5 'C it is advisable to administer Aztreonarn also systemically.

Gram-negative bacteria have assumed a primary lethal role among the causes of burn wound infection and septicaemia in burn patients.' They represent 47-65% of the micro-organisms that cause burn wound invasion. A review of the literature shows that the bacteria isolated from invaded burn wounds were Staphylococcus aureus (17-30% of cases),Pseudomonas pyocyanea (20-28%), Pseudomonas aeruginosa (5-28%), Proteus (9-15%), Escherichia coli (4-15%), Streptococcusfaecalis (2-8%), and Staphylococcus albus (1 -2%)." The presence of mixed wound infection by more than one micro-organism is a common finding.

In mixed second- and third-degree burns, early colonization occurs within the lumen of hair follicles and glands. Colonizations with bacterial growth of less than 101 bacteria per g of tissue are compatible with survival and healing. When the bacterial counts exceeds 101 the bacteria spread from the follicles and colonization occurs along the dermal- subcutaneous junction.' Perivascular colonization is accompanied by thrombosis, vascular occlusion, and necrosis of any viable tissue.` Partial-thickness burns then convert to full-thickness lesions as a result of ischaemia and bacterial autolysis. Bacterial growth beyond 10 constitutes burn wound sepsis, and 10 to 10 Pseudomonas organisms per g of tissue are found in lethal injuries.

Clearly, early permanent wound closure should eliminate the hazards of infection.` In patients whose wounds remain open for several weeks or more, the protracted use of antimicrobial agents is necessary and represents the single most important means of preventing septic morbidity and death. It is evident that delivery of systemically administered antimicrobial agents to the deepest and most severely ischaernic areas of the wound cannot be relied upon, and that the topical application of antimicrobial agents will best ensure their presence in adequate concentration, at least on the wound surface where the risk of bacterial contamination is greatest. Although colonization of the wound can occur by haematogenous spreading from distant foci, this appears to be the exception rather than the rule.

Deitchet al.11 observed that effective topical agents possess the following qualities:

• they have a broad in vitro spectrum of activity and are effective against the most commonly isolated organisms

• they penetrate the eschar yet are not appreciably absorbed systemically

• they do not possess any significant local histotoxicity

• they have a known absorption rate

• they delay colonization for a variable period measurable in days not weeks

• they maintain the wound bacterial count at a lower level than can otherwise be achieved

Yurt et al.11 emphasized that routinely used topical agents associated with a high incidence of emergence of resistant organisms pose a notable problem, particularly in a setting where patient numbers are high and isolation facilities inadequate.
There are two objections against the use of true antibiotics for topical use: firstly, that most of them act by inhibiting a specific metabolic pathway rather than at multiple sites (as most antiseptics do); secondly, that serious systemic toxicity, including renal and pulmonary failure and toxicity (ototoxicity), has resulted from the topical application on burns of antibiotics such as neomycin, polymyxin, gentamicin, and sulphonamide mafenide, owing to their absorption from even relatively small wounds.

Aztreonain is a monobactam, a new family of beta lactain antibiotics.` It is selectively active against gram-negalive micro-organisms and inactive against gram-positives and anacrobes.11 The minimal inhibitory concentration (MIC) for gram-negative micro-organisms ranges from 0.1 to 50 p g/ml, and MIC90 ranges from 0.1 to 25 p g/ml."," It is monocyclic and is therefore easily excreted by the kidney. It has no dangerous effects on renal or hepatic function.` It has little or no effect on immunity and on phagocytic cell function."-" Aztreonam can be used safely in doses of up to 8 g per day and for up to 31 days. It can be given to infants from the age of one week.`

This study was conducted on 68 patients from the burn unit of Assiut University Hospital and Assiut Burn Centre who were subjected to dressing with Aztreonarn solution. The patients were selected when the bacterial culture showed gram-negative infection and the micro-organism showed sensitivity to Aztreonam. All had mixed second- and thirddegree burns and/or raw areas. The results from this group were compared with those of the control group, i.e. 57 patients with gram-negative infection who received a classic method of dressing with antimicrobial ointments available in Egypt (Betadine, microfurazone, silver sulphadiazine). The data relative to the two groups are presented in Table L

The study group of 68 patients was divided into two subgroups. The first subgroup (40 patients) received Aztreonam topically and systemically in their therapeutic dose. These patients were selected to take Aztreonam by both routes because they had high fever (over 39.5 'C). The second group (28 patients) received Aztreonam only topically. The data relative to the two subgroups are presented in Table II.

In the study group we prepared the Aztreonani solution by diluting a I g vial in 250 ml saline in completely aseptic conditions (this dilution exceeds the MIC for all gram-negative micro-organisms). After washing of the wound with saline, or hydrotherapy, we covered the wound with sterile gauze impregnated in Aztreonarn solution. The second layer consisted of sterile vaseline gauze to prevent absorption of the Azactam solution by the overlying dressing. The third layer consisted of sterile cotton. Dressings were performed daily.

The control group received a classic dressing. The wound was washed with saline, covered with an antimicrobial ointment (Betadine, nitrofurazone, or silver sulphadiazinc), and covered with sterile gauze and cotton. Dressings were performed daily.
The effect of topically used Aztreonarn was monitored clinically and bacteriologically. Clinically, we recorded local manifestations of infection and the degree of improvement as well as systemic manifestations of infection (mainly body temperature). The bacteriological study regarded the cultures and sensitivity before the dressing, and subsequently every other day in order to determine the type of micro-organism, if present (i.e. superinfection), and sensitivity to antibiotics. This continued until complete closure of the wound, usually within 21 days. Bacterial counts were performed before initiation of Aztreonarn dressing, on days 3, 4 and 5; and immediately before grafting, if indicated. Two methods of bacterial count were used .29,30

Results

Sixty-eight patients received Aztreonarn either only topically or together with systemic administration. The effect of topically applied Aztreonam in the control of grain-negative burn wound infection was studied and compared with results in the control group (57 patients).
Statistical analysis showed that the study and control groups were similar as regards mean age, sex ratio, and percentage of burn surface
When Aztreonam was administered only topically, control of local manifestations of infection was established after 3.8 ± 1.0 days, control of fever to less than 38.5 'C was established after 4.0 ± 1.0 days, and the bacterial count dropped to less than 10' per gm of granulation tissue after 4.0 ± 0.4 days. These figures were found to be significantly reduced compared with those of the control group, in which patients received a classic method of dressing (Table III).

As already said, the study group was divided into two subgroups of respectively 40 patients, who received Aztreonarn topically and systemically, and 28 patients, who received it only topically. There was no statistical difference between the two subgroups as regards mean age, sex ratio, or mean burn surface area. Statistical analysis showed that there was a non-significant difference in the time periods necessary for the control of local manifestations of infection and for the reduction of bacterial count to less than 101 per gm of tissue whether Aztreonarn was used topically and systemically or only topically.Systemic manifestations of infection were significantly controlled earlier in patients who received Aztreonarn topically and systemically, although this group originally presented high fever.
The bacterial count in this study was performed using two methods, the ordinary and the rapid. The two subgroups presented identical results (i.e. the bacterial count was found to be more than 101 per g of granulation tissue by the ordinary method when more than one micro-organism per field was detected by the rapid method).

Fig. 1 - Control of bacterial count. T-test p>0.05. Fig. 2 - Control of local manifestations. T-test p>0.05. Fig. 3 - Control of temperature to less than 38.5 °C. T-test p>0.05.

Success in the topical use of the antibiotic Aztreonarn to control gram-negative burn wound infection was considered to have been achieved when the criteria of the effective topical agent were fulfilled, as described above.
Aztreonam reduced the bacterial counts in a matter of days (4.0 ± 0.4), which is significantly less than with essings. The reduced bacterial count was maintained for up to 21 days without superinfection, as shown by cultures.
Topical Aztreonam also controlled local and systemic manifestations of infection. However, the presence of high fever necessitated the contemporaneous systemic administration of Aztreonam.
In mixed secon ' d- and third-degree burns, micro-organisms are present within viable tissue. Our study cast light on three issues:

1. The open burn wound has greater absorptive power than normal skin. This explains the toxicity observed in early trials with true antibiotics such as gentamicin, polymyxin, and sulphonamide, in which the preparations had high concentrations, all originally with toxic effects in their therapeutic dose. In our study we used a safe antibiotic without any toxic effect," and at a very low concentration estimated according to the MIC for all gram-negative micro-organisms.

2. Burn wounds, especially in the presence of Pseudomonas infection, are relatively ischaemic and the micro-organisms rarely invade the blood. For this reason we applied the antibiotic topically, in order to ensure adequate contact with the micro-organisms.

3. The p11 of burn wounds presenting gram-negative infection usually ranges from 6.7 to 8.0,11 which allows the drug to be active.

The idea of using antibiotics topically is supported by the finding of Boucher et al .32 that the pharmacokinetics of antibiotics is not the same in burned and nonburned patients. This necessitates dosage adjustment if the antibiotic is to be used systemically.
The emergence of resistant organisms constitutes a problem that has to be faced with all antimicrobial drugs, since it is difficult to reduce the bacterial count to zero per g of tissue unless the wound is covered or healed. The routine use of one or two types of topical agents has been associated with a high rate of resistant organisms, particularly in settings with large numbers of patients and inadequate isolation facilities. A repetition of this trial with other antibiotics would therefore widen the scope of topical antimiocrobials used.

The idea of applying a true antibiotic topically in order to control gram-negative burn wound infection was developed from our use of a pretested agent against certain types of micro-organisms and a low-concentration sensitivity test. We regard the present trial as a precursor to the use of other types of antibiotics, provided they have a wide safety profile, are not irritant, are water-soluble, and act at a pH similar to that of the micro-organisms.
The use of Aztreonam as a topical dressing is very helpful in the control of gram-negative mixed second- and third-degree degree burn wound infections, in particular those due to Pseudomonas. In the presence of high fever over 38.5 'C it is advisable to administer Aztreonam also systemically.

RESUME. Les Auteurs se sont occupés dans cette étude de 68 patients atteints de brûlures mixtes de deuxième et troisième degré et/ou zones cruentées hospitalisés dans l'Unité des Brûlés et le Centre des Brûlés de Assiut (Egypte) dans le but d'étudier l'effet de l'Aztreonam dans le contrôle de l'infection des brûlures due aux bactéries à Gram négatif soit en administrant l'antibiotique seulement en manière topique soit en association avec l'administration systémique. Les résultats ont été comparés avec ceux d'un groupe témoin composé de 57 patients atteints d'une infection de type Gram négatif qui ont reçu une médication classique. Lévaluation a été effectuée sur des bases clinique et bactériologique. Les Auteurs concluent que l'emploi de l'Aztreonam comme médication topique se révèle très utile dans la lutte contre les infections de type Gram négatif des brûlures mixtes de deuxième et troisième degré, et en particulier les manifestations dues à Pseudornonas. Si le patient présente une forte fièvre supérieure à 38,5 'C les Auteurs recommandent l'emploi aussi systémique de l'Aztreonam.

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