Artículo Clínico

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Efficacy of single drug therapy with piperacillin-tazobactam in infections of the maxillofacial area
Eficacia de la monoterapia con piperacilina-tazobactam en infecciones del área maxilofacial

 

M. Delgado Sánchez¹, Y. Herrero Basilio¹, A. Daura Sáez², A. Modelo Pérez³, E. Fernández Ruiz⁴, J. J. Ruiz Masera⁵, J.C. Casado Morente⁶,
A. Martínez Garrido⁷, J. Rodas Ibáñez¹

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1 Servicio de Cirugía Oral y Maxilofacial, Complejo Hospitalario Virgen Macarena, Sevilla. España.
2 Servicio de Cirugía Oral y Maxilofacial, Hospital Carlos Haya, Málaga. España.
3 Servicio de Cirugía Oral y Maxilofacial, Hospital Universitario Puerta del Mar, Cádiz. España.
4 Servicio de Otorrinolaringología, Hospital Clínico Universitario Virgen de la Victoria, Málaga. España.
5 Servicio de Cirugía Oral y Maxilofacial, Complejo Hospitalario Reina Sofía, Córdoba. España.
6 Servicio de Otorrinolaringología, Hospital Costa del Sol, Marbella-Málaga. España.
7 Servicio de Cirugía Oral y Maxilofacial, Hospital San Juan, Alicante. España.

Correspondencia
Dra. María Delgado Sánchez
Servicio de Cirugía Maxilofacial. Complejo Hospitalario Virgen Macarena
Avda. Dr. Fedriani, s/n
41071- Sevilla. España
E-mail: mdelgados@medynet.com

 

Introduction

Infections of the maxillofacial area constitute a frequent entity in the daily practice of the maxillofacial surgeon. When speaking of maxillofacial infection, a wide range of conditions, having a different nature, different etiology, different clinical presentation and seriousness, are included in this definition. They may go from simple cases that are treated as out-patients to entities having important morbidity-mortality that require early and aggressive intrahospital treatment.

This type of infections may endanger life either due to the mechanical involvement of the airway, due to the production of toxins or due to dissemination to distant organs by contiguity as well as by hematogenic propagation. Since the introduction of antibiotics, infections that jeopardize life are unusual and are associated with some lower mortality indexes. However, these infections continue to be frequent in alcoholic, weakened or immunodepressed patients.^1-3

Within the infections of the maxillofacial area, the dental origin ones are the most common. Most evolve favorably with minimum complications, but they can also cause serious morbidity and even be fatal. Other pictures such as the Lemierre syndrome, Ludwig’s angina or peritonsillar abscess are less frequent but extremely serious.^3-5

The most frequently involved microorganisms are variable, depending on the entity evaluated. In general, the microorganisms isolated in head and neck infections are: Non-hemolytic streptococci (46.7%), Hemolytic streptococci (11.3%), S. epidermidis (10.7), Enterobacterias (9.3%), Peptostreptococcus spp, Bacteroides spp. (7.4%), Enterococci (4.7%), S. aureus (1.3%), P. aeruginosa (1.3-10%)^6-8. However, this percentage varies widely according to the disease. Thus, a predominantly anaerobic polymicrobial nature has been demonstrated in odontogenic infection.² A mixed flora generally participates in the more serious infections, whatever their origin, and more aggressive treatment that combines surgery, systemic antibiotic treatment and other life support measures are required.³

As has been seen, all the infectious conditions can seriously affect the upper airways and require early diagnosis and treatment. Different empirical antibiotic treatment regimens, both combined as well as single drug therapy, are accepted. Piperacillin-tazobactam is a wide spectrum betalactamic agent from the ureidopenicillin family that has been associated to a beta-lactamase inhibitor, tazobactam, to improve its action against beta-lactamase producing enterobacterias. ⁹ This compound is very active against gram positive microorganisms, including strains that produce betalactamases (among others methicillin susceptible S. aureus, S. epidermidis, streptococci and enterococci).¹⁰ In addition, piperacillin-tazobactam shows a large activity against the gram negative bacilli (GNB) including Pseudomonas aeruginosa. ¹¹ The spectrum is completed with its activity against anaerobic microorganisms.¹²

To our knowledge, up to now no studies have been done that evaluate the usefulness of piperacillin-tazobactam in infections of the maxillofacial area. Thus, this study aims to assess the efficacy and safety of a wide spectrum antibiotic such as piperacillin-tazobactam in patients with serious infections of the maxillofacial area.

Material and method

Included in the study were patients older than 18 years of age with infections in the maxillofacial area (infection of the salivary glands, cellulitis of sinus origin, cellulitis of dermal origin, cellulitis of dental origin, Ludwig’s angina, cervical adenophlegmon, peritonsillar abscess, cervical necrotizing fasciitis) that had or lacked suppuration, that required drainage or surgical debridement or not, and whose treatment with piperacillin-tazobactam was administered for a minimum of 3 days. Exclusion criteria were considered to be hypersensitivity to beta-lactamics, moderate or serious renal alteration, hepatic alteration, granulocytopenia less than 1,000/mm³, thrombocytopenia less than 50,000/mm³ as well as the presence of another concomitant infection clinically or bacteriologically documented at the time of the patient’s inclusion.

Samples for the microbiological processing were obtained by puncture and aspiration of the zone affected or by swab after the surgical treatment.

The patients abandoned the study when there was serious general toxicity according to the judgment of the responsible physician, loss to follow-up or voluntary drop-out and those in whom no favorable response was seen or no response was obtained after 72 hours of treatment.

We elaborated a case report form, that included demographic characteristics, predisposing factors, clinical and analytic data, microbiology of the lesion, associated surgical or medical treatments and evaluation of the clinical and microbiological response on the third day and at the end of the treatment. In relationship to the appearance of adverse reactions, its causal relationship with the study drug (definitive, probable, possible and remote), its grading in regards to seriousness (mild, moderate, serious, life threatening) and the type of action used to eliminate it were considered.

Clinical evaluation

In order to observe response to treatment, a scoring system was designed to assess the patient’s situation. Table 1 shows the parameters evaluated as well as the score corresponding to each one of them. This evaluation was performed on the day of the onset of treatment, the third day, fifth day and at the end of the treatment.

We define response ratio as the score of the day that the patient was being evaluated divided by the score of the first day. Thus, response was considered as favorable if the ratio was less than 0.7. If it was less than 0.3, it was considered excellent and if it was between 0.3 and 0.7, effective.

Treatment failure was considered to exist when the ratio was greater than or equal to 0.7 according to the same scale. In the same way, the need to perform drainage once antibiotic treatment was initiated or change the antibiotic treatment was considered as treatment failure.

It was considered to be non-evaluable when the infection had a fungal or viral origin or when some of the microorganisms isolated were resistant to piperacillin-tazobactam.

Microbiological evaluation

Microbiological efficacy was evaluated according to the following parameters. We defined eradication as when all the microorganisms isolated in the initial sample were eliminated; presumed eradication when there was clinical improvement but no microbiological cultures were performed to verify the eradication; persistence when the original microorganism was isolated in successive cultures and colonization was defined as the appearance of a new microorganism, different from that causing the initial infection, although this isolation was not accompanied by clinical signs suggestive of infection. Relapse was considered to be the reappearance of the same microorganism once treatment was stopped and reinfection as the appearance of a new microorganism once the treatment was completed.

Description of the treatment

Piperacillin-tazobactam is presented in vials of 4/0.5 g as apyrogenic lyophilized powder. Dilution was performed with saline solution and administered intravenously in continuous perfusion for 30 minutes. The dose applied was 4/0.5 g every eight hours. Administration of another antibiotic was not permitted simultaneously to the study. If the microorganism responsible for the infection was not susceptible to piperacillin-tazobactam, treatment was adjusted according to the antibiogram. When the evolution of the patient made it possible, piperacillin-tazobactam was substituted by another antibiotic that could be administered orally.

Study design

It is a multicentric, prospective and observational study. The analysis was performed according to intention to treat, that is, the duration of the follow-up period of each patient will be understood as the time to appearance of one of the clinical events that corroborate the efficacy of the treatment or until the end of the study.

Results

A total of 79 patients with a mean age of 36.3 years (SD: 14.9 years) were included in the study. Distribution by genders was 59% men and 41% women. A total of 22.7% of the patients were usual drinkers and 40.5% smoked. The diagnoses included (Table 2): cellulitis of any origin: 54 cases; infection of salivary glands: 8 cases; peritonsillar abscess: 8 cases; postsurgical infection. 6 cases; cervical adenophlegmon in 3 cases; Ludwig’s angina: 2 cases and other diagnoses in 7 cases.

The mean score of the situation of the patient in the initial assessment of the patient was 12.9 (SD: 3.6, range: 7-26). Seven patients (8.9%) presented dyspnea in the onset assessment and 38 (48.1%) dysphagia or odynophagia coinciding with the diagnosis. Thirty eight patients required surgery (48.1%) and placement of one or several drainages was performed in 31 cases (39.2%).

Mean treatment duration was 4.1 days (SD: 1.5 days). Fifty patients received less than five days of treatment. Clinical response on the third and fifth day of antibiotic treatment is shown in table 3.

The final clinical evolution of all the patients (n=79) at the end of the treatment was favorable in 97.5% of the patients (77/79) and unfavorable in the remaining 2.5% (2/79). In the two cases having unfavorable evolution, infection was produced by piperacillin-tozobactam resistant microorganisms, in one case methicillin resistant S. aureus and in the other due to Mucor. It was possible to isolate some microorganism in 30 cases, 12 of which were polymicrobial. The microorganisms isolated most frequently can be seen in table 4.

Microbiological efficacy obtained at the end of the treatment was 96.2%, distributed in 12.6% of eradication cases (elimination of the original microorganisms) and 85.5% of cases of presumed eradication (with clinical improvement however, it was not possible to isolate the microorganisms). Table 5 shows the microbiological efficacy on the third and fifth day of treatment (13).

Adverse reactions related with the use of piperacillin-tazobactam presented in 5 patients (mild in the five cases), with two cases of dizziness, two of dyspepsia and one case of phlebitis. Discontinuation of the drug was not required in any case.

Twenty three patients did not present fever at the time of the diagnosis; in the rest, the mean time of disappearance of the fever was 1.5 days (SD: 0.76 days). The mean hospital stay was 5.3 days (SD: 3.31 days). No deaths were produced.

Discussion

Infections of the maxillofacial area represent a usual reason for a visit to the maxillofacial surgeons. Infections of dental origin are the most frequent within the large variety of entities that are grouped under this term. This is corroborated in our study where most of the cases were cellulitis (61.4%). Within these, cellulitis of dental origin was the most frequent.

There are a series of general and local factors that influence the spread of the infectious condition. The infection is spread from the tooth and alveolar bone in a relatively radial way; once it crosses over the bone and periosteum, the dissemination through the soft tissues is conditioned by the position of the muscles and regional aponeurosis. Many spaces in the head and neck have been described, some with fissures (virtual spaces between aponeurotic spaces) and other true compartments with connective tissue and diverse anatomical structures. The sublingual, submaxillary, lateroand retropharyngeal compartments are the most dangerous due to the possible involvement of the air passage or by extension to vital territories such as the mediastinum. Knowledge of these spaces makes it possible to assess the best location of the surgical incision, when this is indicated. In general, treatment success of these infections is found in an early correct treatment.

The antibiotic treatment attempts to stop local extension of the infection, reduce bacterial inoculum in the infectious focus and prevent complications derived from the hematogenic dissemination. While oral antibiotics can be used in mild and moderate cases, hospitalization is required in the case of serious infections, with measures of life support and the administration of parenteral antibiotics with wide spectrum activity.

In general, most of the microorganisms in healthy patients, both aerobic as well as anaerobic, are susceptible to penicillin. The problem of the production of beta-lactamases and resistance to penicillin among certain oral anaerobes is increasing and thus treatment failure with penicillin in infections produced by these microorganisms has been seen. In patients with serious infections, that can be life threatening and in patients who have poor or slow response to penicillin, alternative treatments with greater spectrum antibiotics with activity against anaerobes as well as gram negative bacilli should be used.

Out-patients can be treated with anoxicillin with or without a beta-lactamase inhibitor or with penicillin or a fluoroquinolone in combination with metronidazole. Clindamycin or cefoxitin can also be used. However, the growing resistance of anaerobic microorganisms to these drugs limits their utility. Erythromycin and tetracyclines are not recommended due to the growing resistance among some strains of Streptococcus.² Although Metronidazole is very active against gram negative anaerobic bacilli and the spirochetes, it is only moderately active against anaerobic cocci and is not active against aerobic microorganisms, including Streptococcus.¹⁴

In patients with more serious pictures, that require hospitalization, there are microorganisms such as P. aeruginosa that play a fundamental role, as we have seen in this study. Thus, it would be wise in these patients to cover facultative gram negative bacilli, among them P. aeruginosa, and anaerobic microorganisms.^15-20 Traditionally, treatment of these infections with single drug therapy was performed with anoxicillin- clavulanic acid. However, the increasingly important role of P. aeruginosa in these diseases, corroborated in our study, could limit their role in the empiric treatment of serious patients with this type of infections. Another aspect that conditions the problems of empiric treatment with amoxicillin- clavulanic acid is the growing resistance of enteric gram negative bacilli, especially E.coli. In our setting, in recent studies with strains of urinary origin, the resistance is at about 6%,²¹ however, in France, resistances up to 37% are reported. ²² In addition, tazobactam supplies better inhibition of the beta-lactamases of tazobactam than of clavulanic acid²³ and less induction of them.^24,25

In many cases, antibiotic treatment will not be sufficient to eradicate the infection and thus should be accompanied by other measures such as abscess drainage, surgery or dental extraction. In our study, 48.1% of the cases required surgery and 39.2% the placement of one or several drainages.

Regarding the diagnostic attitude, the ideal situation would be that which makes it possible to accurately know the microorganisms involved in each condition and adapt the antibiotic treatment in this way. However, in maxillofacial infections, this is not an easy task. On the one hand, the large variety of aerobic and anaerobic microorganisms isolated and on the other hand, the obtaining of clinical samples contaminated with commensal flora, adds difficulty to the microbiological isolation. When an attempt is made to obtain samples for the microbiological diagnosis of the infections deep in the head and neck, special care must be given to contamination of the usual flora of the zone. This can be achieved by an extraoral approach with aspiration with syringe or by surgical drainage. Treatment of these infections should be individualized in each case. However, and in spite of its limitations, the microbiological study is essential and should always be performed when possible, for better knowledge of the microorganisms involved in this disease. This would allow for better adjustment of the empiric antibiotic treatment than the usual one.

During the past decades, the predominantly anaerobic nature of the flora of odontogenic infections has been observed. Brook found that 50% of the deep infections of odontogenic origin only isolated anaerobic microorganisms, in 44% a mixed aero-anaerobic flora and a pure culture of aerobic microorganism only in 6% (26). Our study shows an especially low proportion of anaerobic microorganisms. This could be due to two facts, first, non-odontogenic diseases have been included, in which the flora would be characteristic of other infections of the skin and soft tissues and second, the sample was not always obtained in adequate conditions for the culture of anaerobic microorganisms. In general, the microbiological study was not performed as much as would be desired. In our opinion, this is due to the difficulty of the microbiologic diagnosis in maxillofacial infections. On the one hand, there is the large number of odontogenic infections in which it is difficult to specify the role of the microorganisms isolated, either as responsible for the infectious picture, or as a commensal flora. On other occasions, microorganisms that are considered usual flora in this zone may be responsible for the infection. The isolation of P. aeruginosa also stands out in our study. This flora is more characteristic in cases of very serious patients, with different baseline diseases and who require hospitalization. In our study, P. aeruginosa represents the fourth microorganism characteristic of the oropharyngeal flora. Thus, it would be reasonable to cover P. aeruginosa in the initial empirical treatment in these patients with more serious pictures who require hospitalization and with baseline disease.

Our study communicates results that reach those of favorable clinical evolution in 97.5% of the cases with the use of piperacillin-tazobactam in single drug therapy with a very limited incidence of adverse effects (6.3% of the patients), and that did not make it necessary to discontinue the drug in any case. This manifests the usefulness of the antibiotic treatment in single drug therapy in this type of infection, as has been demonstrated in another type of infectious diseases. The economic savings that this type of antibiotic treatment means should also be considered.²⁷

Conclusions

In conclusion, the clinical and microbiological efficacy together with the limited adverse effects presented make piperacillin-tazobactam an effective alternative in the management of this type of infections.

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