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13 - 208 - eficácia e segurança de sultamicilina.indd

Rev Bras Otorrinolaringol2006;72(1):104-11 ORIGINAL ARTICLE
Efficacy and safety of
Sultamicillin (Ampicillin/
Sulbactan) and Amoxicillin/
Clavulanic Acid in the
treatment of upper respiratory
tract infections in adults -
an open-label, multicentric,
randomized trial

João Batista Ferreira1, Priscila Bogar Rapoport2,
Eulália Sakano3, Arthur Octávio De Ávila Kós4,
Key words: ampicillin, sulbactan, amoxicillin, clavulanic, in- Otávio B. Piltcher5, Shirley Shizue Nagata
Pignatari6, Sebastião Diógenes Pinheiro7, Marcos
Mocellin8
Upper respiratory tract infections are the most common causes of medical visits in children and adults, demanding
massive use of antibiotics. Bacterial resistance caused by beta-
lactamase is one of the most serious problems in this matter.
Sultamicillin, a double pro-drug of Ampicillin/Sulbactan,
is a potent beta-lactamase inhibitor which can face this
challenge. Aim: evaluate efficacy, safety and tolerability of
Ampicillin/Sulbactan compared to Amoxicillin/Clavulanate
in upper respiratory tract infections in adults. Methods:
102 patients were enrolled and randomized to receive
Ampicillin/Sulbactan or Amoxicillin/Clavulanate during 10
days. They were evaluated 10 and 30 days after treatment to
learn about the therapeutic response. Results: There were
no differences between the two groups respecting cure at
the end of treatment (visit 2) or at the end of the study (visit
3). Cure ratio was 61.7% and 93.2% (visits 2 and 3) in the
Amoxicillin/Clavulanate group compared to 64.4% and 97.4%,
respectively, in Ampicillin/Sulbactan group. The adverse
events ratio for the two groups was the same (p=0.940). The
number of patients with diarrhea was greater in the group
of patients receiving Amoxicillin/Clavulanate (70.6%) than in
the group receiving Ampicillin/Sulbactan (29.4%) (p=0.0164).
Conclusions: Ampicillin/Sulbactan is as safe and efficient
as Amoxicillin/Clavulanate in the empiric treatment of upper
respiratory infections in adults. The low occurrence of
diarrhea in the group receiving Ampicillin/Sulbactan needs
confirmation in other studies.
1 Assistant Professor, Head of the Otolaryngology Department – Surgery Department – Medical School of the UFG.
2 PhD in Otolaryngology by the Medical School of the USP, Full Professor of Otolaryngology of the Medical School of the ABC.
3 Head of the Rhinology Department of the Otolaryngology Service of the UNICAMP.
4 Associate Professor of Otolaryngology by the Universidade Federal do Rio de Janeiro. Full Professor of the Federal University of Rio de Janeiro.
5 Physician hired by the Otolaryngology Department of the University Hospital of Porto Alegre - RS.
6 Assistant Professor of the Otolaryngology and Head and Neck Department - UNIFESP / EPM.
7 PhD in Medicine. Physician from the University of the Walter Cantídio Hospital of the Medical School of Ceará.
8 MSc and PhD from the Paulista School of Medicine – SP. Full Professor of the Otolaryngology Department of the University of Paraná.
Medical School of the Federal University of Goiás.
Mailing address: João Batista Ferreira - a/c Aline Guerra Rua Ministro Gastão Mesquita 515 ap. 112 Pompéia São Paulo SP 05012-010 Tel (0xx11) 9404-2344 - E-mail: [email protected] Paper submitted to the ABORL-CCF SGP (Management Publications System) on April 5th, 2005 and accepted on May 24th, 2005.
BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected] INTRODUCTION
difficult to have in our settings6-9.
AURTI etiology rests on the knowledge of the Upper airway infections in children and adults are habitual flora in the upper airways and the rarely iso- the most common diseases, and also the most common lated prevalent micro-organisms. In pharyngo-tonsillitis reasons for seeking medical consult in primary care. They the prevalent bacterial agent is the group A hemolytic β also constitute the major diagnosis that require the use of streptococcus. In AOM and sinusitis the prevalent micro- antibiotics. Its diagnosis and treatment have an impact not organisms are Streptococcus pneumonia, Haemophilus only from the stand point of population health, but also from the social and economical stand point, because of The choice of the antimicrobial agent should be the cost of medical care, cost of antibiotic used and for the guided by this knowledge. For clinicians and pediatricians, loss they represent as far as work and school absenteeism the choice of antimicrobial agent is a key issue. Right now are concerned. Taking Acute Otitis Media in children for the attention of the medical community and the general instance, American data points towards a total of 16 million public is directed towards the high cost of medication visits on this account in the year 2000. These visits gener- and the growing rates of antibiotic resistance10. Therefore, ate a total 13 million prescriptions, meaning 802 antibiotic judicious choice of antimicrobial agents is becoming a prescribed for each group of 1,000 visits. The cost of each antibiotic therapy varied from US$ 10 to US$ 100.
Ampicillin/Sulbactan is a combination of antibiotics The proper use of antibiotics not only in a hospital made up of ampicillin, a betalactam and sulbactam, a beta- setting, but also in handling the most common infections in lactamase inhibitor11. By adding sulbactan we consider- the community, has been the objective of ever increasing ably broaden the ampicillin action spectrum, including B debates, in an attempt to contain the growing resistance fragilis, Klebsiella sp, S aureus (MS) and H influenza.
rates that have been seen. Great emphasis have been The betalactam core destruction of penicillin and given to standardizations published by national entities cephalosporin by bacterial b-lactamase, constitutes the and universities, where evidence based approach reviews clinical most important mechanism of bacterial resistance the major points related to the diagnosis and treatment of against these antibiotics. The lack of receptor binding may infections. Many standardizations have been recently pub- be caused by: (1) changes in the permeability of the cell lished about otitis, sinusitis and pharyngo-tonsillitis2-5.
membrane and/or (2) changes in target site biding capacity The major discussions in these documents are fo- and (3) enzymatic destruction by antibiotics.
cused on whether or not it is necessary to use antibiotics The third of these three main causes is the most in AURTI (acute upper respiratory tract infections) and, frequent origin of antibiotic inefficacy. Beta-lactamase specially in non-complicated Acute Otitis Media (AOM). production causing bacterial resistance is one of the most The recommendation of initial use of symptomatic medica- severe problems of clinical practice today. B-lactamase may tion followed by antibiotics if there is no clinical improve- be produced either by gram positive or by gram negative ment with the patient, is based on the high incidence of bacteria. They destroy the antibiotic Betalactam core, turn- viral etiology in these pathologies. Notwithstanding, it can ing them useless. This destruction occurs by the hydrolysis not be followed in many cases when the decision has to of the amide bond in the betalactam ring, resulting in the be made quickly, without the possibility of having the production of acid derivatives that do not have antibacte- patient return, as is the case of ER visits. For this reason, rial properties. Clinical failure appears when a sufficient great emphasis should be given to aspects that support number of antibiotic molecules is neutralized12,13.
the most accurate possible diagnosis. And, from then, the Unasynâ (sultamicillin) is an antibiotic developed specifically to face these problems14,15. It is an ampicilin As far as diagnosis is concerned, there is some con- and sulbactam double pro-drug, a powerful beta-lactamase sensus: history of acute onset of symptoms; presence of inhibitor. The ampicillin/sulbactam mechanism of action exudation/inflammation signs in the middle ear, choanae depends mainly on the sulbactam bond, a suicide inhibitor, and nasal cavities or throat; pain, satellite lymph node with a large number of b-lactamase molecules. Sulbactam hydrolyzed fragments remain irreversibly bound to this The difficulties lie on the real possibility of estab- enzyme, thus forming an inactive complex.
lishing reliable and reproductive parameters to establish Ampicillin/Sulbactam pharmacokinetic studies have the presence of inflammatory and/or exudative clinical shown that the inactive pro-drug is well absorbed in the signs. The different clinical experiences and the available intestine. Ampicillin/Sulbactam is hydrolyzed in two com- technology translate themselves into different diagnostic pounds in the intestine wall, sulbactam and ampicillin. The approaches in about 50% of the non-complicated cases. total ampicillin distributed is approximately twice larger Particularly in pharyngo-tonsillitis, the germ culture and when compared to the oral distribution of ampicillin alone. the quick strep test are recommended, however they are The high serum level achieved is followed by optimum BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected] ampicillin and sulbactam tissue penetration. And finally, between days 10 and 13 (V-2 – end of treatment) and the clearance route for both active drugs is the urine16-18.
between days 26 and 34 (V-3 – end of trial).
The Ampicillin/Sulbactam action spectrum en- On visit 1, male and female patients older than 12 compasses gram positive coccus and rods, aerobic gram years and weighing 30 Kg and more were diagnosed as car- riers of bacterial infections in the ears, nose and/or throat, Peptococcus and Peptostreptococcus spp, anaer- concomitant or not, through clinical history and physical obes, Group B Streptococcus, Enterococcus faecalis, exam data. Inclusion criteria were defined as follows: Streptococcus pneumoniae, Streptococcus pyogenes, • Having at least 3 of the following signs/symptoms Streptococcus viridans (alpha-hemolytic), C diphtheriae, for sinusitis patients: bi-phased disease, defined as the Clostridium spp (Cl tetani, Cl perfringens, Cl botulinum), presence of two phases of the current disease; purulent Listeria monocytogenes, Haemophilus influenza, E coli anterior or posterior rhinorrhea; purulent secretion in the (over 50% of the strains may be resistant), P mirabilis, nasal cavity; facial/maxillary or teeth pain; OR Salmonella spp (S typhimurium may be 30% to 40% resist- • Having at least 3 of the following signs/symp- ant), Shigella flexneri, Fusobacterium spp.
toms for otitis patients: local pain, fever of 38°C or more; The Ampicillin-Sulbactam combination (Sultamicil- otoscopy findings such as tympanic hyperemia; tympanic lin) shows marked synergy. The MIC of many ampicillin- bulging; purulent or mucous-purulent secretion in the resistant pathogens is reduced, being very similar to those sensitive organisms of the same species. The ampicillin • Having at least 4 of the following signs/symptoms activity against sensitive organisms remains the same19,20.
for pharyngo-tonsillitis patients: sudden onset, intense pain On the other hand, the production of significant on swallowing; tonsillar enlargement; tonsillar hyperemia; quantities of b-lactamase have been associated to ce- exudate on the tonsils; painful anterior cervical lymph phalosporin resistance (Cephoxytin is the most powerful node disease; fever of 38°C or more.
resistance inducer) and to the ureidopenicillins. Incubation Patients were excluded when mentioned: hypersen- with sub lethal concentrations of sulbactam clavulanic sitivity to the trial drugs or to the betalactamic; pregnancy, acid and numerous betalactam antibiotics has shown that breast feeding or pregnancy possibility during the trial; sulbactam did not induce measurable levels of chromo- specific systemic disease or other medical conditions, some betalactam, while clavulanic acid induced 30% in including viral and urinary infections and meningitis that could interfere in the therapeutic response assessment, in Therefore, clavulanic acid may cause significant the absorption of medications, or safety of the trial drug; induction. This fact is in agreement with the results of an treatment with any systemic antibacterial drug within 14 in vitro study on the negative R factor of the carbenicillin- days before the randomization; concomitant participation resistant P. aeruginosa strains which suggests the existence in any other investigational drug clinical trial; blood dona- of an antagonism between the clavulanic acid and azlocillin tion or blood derivatives for transfusion in the 30 days prior combination, while adding sulbactam does not seem to to the treatment with the trial drugs at any time during affect the penicillin minimum inhibitory concentrations. So the trial or after 30 days of the trial end; treatment with far, no antagonism between sulbactan and other betalactam halopurinol, metrotrexate, probenecide and disulfiram, or other medications that may interfere on the trial drug The objective of this trial was to assess Sultamicil- assessment, and, transaminase values (ALT/SGPT or AST/ lin efficacy, safety and tolerability compared to that of SGOT) above 3 fold the upper limit of normality (ULN), Amoxicillin/Clavulanic acid, in the treatment of community and serum creatinin above 2 times the ULN.
acquired infections of the upper respiratory tract, specially On visits 1, 2 and 3, the patients underwent a ma- otitis, sinusitis and pharyngo-tonsillitis.
terial collection for safety exams (Complete blood count, biochemistry and pregnancy test, when indicated) and general clinical evaluation. Besides all of this, the patients underwent specific evaluation for signs and symptoms Eight Brazilian research centers participated in this related to upper respiratory tract infections, which include study, recruiting 102 patients from March 22, 2002 to July the same aspects used to confirm the diagnosis. 04, 2003. The protocol design established a comparative, multicentric, open and randomized trial of Ampicillin/Sul- Evaluation of the clinical response
bactan compared to Amoxicillin/Clavulanic acid. Patients Efficacy was evaluated based on the clinical re- were given 375mg bid PO Ampicillin/Sulbactan or 500mg sponse seen on visits 2 and 3 classified by the investigator tid PO Amoxicillin/Clavulanic acid after randomization. The study included 3 medical visits and lasted 34 days, Cure: absence of all signs and symptoms of the having one initial visit (V-1), followed by a treatment pe- disease being studied, described in the inclusion criteria riod of 10 consecutive days, and 2 later follow up visits BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected] at least one dose of the medication. Only 83 patients Improvement: presence of at least one of the studied completed the 30 days of the trial. The reasons why 14 disease signs and symptoms described in the inclusion patients were taken off the trial are as follows: adverse criteria, without the need to prescribe another antibiotic events - 5 patients; removal from the post-informed consent - 3 patients; loss of follow up - 3 patients; and protocol Failure: Persistence of one or more signs or symp- violation - 2 patients. Patient 107 was taken off because toms of the studied disease described in the inclusion criteria, or the appearance of new signs and symptoms Table 1 depicts the traits of the 97 security popula- of the studied disease and/or the need to add another tion patients at the trial onset. There was no statistically antibiotic agent or to change the study therapy.
significant difference among the demographic and clinical traits of the patients belonging to the two groups.
The infection time, in other words, the time span All adverse events seen or reported were registered between symptoms onset and diagnosis also did not show with specifications of the date of onset, the duration, the significant difference between the groups, varying from 1 severity, the evolution and the possible relation with the to 40 days with a 4 day median in both groups (Table 1). trial drug. Altered findings in the lab exams were also The type of infection presented by patients varied in both groups, although it was not significant. The Amoxicillin/Clavulanic acid group had a greater incidence of sinusitis Statistical analysis
and otitis whilst the Ampicilin/Sulbactan group patients The safety population was formed by 97 patients had a larger number of pharyngo-tonsillitis.
that took at least one dose of the trial medication. The Table 2 lists the signs and symptoms that were part ITT (intention to treat) efficacy population was made up of diagnostic criteria for each type of infection. Table 3 by the patients who were given at least one dose of the depicts signs and symptoms of patients along the trial, assigned treatment and had at least one subsequent clas- that is, at diagnosis – visit 1 – and their development in sification of clinical response to the instituted therapy. In other words, it was made up of 92 patients: all the 97 safety population patients minus the 5 patients who had Efficacy and clinical answer
unknown clinical response on visits 2 and 3. The efficacy There were no evidences of differences between PP population is made up of the patients who received the two groups in regards to the proportion of patients at least 6 doses of the assigned treatment and had at least who did not show cure at treatment end (visit 2) or at one subsequent clinical response to therapy classification. trial end (visit 3). In the Amoxicillin/Clavulanic acid In this study, population PP is formed by the same ITT group, cure rates were 61.7% and 93.2% on visits 2 and population patients, because all had at least 6 doses of 3, respectively . In the Ampicilin/Sulbactan group, cure rates were 64.4% and 97.4%, respectively. Table 4 depicts For clinical response we created a confidence inter- Confidence intervals for the difference among cure ratios val of 95% for the difference in cure and cure + improve- for both groups, as well as the results of the Fisher exact ment ratio among the treatment modalities. In order to test. Four patients had treatment failure on the third visit compare the average of vital signs along the visits we used after having reported cure on the second visit. Of these, the Variance Analysis with Repeated Measures, using the 3 were from the Amoxicillin/Clavulanic acid and 1 from non-structured co-variance matrix in order to model the existing correlation among the visits of a same patient. This technique takes into account the incomplete observations Adverse Effects
and, therefore, does not rule out the patient as a whole if There were 56 adverse effects along the trial (30 he/she does not have all the observations in all the visits. in the Amoxicillin/Clavulanic acid group and 26 in the All the aforementioned analysis require data normality as- Ampicillin/Sulbactan group). The total number of patients sumption which was verified and confirmed in all cases. who had adverse effects was 34, representing 35% of the Statistical analysis was made by the SAS version 8 software. total number of participants in the trial. Of these, 17 be- The adopted significance level was of 0.05.
longed to the Amoxicillin-Clavulanic acid group and 17 to the Ampicillin/Sulbactan group. The ratio of patients who experience at least one adverse effect was similar in both groups (p = 0.940). Notwithstanding, among the 34 patients who had adverse effects, the ratio of patients with diarrhea Patient traits
was significant higher in the Amoxicillin-Clavulanic acid Eight Brazilian centers recruited 102 patients for the group (70.6%) when compared to the Ampicilin/Sulbactan trial. Of these, ninety seven started the trial and received BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected] Table 1. Patient characteristics in the beginning of the study: age, gender and race.
Table 2. Type of infection; and signs and symptoms at diagnosis
Type of infection and symptoms at diagnosis Purulent anterior or posterior rhinorrhea Mucus-purulent secretion in the middle year BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected] Table 3. Proportions (%) of patients who presented one of the following signs/symptoms along the study, according to treatment group
Obstructive nasal secretion, epistaxis, cacosmia V1: Visit 1 – Study onset
V2: Visit 2 – Treatment end
V3: Visit 3 – Trial end
Table 4. Ratio of cured patients at treatment end (V2) and at trial end (V3).
Table 5. Adverse effect of which causality was not ruled out by the investigator.
BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected] the bacteriological cure and S pneumoniae was the most As to laboratory work up, no relevant alterations frequently found micro-organism. Other trials show the were found after the use of trial medications. The altered comparative performance of Sultamicillin with amoxicil- values were already present on visit 1 for both groups.
lin alone or in combination with Clavulanic Acid in lower According to protocol criteria, there was no severe respiratory tract infections. The clinical response was, once adverse effect. Only 5 patients were removed from the trial again, comparable with efficacy rates varying between 84% because of adverse events (2 on the Ampicillin/Sulbactan and 94%29. Considering the treatment of otitis in children, group and 3 on the Amoxicillin-Clavulanic acid group). Ampicillin/Sulbactan proved to be efficient, with cure The 9 adverse effects of these 5 patients were: diarrhea rates above those seen with the use of Cefaclor24. From – 3 Amoxicillin-Clavulanic acid related events and one the safety stand point, our study confirms literature reports Ampicilin/Sulbactan-related event; lethargy – 1 Amoxi- that Ampicillin/Sulbactan is a well tolerated drug. There cillin-Clavulanic-acid-related event; irritability – 1 case; were no severe adverse effects, and in those that really worsening of tonsillitis – 1 case; worsening of sinusitis happened, both groups had similar distribution. Only – 1 case; and abdominal pain – 1 case. Bellow we listed diarrhea was significantly higher in the Amoxicillin/Cla- the adverse effects with cause related to the drugs used. 5 vulanic acid group (p=0.016). Gastrointestinal symptoms Ampicillin/Sulbactan group patients had diarrhea, however seem to be the most frequent adverse effect related to only 4 are listed here because the investigator considered the use of Ampicillin/Sulbactan. In the same way, these that one was not related to the trial drug. symptoms and, diarrhea most specifically, are very com-mon with the use of Amoxicillin/Clavulanic acid, making Concomitant medication
its use rather difficult sometimes, specially by children. Sixty patients (61.8%) received at least one concomi- In some measure, our data may have pointed towards a tant medication. Of these, 29 belonged to the Amoxicillin/ greater tolerability of Ampicillin/Sulbactan in comparison Clavulanic acid group and 31 to the Ampicillin/Sulbactan to Amoxicillin/Clavulanic acid, according to what has been group. Among the drugs used, the most frequent were reported in the literature30. Other studies must follow in Dipirone and paracetamol, and there was no difference order to investigate these aspects, with more cases and in its use among the two treatment groups. In short, we have concluded that Ampicilin/Sul- DISCUSSION
bactan is as efficient and safe as Amoxicillin/Clavulanic acid in the empirical treatment of adult acute upper res- The results of this trial show the comparable effi- piratory tract infections, thus representing an important cacy of Ampicillin/Sulbactan and Amoxicillin/Clavulanic therapeutic alternative. This lower occurrence of diarrhea acid combinations in the treatment of acute upper res- in the Ampicillin/Sulbactan group that has been observed piratory tract infections in adults. Such results correlate to literature reports on the use of Ampicillin/Sulbactan combination in the treatment of both upper and lower There was no significant difference in the propor- This investigation was financed with resources from tion of patients who were cured at the end of treatment and at the end of trial in both groups. In the Ampicillin/Sulbactan group, the cure ratios increased from 64.4%, at BIBLIOGRAPHY
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Clinical effect of ampicillin with beta-lactamase inhibitor (sulbactam/ampicillin) on community-acquired pneumonia in the elderly. J Infect Chemother 2003; 9(2); 183-6. BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY 72 (1) JANUARY/FEBRUARY 2006 http://www.rborl.org.br / e-mail: [email protected]

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