Acute Bacterial Maxillary Sinusitis: Results of U.S. and European Comparative Therapy Trials RICHARD W. NIELSEN, M.D., Salt Lake City, Utah
Loracarbef, which is the first agent of the carbacephem class of fl-lactam antibiotics to be developed, provides good activity against a broad spectrum of bacteria. A single-blinded, randomized, parallel clinical trial in 10 centers in the United States compared the efficacy and safety of loracarbef with that of amoxicillin/ clavulanate potassium in the treatment of acute bacterial maxillary sinusitis. A 7-10-day regimen of loracarbef (400 mg twice daily) was as effective as amoxicillin/clavulanate (500/125 mg three times a day) and resulted in somewhat fewer side effects. The results of a European trial in Sweden, Finland, and Iceland showed that loracarbef was clinically more effective than doxycycline in the treatment of acute bacterial maxillary sinusitis.
" ost cases of acute sinusitis are caused by secM ondary bacterial infection following a viral upper respiratory tract infection, with Streptococ-
cus pneumoniae and unencapsulated strains of Haemophilus influenzae accounting for one half of all cases [1]. The reported incidence of Moraxella (BranhameUa) catarrhalis is as high as 23% of the positive isolates in pediatric populations [2]. Streptococcus pyogenes, Staphylococcus aureus, and other gram-negative bacteria have been reported less frequently as part of the microbial etiology of acute maxillary sinusitis. A total of 5-10% of cases of acute maxillary sinusitis originate from associated dental disease, often due to anaerobic bacteria. The only reliable means of identifying the specific pathogen responsible for the illness is by culture of an exudate or a rinse obtained directly from the sinus by puncture or aspiration, which prevents contamination of the specimen with bacterial flora that normally reside in the nose [1]. However, sinus puncture is not indicated for the average case of sinusitis, in which the likely causative agents usually can be predicted from past studies.
TREATMENT
From the Ear, Nose, and Throat Center of Salt Lake City, Salt Lake City, Utah. Requestsfor reprints should be addressedto Richard W. Nielsen, M.D.,900 East, 22 South, Salt Lake City, Utah 84102.
6A-70S
Some of the antimicrobial agents used to treat acute sinusitis include ampicillin, amoxicillin, amoxicillin/clavulanate, cyclacillin, bacampicillin, doxycycline, minocycline, spiramycin, trimethoprim/ sulfamethoxazole, cefaclor, and cefuroxime axetil [1,3-9]. Several drawbacks have been recognized in the various therapies for sinusitis. Both ampicillin and amoxicillin are often used for the initial treatment of uncomplicated sinusitis, and trimethoprim/sulfamethoxazole has been recommended as an alternative therapy for patients allergic to penicillin. However, treatment with ampicillin and amoxicillin is decreasing because of the increasing frequency of fl-lactamase-producing strains of H. influenzae and M. catarrhalis. Although amoxicillin is well tolerated, it must be administered three times daily, which can reduce patient compliance and cause inconvenience for parents with children in school or day-care programs who require treatment with the drug. The combina-
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUMON ANTIMICROBIALTHERAPY/ NIELSEN
tion of amoxicillin and clavulanate potassium overcomes the problem of resistance of fi-lactamaseproducing strains, but several studies have reported the occurrence of diarrhea in 20% or more of patients using this combination [10]. Cefuroxime axetil and cefixime are newer-generation oral cephalosporin antibiotics used for the treatment of respiratory infections. Although cefuroxime has excellent activity against respiratory pathogens and is stable in the presence of many fl-lactamases, side effects such as nausea, vomiting, and diarrhea are relatively common, and it has an extremely bitter taste that young children find unacceptable. Although cefixime's long serum half-life allows once- or twice-daily dosing, it has only moderate activity against S. pneumoniae¢ a common cause of sinusitis. It has relatively low bioavailability after oral administration, and gastrointestinal events are relatively common. Loracarbef is the first agent of the carbacephem class of/~-lactam antibiotics to be developed. It provides good activity against a broad spectrum of bacteria [11-14]. It is active in vitro against S. pyo-
genes, S. aureus, Staphylococcus epidermidis, S. pneumoniae, H. influenzae, M. catarrhalis, Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, including fl-lactamase-producing strains of staphylococci, Haemophilus, and most M. catarrhalis [15]. Recently, two clinical trials have evaluated loracarbef in the treatment of acute sinusitis. A trial conducted in the United States compared loracarbef with amoxicillin/clavulanate [16], and a European trial conducted in Sweden, Finland, and Iceland compared loracarbef with doxycycline [17].
CLINICAL TRIAL: LORACARBEFVERSUS AMOXICILLIN/CLAVULANATE A single-blind, randomized, parallel clinical trial conducted in centers in the United States compared the efficacy and safety of loracarbef with that of amoxicillin/clavulanate potassium in the treatment of acute bacterial maxillary sinusitis [16].
Patients and Methods The 27-month study included 113 patients, with 59 patients in the loracarbef group (22 male, 37 female) and 54 patients in the amoxicillin/clavulanate group (17 male, 37 female). In the loracarbef group, the mean age (-+standard deviation) was 41.0 - 13.9 years, and in the amoxicillin/clavulanate group, the mean age was 36.2 + 13.3 years. Patients had a diagnosis of acute bacterial maxillary sinusitis, no history of chronic sinusitis (dura-
tion of symptoms >14 days), and no prior episodes of acute sinusitis within the previous 12 months. The diagnosis of maxillary sinusitis was based on clinical, radiologic, and bacteriologic factors. The clinical syndrome was defined as purulent rhinorrhea, facial pain, and/or headache of 108 colony-forming units (CFU)/mL of recognized respiratory pathogens (including H. influenzae, S. pneumoniae, and M. catarrhalis) or ->105 CFU/mL of any other bacteria. Patients were given 7-10-day regimens of either two 200 mg loracarbef capsules (total 400 mg) twice a day or one 500/125 mg amoxicillin/clavulanate potassium tablet three times a day. Patients were evaluated with a history, physical examination, and sinus X-rays before therapy. During therapy (days 4-6), within 72 hours after the conclusion of therapy (posttherapy), and 1-2 weeks after conclusion of therapy (late-posttherapy), patients were evaluated for response to treatment and possible recurrence of infection. Clinical responses were defined as follows: cure (total alleviation of symptoms); improvement (substantial improvement of symptoms); failure (symptoms were not at all or not substantially improved); relapse (recurrence or worsening of symptoms after initial cure or improvement); or unable to evaluate. Bacteriologic responses were defined as eliminated (culture-documented pathogen eradication or presumed eradication in patients who had clinical cure or improvement) or failure (persistence of the original pathogen).
Results A total of 59 patients were randomized to the loracarbef group and 54 patients to the amoxicillin/ clavulanate group. Of the original 113 patients, only 48 were evaluable: 24 in the loracarbef group and 24
June 22, 1992 The AmericanJournal of Medicine Volume92 (suppl 6A)
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SYMPOSIUM ON ANTIMICROBIAL THERAPY/NIB.SEN
TABLE I Posttherapy Correlation: Bacteriologic Response Following Treatment with Loracarbef or Amoxicillin/Ciavulanate Bacteriologic Response Failed To Eliminate
Eliminated Clinical Response
Total
n
%
n
%
n
%
Loracarbef Successful Relapse TOTAL
21 2 23
87.5 8.3 95.8
1 0 1
4.2
91.7 8.3
4.2
22 2 24
Amoxicillin/clavulanate Successful Failure TOTAL
23 0 23
95.8
0 1 1
4.2 4.2
23 1 24
95.8 4,2
95.8
in the amoxicillin/clavulanate group. Reasons for pathogens isolated, were H. influenzae (27.3%), S. exclusion were bacteriologic disqualification (34 pneumoniae (22.7%), Streptococcus species patients in the loracarbef group and 29 patients in (13.6%), and M. catarrhalis (13.6%). the amoxicillin/clavulanate group), concomitant use Clinical response, determined within 72 hours of of an antibiotic (one patient in the loracarbef completion of drug therapy, was considered to be group), and insufficient therapy (one patient in the successful if there was improvement or cure. Both amoxicillin/clavulanate group did not finish ther- drug regimens were effective, as shown in Table I. apy). In the loracarbef group, there were 22 (91.7%) sucBacteriologic reasons for exclusion were negative cessful clinical responses and 2 (8.3%) relapses; in pretherapy culture (20 patients in the loracarbef the amoxicillin/clavulanate group, there were 23 group and 16 in the amoxicillin/clavulanate group), (95.8%) successful clinical responses and 1 (4.2%) no or low colony count of pretherapy isolates (eight failure. Both loracarbef and amoxicillin/clavulanate patients in the loracarbef group and eight patients produced clinical success rates of 100% in patients in the amoxicillin/clavulanate group), and resis- with infections due to S. pneumoniae or M. catance of the causative organism to one or both anti- tarrhalis; in patients with infections due to H. inmicrobials (six patients in the loracarbef group and fluenzae, however, loracarbef produced a 100% five patients in the amoxicillin/clavulanate group). clinical response rate, whereas that produced by In evaluable patients, the most common single amoxicillin/clavulanate was only 75% (Figure 1). With regard to posttherapy bacteriologic response, 23 (95.8%) patients in the loracarbef group Loracarbef had elimination of the pathogen and one (4.2%) paAmoxicillin/clavulanate tient did not. In the amoxicillin/clavulanate group, 100 100 100 100 100 the figures were 23 (95:8%) and 1 (4.2%), respec(n=5) (n=9) (n=3) (n=2~) (n=6) tively. Pretherapy pathogens for two patients in 100 95,8 91.7 (n=24) the loracarbef group who relapsed clinically were I ~/////A Streptococcus species and group A streptococci. At 90 ! ~/J///K4 posttherapy, their cultures were negative. The loracarbef-treated patient who failed to eliminate 80 the pretherapy pathogen (S. pneumoniae) was clinically improved at posttherapy. The patient in the #_ 70 amoxicillin/clavulanate group whose treatment failed clinically and bacteriologically had fi-lactamase-negative H. influenzae, which was not 60 eliminated by treatment. Of the 15 patients in the loracarbef group who ___1~ 5o J returned for late-posttherapy evaluation, all felt Moraxel~ All pathogens Streptococcus Haemophilus well and were presumed to be free of the prether(B~nhamella) influenzae pneumoniae ca~rrhal~ apy pathogen. The same was true of the 15 patients in the amoxicillin/clavulanate group who returned Figure 1. Posttherapy clinical success rates (cure and improvement) by pathogen for the late-posttherapy visit. There were no refor acute bacterial maxillary sinusitis following treatment with Ioracarbef or amoxilapses in either group. cillin/clavulanate. 6A-72S June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A) I
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IN I ~//////t
iN
SYMPOSIUM ON ANTIMICROBIALTHERAPY/ NIELSEN
Adverse events were reported without regard to causality. The number of patients with at least one event during therapy was 12 (20.3%) in the loracarbef group and 23 (42.6%) in the amoxicillin/clavulanate group (p = 0.011). The most common adverse event in both treatment groups was diarrhea, reported in four (6.8%) patients in the loracarbef group and 11 (20.4%) patients in the amoxicillin/ clavulanate group (p = 0.033). The difference in the incidence of vaginitis between females in the two groups was statistically significant: 10.8% of those in the amoxicillin/clavulanate group and none in the loracarbef group (p = 0.040) reported this adverse event. Other adverse events occurring in >2% of the total population included nausea and abdominal pain, but the differences between the two groups were not statistically significant. Only one patient in the loracarbef group discontinued drug therapy early because of an adverse event (abdominal pain). In the amoxicillin/clavulanate group, six patients discontinued drug therapy early because of adverse events: two because of diarrhea, one because of nausea, one because of vaginitis, one because of pruritus, and one because of urticaria. Thus, this study demonstrates that loracarbef is comparable in efficacy to amoxicillin/clavulanate in the treatment of acute bacterial maxillary sinusitis and that loracarbef has a more desirable safety profile. Furthermore, the twice-a-day dosing schedule of loracarbef compared with three times a day for amoxicillin/clavulanate should increase patient compliance.
CLINICALTRIAL: LORACARBEFVERSUS DOXYCYCLINE A trial conducted in Sweden, Finland, and Iceland compared loracarbef with doxycycline in the treatment of acute bacterial maxillary sinusitis [17]. Doxycycline was chosen because it is commonly prescribed in Sweden for this disease and is administered once a day. In the United States, it is more commonly given twice a day. A total of 662 patients were enrolled in this double-blind, randomized, parallel trial. Inclusion and exclusion criteria were similar to those in the U.S. study. Loracarbef was given at 400 mg twice daily for 7-10 days, and doxycycline was given at 100 mg once a day, also for 7-10 days. Data from the study showed that loracarbef produced statistically significant better posttherapy clinical results (98.2% cure or improvement) than did doxycycline (93.3% had a favorable response); with regard to bacteriologic results, there was no significant difference between the two treatment groups. The correlation of clinical and bacteriologic
outcomes indicated that loracarbef was more efficacious than doxycycline in treating acute bacterial maxillary sinusitis. Adverse events in both treatment groups were generally mild and similar between the groups, although the incidence of diarrhea was higher in the loracarbef group (5.7%) than in the doxycycline group (2.1%). However, the overall incidence of events related to the digestive system was similar in the two therapy groups during therapy. The investigators concluded that loracarbef was as safe as doxycycline for patients with acute sinusitis.
CONCLUSION In summary, the U.S. study demonstrates that loracarbef given 400 mg twice daily was as effective as amoxicillin/clavulanate given 500/125 mg three times a day in the treatment of acute bacterial maxillary sinusitis and had fewer adverse effects. In the European study, loracarbef given 400 mg twice daily was clinically more effective than doxycycline 100 mg given once a day.
REFERENCES 1. Gwaltney JM Jr. Sinusitis. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone, 1990; 510-4. 2. Wald ER, Byer C, Guerra N, et al. Subacute sinusitis in children. J Pediatr 1989; 115: 28-31. 3. Carenfelt C, Eneroth C-M, Lundberg C, Wretlind B. Evaluation of the antibiotic effect of treatment of maxillary sinusitis. Scand J Infect Dis 1975; 7: 259-64. 4. Gwaltney JM Jr, Sydnor A Jr, Sande MA. Etiology and antimicrobial treatment of acute sinusitis. Ann Otol Rhinol Laryngol 1981; 90 (Suppl 84): 68-71. 5. Farr B, Scheld WM, Gwaltney JM Jr, et al. Bacampicillin HCI in the treatment of acute maxillary sinusitis. Bull NY Acad Med 1983; 59: 477-81. 6. Scheld WM, Sydnor A Jr, Farr B, et aL Comparison of cyclacillin and amoxicillin for therapy of acute maxillary sinusitis. Antimicrob Agents Chemother 1986; 30: 350-3. 7. Sydnor A Jr, Gwaltney JM Jr, Cocchetto DM, Scheld WM. Comparative evaluation of cefuroxime axetil and cefaclor for treatment of acute bacterial maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1989; 115: 1430-3. 8. Boezeman AJ, Kayser AM, Siemelink RJG. Comparison of spiramycin and doxycycline in the empirical treatment of acute sinusitis: preliminary results. J Antimicrob Chemother 1988; 22 (Suppl B): 165-70. 9. Axelsson A, Chidekel N, Grebelius N, et aL Treatment of acute maxillary sinusitis. Ann Otol Rhinol Laryngol 1973; 82: 186-91. 10. Wald ER, Chiponis D, Ledesma-Medina J. Comparative effectiveness of amoxicillin and amoxicillin-clavulanate potassium in acute paranasal sinus infections in children: A double-blind, placebo-controlled trial. Pediatrics 1986; 77: 795-800. 11. Blaszczak LC, Brown RF, Cook GK, et aL Comparative reactivity of 1-carba-1dethiacephalosporins with cephalosporins. J Med Chem 1990; 33: 1656-62. 12. Crowetl TA, Halliday BD, McDonald JH III, et aL 3-Sulfonyl-l-carba-ldethlacephems. J Med Chem 1989; 32: 2436-42. 13. Knapp CC, Washington JA II. In vitro activities of LY163892, cefaclor and cefuroxime. Antimicrob Agents Chemother 1988; 32: 131-3. 14. Shelton S, Nelson JD. In vitro susceptibilities of common pediatric pathogens to LY163892. Antimicrob Agents Chemother 1988; 32: 268-70. 15. Jones RN, Barry AL. Beta-lactamase hydrolysis and inhibition studies of the new I-carbacephem LY 163892. Eur J Clin Microbiol 1987; 6: 570-1. 16. Sydnor TA, Scheld WM, Gwaltney J Jr, Nielsen RW, Huck W, Therasse DG. Loracarbef (LY163892) versus amoxicillin/clavulanate in bacterial maxillary sinusitis. Ear Nose Throat J. In press. 17. Nord CE. Loracarbef versus doxycycline in acute sinusitis. Presented at Loracarbef Clinical Investigators' Meeting; June 14, 1991; San Francisco, CA.
June 22, 1992 The American Journal of Medicine
Volume 92 (suppl 6A)
6A-73S
Loracarbef, which is the first agent of the carbacephem class of fl-lactam antibiotics to be developed, provides good activity against a broad spectrum of bacteria. A single-blinded, randomized, parallel clinical trial in 10 centers in the United States compared the efficacy and safety of loracarbef with that of amoxicillin/ clavulanate potassium in the treatment of acute bacterial maxillary sinusitis. A 7-10-day regimen of loracarbef (400 mg twice daily) was as effective as amoxicillin/clavulanate (500/125 mg three times a day) and resulted in somewhat fewer side effects. The results of a European trial in Sweden, Finland, and Iceland showed that loracarbef was clinically more effective than doxycycline in the treatment of acute bacterial maxillary sinusitis.
" ost cases of acute sinusitis are caused by secM ondary bacterial infection following a viral upper respiratory tract infection, with Streptococ-
cus pneumoniae and unencapsulated strains of Haemophilus influenzae accounting for one half of all cases [1]. The reported incidence of Moraxella (BranhameUa) catarrhalis is as high as 23% of the positive isolates in pediatric populations [2]. Streptococcus pyogenes, Staphylococcus aureus, and other gram-negative bacteria have been reported less frequently as part of the microbial etiology of acute maxillary sinusitis. A total of 5-10% of cases of acute maxillary sinusitis originate from associated dental disease, often due to anaerobic bacteria. The only reliable means of identifying the specific pathogen responsible for the illness is by culture of an exudate or a rinse obtained directly from the sinus by puncture or aspiration, which prevents contamination of the specimen with bacterial flora that normally reside in the nose [1]. However, sinus puncture is not indicated for the average case of sinusitis, in which the likely causative agents usually can be predicted from past studies.
TREATMENT
From the Ear, Nose, and Throat Center of Salt Lake City, Salt Lake City, Utah. Requestsfor reprints should be addressedto Richard W. Nielsen, M.D.,900 East, 22 South, Salt Lake City, Utah 84102.
6A-70S
Some of the antimicrobial agents used to treat acute sinusitis include ampicillin, amoxicillin, amoxicillin/clavulanate, cyclacillin, bacampicillin, doxycycline, minocycline, spiramycin, trimethoprim/ sulfamethoxazole, cefaclor, and cefuroxime axetil [1,3-9]. Several drawbacks have been recognized in the various therapies for sinusitis. Both ampicillin and amoxicillin are often used for the initial treatment of uncomplicated sinusitis, and trimethoprim/sulfamethoxazole has been recommended as an alternative therapy for patients allergic to penicillin. However, treatment with ampicillin and amoxicillin is decreasing because of the increasing frequency of fl-lactamase-producing strains of H. influenzae and M. catarrhalis. Although amoxicillin is well tolerated, it must be administered three times daily, which can reduce patient compliance and cause inconvenience for parents with children in school or day-care programs who require treatment with the drug. The combina-
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUMON ANTIMICROBIALTHERAPY/ NIELSEN
tion of amoxicillin and clavulanate potassium overcomes the problem of resistance of fi-lactamaseproducing strains, but several studies have reported the occurrence of diarrhea in 20% or more of patients using this combination [10]. Cefuroxime axetil and cefixime are newer-generation oral cephalosporin antibiotics used for the treatment of respiratory infections. Although cefuroxime has excellent activity against respiratory pathogens and is stable in the presence of many fl-lactamases, side effects such as nausea, vomiting, and diarrhea are relatively common, and it has an extremely bitter taste that young children find unacceptable. Although cefixime's long serum half-life allows once- or twice-daily dosing, it has only moderate activity against S. pneumoniae¢ a common cause of sinusitis. It has relatively low bioavailability after oral administration, and gastrointestinal events are relatively common. Loracarbef is the first agent of the carbacephem class of/~-lactam antibiotics to be developed. It provides good activity against a broad spectrum of bacteria [11-14]. It is active in vitro against S. pyo-
genes, S. aureus, Staphylococcus epidermidis, S. pneumoniae, H. influenzae, M. catarrhalis, Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, including fl-lactamase-producing strains of staphylococci, Haemophilus, and most M. catarrhalis [15]. Recently, two clinical trials have evaluated loracarbef in the treatment of acute sinusitis. A trial conducted in the United States compared loracarbef with amoxicillin/clavulanate [16], and a European trial conducted in Sweden, Finland, and Iceland compared loracarbef with doxycycline [17].
CLINICAL TRIAL: LORACARBEFVERSUS AMOXICILLIN/CLAVULANATE A single-blind, randomized, parallel clinical trial conducted in centers in the United States compared the efficacy and safety of loracarbef with that of amoxicillin/clavulanate potassium in the treatment of acute bacterial maxillary sinusitis [16].
Patients and Methods The 27-month study included 113 patients, with 59 patients in the loracarbef group (22 male, 37 female) and 54 patients in the amoxicillin/clavulanate group (17 male, 37 female). In the loracarbef group, the mean age (-+standard deviation) was 41.0 - 13.9 years, and in the amoxicillin/clavulanate group, the mean age was 36.2 + 13.3 years. Patients had a diagnosis of acute bacterial maxillary sinusitis, no history of chronic sinusitis (dura-
tion of symptoms >14 days), and no prior episodes of acute sinusitis within the previous 12 months. The diagnosis of maxillary sinusitis was based on clinical, radiologic, and bacteriologic factors. The clinical syndrome was defined as purulent rhinorrhea, facial pain, and/or headache of 108 colony-forming units (CFU)/mL of recognized respiratory pathogens (including H. influenzae, S. pneumoniae, and M. catarrhalis) or ->105 CFU/mL of any other bacteria. Patients were given 7-10-day regimens of either two 200 mg loracarbef capsules (total 400 mg) twice a day or one 500/125 mg amoxicillin/clavulanate potassium tablet three times a day. Patients were evaluated with a history, physical examination, and sinus X-rays before therapy. During therapy (days 4-6), within 72 hours after the conclusion of therapy (posttherapy), and 1-2 weeks after conclusion of therapy (late-posttherapy), patients were evaluated for response to treatment and possible recurrence of infection. Clinical responses were defined as follows: cure (total alleviation of symptoms); improvement (substantial improvement of symptoms); failure (symptoms were not at all or not substantially improved); relapse (recurrence or worsening of symptoms after initial cure or improvement); or unable to evaluate. Bacteriologic responses were defined as eliminated (culture-documented pathogen eradication or presumed eradication in patients who had clinical cure or improvement) or failure (persistence of the original pathogen).
Results A total of 59 patients were randomized to the loracarbef group and 54 patients to the amoxicillin/ clavulanate group. Of the original 113 patients, only 48 were evaluable: 24 in the loracarbef group and 24
June 22, 1992 The AmericanJournal of Medicine Volume92 (suppl 6A)
6A-71S
SYMPOSIUM ON ANTIMICROBIAL THERAPY/NIB.SEN
TABLE I Posttherapy Correlation: Bacteriologic Response Following Treatment with Loracarbef or Amoxicillin/Ciavulanate Bacteriologic Response Failed To Eliminate
Eliminated Clinical Response
Total
n
%
n
%
n
%
Loracarbef Successful Relapse TOTAL
21 2 23
87.5 8.3 95.8
1 0 1
4.2
91.7 8.3
4.2
22 2 24
Amoxicillin/clavulanate Successful Failure TOTAL
23 0 23
95.8
0 1 1
4.2 4.2
23 1 24
95.8 4,2
95.8
in the amoxicillin/clavulanate group. Reasons for pathogens isolated, were H. influenzae (27.3%), S. exclusion were bacteriologic disqualification (34 pneumoniae (22.7%), Streptococcus species patients in the loracarbef group and 29 patients in (13.6%), and M. catarrhalis (13.6%). the amoxicillin/clavulanate group), concomitant use Clinical response, determined within 72 hours of of an antibiotic (one patient in the loracarbef completion of drug therapy, was considered to be group), and insufficient therapy (one patient in the successful if there was improvement or cure. Both amoxicillin/clavulanate group did not finish ther- drug regimens were effective, as shown in Table I. apy). In the loracarbef group, there were 22 (91.7%) sucBacteriologic reasons for exclusion were negative cessful clinical responses and 2 (8.3%) relapses; in pretherapy culture (20 patients in the loracarbef the amoxicillin/clavulanate group, there were 23 group and 16 in the amoxicillin/clavulanate group), (95.8%) successful clinical responses and 1 (4.2%) no or low colony count of pretherapy isolates (eight failure. Both loracarbef and amoxicillin/clavulanate patients in the loracarbef group and eight patients produced clinical success rates of 100% in patients in the amoxicillin/clavulanate group), and resis- with infections due to S. pneumoniae or M. catance of the causative organism to one or both anti- tarrhalis; in patients with infections due to H. inmicrobials (six patients in the loracarbef group and fluenzae, however, loracarbef produced a 100% five patients in the amoxicillin/clavulanate group). clinical response rate, whereas that produced by In evaluable patients, the most common single amoxicillin/clavulanate was only 75% (Figure 1). With regard to posttherapy bacteriologic response, 23 (95.8%) patients in the loracarbef group Loracarbef had elimination of the pathogen and one (4.2%) paAmoxicillin/clavulanate tient did not. In the amoxicillin/clavulanate group, 100 100 100 100 100 the figures were 23 (95:8%) and 1 (4.2%), respec(n=5) (n=9) (n=3) (n=2~) (n=6) tively. Pretherapy pathogens for two patients in 100 95,8 91.7 (n=24) the loracarbef group who relapsed clinically were I ~/////A Streptococcus species and group A streptococci. At 90 ! ~/J///K4 posttherapy, their cultures were negative. The loracarbef-treated patient who failed to eliminate 80 the pretherapy pathogen (S. pneumoniae) was clinically improved at posttherapy. The patient in the #_ 70 amoxicillin/clavulanate group whose treatment failed clinically and bacteriologically had fi-lactamase-negative H. influenzae, which was not 60 eliminated by treatment. Of the 15 patients in the loracarbef group who ___1~ 5o J returned for late-posttherapy evaluation, all felt Moraxel~ All pathogens Streptococcus Haemophilus well and were presumed to be free of the prether(B~nhamella) influenzae pneumoniae ca~rrhal~ apy pathogen. The same was true of the 15 patients in the amoxicillin/clavulanate group who returned Figure 1. Posttherapy clinical success rates (cure and improvement) by pathogen for the late-posttherapy visit. There were no refor acute bacterial maxillary sinusitis following treatment with Ioracarbef or amoxilapses in either group. cillin/clavulanate. 6A-72S June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A) I
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SYMPOSIUM ON ANTIMICROBIALTHERAPY/ NIELSEN
Adverse events were reported without regard to causality. The number of patients with at least one event during therapy was 12 (20.3%) in the loracarbef group and 23 (42.6%) in the amoxicillin/clavulanate group (p = 0.011). The most common adverse event in both treatment groups was diarrhea, reported in four (6.8%) patients in the loracarbef group and 11 (20.4%) patients in the amoxicillin/ clavulanate group (p = 0.033). The difference in the incidence of vaginitis between females in the two groups was statistically significant: 10.8% of those in the amoxicillin/clavulanate group and none in the loracarbef group (p = 0.040) reported this adverse event. Other adverse events occurring in >2% of the total population included nausea and abdominal pain, but the differences between the two groups were not statistically significant. Only one patient in the loracarbef group discontinued drug therapy early because of an adverse event (abdominal pain). In the amoxicillin/clavulanate group, six patients discontinued drug therapy early because of adverse events: two because of diarrhea, one because of nausea, one because of vaginitis, one because of pruritus, and one because of urticaria. Thus, this study demonstrates that loracarbef is comparable in efficacy to amoxicillin/clavulanate in the treatment of acute bacterial maxillary sinusitis and that loracarbef has a more desirable safety profile. Furthermore, the twice-a-day dosing schedule of loracarbef compared with three times a day for amoxicillin/clavulanate should increase patient compliance.
CLINICALTRIAL: LORACARBEFVERSUS DOXYCYCLINE A trial conducted in Sweden, Finland, and Iceland compared loracarbef with doxycycline in the treatment of acute bacterial maxillary sinusitis [17]. Doxycycline was chosen because it is commonly prescribed in Sweden for this disease and is administered once a day. In the United States, it is more commonly given twice a day. A total of 662 patients were enrolled in this double-blind, randomized, parallel trial. Inclusion and exclusion criteria were similar to those in the U.S. study. Loracarbef was given at 400 mg twice daily for 7-10 days, and doxycycline was given at 100 mg once a day, also for 7-10 days. Data from the study showed that loracarbef produced statistically significant better posttherapy clinical results (98.2% cure or improvement) than did doxycycline (93.3% had a favorable response); with regard to bacteriologic results, there was no significant difference between the two treatment groups. The correlation of clinical and bacteriologic
outcomes indicated that loracarbef was more efficacious than doxycycline in treating acute bacterial maxillary sinusitis. Adverse events in both treatment groups were generally mild and similar between the groups, although the incidence of diarrhea was higher in the loracarbef group (5.7%) than in the doxycycline group (2.1%). However, the overall incidence of events related to the digestive system was similar in the two therapy groups during therapy. The investigators concluded that loracarbef was as safe as doxycycline for patients with acute sinusitis.
CONCLUSION In summary, the U.S. study demonstrates that loracarbef given 400 mg twice daily was as effective as amoxicillin/clavulanate given 500/125 mg three times a day in the treatment of acute bacterial maxillary sinusitis and had fewer adverse effects. In the European study, loracarbef given 400 mg twice daily was clinically more effective than doxycycline 100 mg given once a day.
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June 22, 1992 The American Journal of Medicine
Volume 92 (suppl 6A)
6A-73S
