Cefcanel daloxate versus penicillin in acute streptococcal pharyngotonsillitis

OBJECTIVE
To determine the efficacy, safety and tolerance of cefcanel daloxate and phenoxymethylpenicillin (PcV) in the treatment of acute pharyngotonsillitis caused by beta-hemolytic streptococci group A (bhsga).


PATIENTS AND METHODS
Randomized, double-blind, multicentre study with subjects randomized 1:1:1:1 to four parallel treatment groups: cefcanel daloxate 150 mg bid, 300 mg bid, 600 mg daily and PcV 300 mg tid. Patients were treated for 10 days with clinical, bacteriological and safety evaluation at inclusion, during therapy (day 5), early after completion of therapy (day 14) and two weeks later (day 28).


RESULTS
Of 340 subjects enrolled, 324 were valid for safety analysis and 249 for efficacy analysis. At the short term visit, clinical cure rates for cefcanel daloxate 300 mg bid and PcV groups were similar at approximately 70%. The cure rates for cefcanel daloxate 150 mg bid and 600 mg daily were significantly worse at 57.4 and 54.4%. Approximately 80% of all pretherapy throat swabs grew bhsga. All bhsga were susceptible or intermediately susceptible to PcV and cefcanel. The bacterial elimination rate for cefcanel daloxate was 82.8% and for PcV it was 89.8%. The elimination rate was significantly lower in the cefcanel daloxate 150 mg bid and 600 mg daily groups. The clinical cure rates and the bacteriological elimination rates increased by about 10% for cefcanel daloxate 300 mg bid and the PcV groups at the last valid visit and remained significantly better than the other two cefcanel daloxate doses. Adverse events were not significantly different among the four treatment groups.


CONCLUSIONS
Cefcanel daloxate 300 mg bid was as effective and as well tolerated as PcV 300 mg tid in the treatment of acute pharyngotonsillitis. A lower dose or once-daily dose regimen of cefcanel daloxate was not as effective clinically or bacteriologically.

RtsULTATS : Des 340 s uj els inscrils .324 se confor ma ie nl a !"ana lys e d 'innocuile e l 249 a !"analyse cl'efficacile.A Ia visile co url-lerme.les laux de guerison clinique pour cefcanel daloxale 300 mg bid e l PcV elaienl sem b lables a en vi ron 70 %.Les laux de g uerison pour cefcanel daloxale 150 mg bid e l600 mg par jou r elaienl nelle men l m oind res a 57.4 % el 54.4 %.Environ 8 0 % d e lo us les preleve m enls d e gorge pre-lra ilemenl on l permis Ia croissan ce de slrc plocoqu es bela-evoluUfs du groupe A. Ces clemiers etaien l sensibles ou mod eremenl sen s ibles a Ia PcV el a u cefcanel.Le laux d'elimina Uon bac leri enne pour le cefcanel daloxale a He d e 82.8% el pour lc PcV de 89.8 %.Le la ux cl'elimina Uon Hail ne llem enl plu s bas clans les groupes cefcan el daloxalc 150 mg bid e l 600 mg pa r j ou r .Les laux d e gu eris on clinique e l d'e lim inaUo n bacleriologique onl augm enle d 'en viron 10 % pour le groupe cefcan el d a loxale 300 mg bid el PcV lors de Ia den1iere visile valicle el s onl cle me ures nelle menl m eille urs qu'avec les d eux a ulres closes de cefcanel daloxale .Les reactions indes ira bles ne se s onl pas revelees nellemenl diffe re nles entre les qua lre groupes lherapeuUques .CoNCLUSION : Le cefcane l d a loxale 300 mg bid a e le a ussi e ffi cace el a u ssi bie n lole re qu e Ia PcV 300 mg Ucl dans le lrailem enl d e Ia phary ngoamygdalile a igue .une close plus faib le ou un s ch em a U1 era pe uUq ue un iquo Udie n de cefcane l d a loxale ne s'esl pas revele a ussi e ffi cace s ur le plan clinique el ba clei;oiogique.S TREPTOCOCCAL PHARYNGOTONSILLIT IS SIIOULD BE TREATED with antibiotics.Ph enoxymethylpenicillin (PcV) h as been the agen t of c h oice worldwid e s ince its introdu ction .This antimicrobial agent is rela tively ine>.. '})ens ive and h as few side effects.S everal s tu dies.however .h ave reported high clinica l a nd bacteriological fa ilure ra tes a fter treatment with PcV, with 19 to 3 0% b acteriological persis ten ce in the pharynx a fter PcV th era py (1 -4).Penicillin -resis tant group A streptococcu s h as not been id entified to exp lain this failure ra te.Th e poor outcomes m ay b e du e to poor compliance.inactiva tion of penicillin by peni cillinase-produ cing bacterial s pecies in the ph a rynx.improper dose or in a d equ a te a ntibacteria l activity a t the infection s ite (4) .The bacteriological failure with other antimicrobia ls , p a rtic ularly oral cepha los porins, ranges from 2 to 14%, ra tes lower th a n those s een with PcV (2 -9).For some cephalosporins.on ce-or twice-daily dos ing regimen s ar e as effective as or s uperior to PcV in th e Lreatm ent of s treptococcal pha ryngotonsilli tis (4, 7 -9).
Cefcanel daloxate is a cephalosporin prod rug for ora l use (10).It dem on s tra tes improved in vi tro activity agains t Gra m -positive bacteria compared with cepha lexi n .cefa droxil an d cefa clor, a nd re ta ins ac tivi ty against Gra m -n egative ba cteria .Cefcanel daloxate is s imilar to cefaclor with respec t to b e ta-lactamase s tability .alth ou gh each drug d emonstra tes s lighlly different s ta bil ity depending on th e type of beta-lacta mase tes ted .Th e prodrug b ecomes active only after hydrolys is in th e intestina l lumen a nd mucosa to cefca n el, carbon dioxide and di acetyl.Th e active an tibac terial compon ent.cefcanel.is released into the circ ula tion (10) .

120
The present s tudy was conducted to investigate the efficacy .s a fety and tolerance of three dosage regimens of cefcan e l d a loxa te (150 mg b id , 300 mg bid and 600 mg da ily) compared with PcV (300 mg tid) in adu lt a nd a doles cent pa tients with acute beta-hemolytic s treptococci group A (BHSGA) pharyngotonsillitis.It was hypoth esized th a t the prodrug characteristic and betalacta m ase s ta bility of cefcan el daloxate wou ld produce b e tter tolerance a nd lower b acteriological fai lure rates .

PATIENTS AND METHODS
Study design: This was a Cana dian multice ntre study .The study wa s double-blind , computer randomized and u sed p a rallel trea tment groups.Study investigators were gen era l practitioners, e m ergency physicians and infectious disease specialists.Th e study was a pproved by ea c h of the applicab le institutional or regional ethics committees.Patient population: A total of340 p a tients wa s enrolled in the s tudy a t 16 Cana dian centres .Out-patients of either sex b e tween 12 and 80 years of age were eligib le.In a ddition , pa tients h a d one or more of th e following s igns of acute pharyngotons illi ti s : fever , tonsillar eryth ema, exuda te or hypertrophy .A positive rapid screen test indicating BHSGA in the tonsillar area (Phadirect.Pha rmacia or Strep A Test Pack , Abbott La bora tori es Ltd) was required for inclusion.with subsequent confirma tion through b acteriological c ulture.Written infom1ed consent wa s obtained .
Pa tients were excluded if they h a d concomitant infections other than pharyngotonsillitis, with known or s u s p ected allergies to penicillin or cephalosporins , or if they h a d received antimicrobial treatment within s even days of entry.Patients with severe underlying disease, immunological deficiencies.impai red liver or renal function, and/ or pregnant or lactating fema les were also not eligible.Subjects were enrolled only once.Treatment regimens: Treatment with cefcanel daloxate 150 or 300 mg bid.600 mg once per day.or PcV 300 mg tid was allocated randomly at a ratio of l: l: l: l.No dosage adjustment was allowed.Drugs were dispensed using a double-dummy technique.Duration of treatment was l 0 days in each group.Patients were instructed to take the medication in a fasting state.l h before or 2 h after meals .Compliance was checked by asking patients to return drug packaging at the third visit.Patients also completed a diary card for the first 10 days of the study.indicating daily symptoms and temperature.The diary card also contained instructions reminding the patient to take doses in the morning, midday and even ing.Treatment with other antimicrobial drugs was prohibited during the study period.

Mic robiologic al methods:
A rayon-tipped swab was used to collect a sample from the tonsillar, uvula and soft palate areas at inclusion and follow-up visits.Swabs were transported to local m icrobiological laboratories for culture on sheep blood agar plates.Plates were incubated at 37°C for 18 to 24 h and subsequently examined for growt.h of beta-hemolytic streptococci.Colonies of BIISGA were quantified and isolated.and Lancefield grouping performed.In vitro susceptibility of all isolates to cefcanel daloxate and PcV was determined using the Kirby Bauer disc diffusion method .Susceptibility was reported as sensitive.inter mediate or resistant.with corresponding zone diameters measured in millimetres.All laboratories assessed beta-lactamase activity using the n itrocefin test \vith results reported as 'yes• or •no•.Beta-hemolytic streptococci were suspended in Todd-Hewitt broth and stored at -70°C.
At study termination.strains were thawed, checked for viability and sent to the National Centre for St.reptococcus at the Provincial Laboratory of Public Health for Northern Alberta (University of Alberta.Edmonton.Alberta T6G 2J2).Cultures were plated.grown and Lancefield grouped to confirm the assigned group.M typing.T agglutination and serum opacity factor were perfom1ed for all BJISGA.Strains that had a positive serum opacity reaction and were 'M' nontypable were further analyzed with respect to antiopacity factor typing.In addition.all strains were tested for susceptibility to cefcanel and benzylpenicillin using the agar dilution technique to obtain the 90% m in imum inhibitory concentration (MICgo).Assessment: Patients were requ ired to visit the clinic four times: at entry.during therapy (day 5).after therapy (day 14) and at long term fo llow-up (day 28) .Clinical.bacteriological and safety evaluations were performed at each clinic visit.Age, sex, med ical history.concomitant disease and baseline medical events were recorded at the first visit.and the patient was subjected to a physical examina tion.Oral temperature was recorded.Pharyngeal status, including tons ill ar cryU1ema .exudate and hypertrophy.was assessed as •yes• or •no•.The patien t's s u bj ective assessment of feeli ng of ill ness .sore throat and fever was a lso recorded as •yes• or •no•.Signs and symptoms were s im ilarly recorded at the second.third and fo urth visits.Adverse events: Al l adverse events spontaneously reported by the patient or observed by the investigator were registered.At follow-up visits .a nonspecific question.such as "apart from your disease, have you experienced any other symptoms.illness or injury since we last met?" was asked.Adverse events were recorded with respect to description/d iagnosis.date of onset.duration.severity.causal relationship to study drug.final outcome and the source of information .
Venous blood samples and midstream urine samples were collected at the initial.second and third visits.Analysis was performed at each centre.and included: hemoglobin.leukocytes, lhrombocyt.es.activated partial thromboplastin lime, erythrocyte sedimentation rate, Coomb's test, sodium, potassium, alanine a minotransferase.aspartate an1inot.ransferase.alkaline phosphatase.gamma glularyl transpeptidase, bilirubin.creatinine and routine urinalysis.Outcome asse ssment: Clinical outcome was classified as cure, improvement, failure and recurrence.Cure was defined as U1e disappearance of all signs and/or symptoms, and recurrence was the reappearance of s igns and/or symptoms after an inlenral free from symptoms .Patients \vithdrawn from the study during treatment due to lack of effect were classified as an •early treatment failure'.
Bacteriological outcome was defined as elimination.persistence.relapse.reinfection or unassessable.Elimination was defmed as the eradication of BJJSGA of the original type.while persistence was the repeal isolation of the same type .Reinfection was defined as recolonization with a type d ifferent from the original , and relapse was recolonization with the same type as the original with intervening negative cultures.Cases with cu lture not available were considered unassessable.Patients who were asymptomatic on third or fourth visit but continued to harbour BIJSGI\ of the same type isolated at enrolment were considered to be •carriers'.Statistical analysis : The primary comparison was for the short term (visit 3) bacteriological and clinical outcomes among the treatment groups using pairwise Wilcoxon two-sample tests.To be valid for these analyses.subjects were required to have their third visit before day 20, and to have taken at least five clays of study medication.un less they were an early treatment faJ lure.ie.given other antimicrobial treatment before posttreatment follow-up due to lack of response.The above comparisons were also applied to the last valid visit results up to clay 45.Interim analyses were performed by an independent group when patient enrolment reached 96 and 200.The interim results were not transmitted to the project study group so there was no effect on study outcome.

RESULTS
P a tie nts : From July 1988 to February 1991, 340 patients were enrolled in the study.At completion, 324 patients were valid for safety evaluation and 249 for efficacy analysis.Sixteen patients not included in the safety evaluation were lost to follow-up.In addition, 75 patients were not valid for efficacy analysis for the following reasons: age (two patients aged 10 and 11 years).adverse effects (two).clinical deterioration (one).patient refusal (four).no BHSGA on the first visit (55) and no valid follow-up visit (11).The proportion of patients evaluable for efficacy was consistent in the four treatment groups, ranging from 59 in the cefcanel daloxate 300 mg bid group to 69 in the cefcanel daloxate 600 mg daily group.For all randomized patients, and for patients retained for efficacy analysis, the four treatment groups were similar with respect to age, sex, weight, background medical history, concomitant diseases, concomitant medications and the presence of signs and symptoms at the initial visit.Clinical efficacy: Thirty patients had visit 3 outside the initially established window of day 12 to 16.To include as many of these patients as possible in the efficacy analysis, the window was widened to day 10 to 20, provided the patients discon tinued study drug at least one day before the follow-up visit.Analysis was not significantly different when these patients were included with the original short term efficacy group.Three patients were excluded from the short term analysis because they did not have a valid third visit.
No s ignificant differences were found in the clinical outcome at the short term visit (P=0 .1 764, Kruskal-Wallis test) (Table 1).The cure rate was approximately 70% in both the 300 mg b id cefcanel daloxate and the PcV groups.The cure rate was lower in the cefcanel  1).Using pair-wise Wilcoxon one-sample tests, significant differences were found between 150 mg cefcanel daloxate and PcV (P=0.027).between 300 mg and 600 mg cefcanel daloxate (P=O.Oll) and between 600 mg cefcanel daloxate and PcV (P=0.001) .Bacteriological efficacy : Of the 277 patients with BHSGA on the first visit, 246 had cu ltures obtained at the first post-therapy visit and were valid for short term efficacy analysis.At the short term visit the elimination, relapse and persistence rates were comparable in the cefcanel daloxate 300 mg and the PcV groups (P=0.21)(Table 2).The difference between the worst group (600 mg cefcanel daloxate) and the 300 mg cefcanel daloxate and PcV groups, respectively, was statistically significant (P=0.0001 for both).High dose once daily (600 mg) cefcanel daloxate had a significantly poorer elimination rate than 150 mg bid (P=0.023).Approximately 20% of patients in both of these groups had relapses (Table 2) .The incidence of reinfection was low in all treatment groups.Persistence occurred s ignificantly more frequently for the 150 mg bid cefcanel daloxate group or the 600 mg cefcanel daloxate group compared with either 300 mg bid cefcanel daloxate or PcV (P<0 .01,all comparisons) .
At the last valid visit (Table 2) bacteriological outcome was similar for cefcanel daloxate 300 mg bid and PcV groups.There were statistically significant differences in elimination rates in the low and high dose cefcanel groups compared with the 300 mg cefcanel daloxate and the PcV groups (P<0 .001).No significant difference was found between the low and high dose cefcanel daloxate groups (P=0 .057).Relapse rates were similar in the four treatment groups.Persistence was lower for the low and high dose cefcanel daloxate groups, but remained elevated for both rela tive to cefcanel daloxate 300 mg bid and PcV groups.
The bacteriological type and frequency of all strains isolated at the first visit for all cases with relapse is shown in Table 3 .Eighteen distinct types were isolated, with MlTl , M2T2, T28 and Ml2Tl2 types isolated from over 50% of all relapses.Eight patients had reinfections at the third or fourth visit with a strain not of the same type as that at inclusion.Thirty-one patients at the short term visit and 22 patients at the last valid visit were clinically cured but had persistent growth of BHSGA, meeting the criteria for 'carriers'.The high dose cefcanel daloxate group had a significantly higher rate of bacteriological persistence (Table 2).The low dose cefcanel daloxate group also h a d more bacteriological persistence than the cefcanel daloxate 300 mg bid and the PcV groups, but not as elevated as the high dose cefcanel daloxate group.Safety: A total of 324 patients was evalua ble for safety.The number of patients reporting adverse events was not significantly different in the four treatment groups, ranging from 39 with cefcanel daloxate 150 bid to 51 in the cefcanel daloxate 600 mg daily group.No significant differences were detected among treatment groups with respect to single symptoms.When symptoms were grouped using World Health Organization codes into system organ classes, for 'body as a whole -general disorders', cefcanel daloxate 150 mg bid was significantly better than cefcanel 300 mg bid (P=0.014) and 600 mg once daily (P=0.02).No significant differences were detected between all cefcanel daloxate groups and the PcV group.Most adverse events were mild and the distribution of severity was equal in the four treatment groups.
Four patients discontinued study medication due to adverse events , all ~th nausea and vomiting.Two of these were in the cefcanel daloxate 150 mg bid group  and two were in the cefcanel daloxate 600 mg once daily group.Two patients were hospitalized, one with a peritonsillar abscess and another with persisting fever and worsening infection.Both pa tients recovered with intravenous antibiotics.

DISCUSSION
PcV is considered to be the agent of choice for the treatment of streptococcal pharyngotonsilHtis, despite reported failure rates as high as 30% (l -4).Reported bacteriological failure for oral cephalosporins ranges from 2 to 14%, a third lower than that reported with PcV (2-9).High b a cteriologica l failure rates have b een a t-tributed to poor patient compliance, inactivation of penicillin by penicillinase-producing bacterial species in the pharynx, or improper dose or inadequate antibacterial activity at the infection site.Poor patient compliance is unlikely to be the sole reason for high failure rates with penicillin, because both oral and intramuscular administration give similar outcomes ( 1, 6).Inadequate concentration of antibiotics at the infection site has also been excluded for penicillin and cefadroxil (11).Penicillin tolerance also does not appear to contribute to the failure rates (11,12).Several authors have, however, suggested an association between the presence of beta-lactamase-secreting organisms in the pharynx and the failure of penicillin therapy.
In the present study, three doses of cefcanel daloxate were chosen to bracket the doses of cephalosporins that had been used in other tonsillitis studies (4)(5)(6)(7)(8)(9).The prodrug characteristics, pharmacokinetics and betalactamase stability of cefcanel daloxate were expected to produce better tolerance and less bacteriological failure .Clinical efficacy and bacteriological elimination rates were comparable in the cefcanel 300 mg bid and PcV groups.Clinical and bacteriological outcomes for the other two cefcanel daloxate regimens, 150 mg bid and 600 mg daily, were significantly poorer.This is likely due to inadequate dose and frequency, respectively.Reported adverse events were similar in the four treatment groups, and were most commonly gastrointestinal.Serious adverse events and treatment discontinuations due to adverse events occurred rarely.
The study shares one weakness with other tonsillitis studies: it does not allow the separation of patients with viral upper respiratory tract infection and chronic streptococcal carrier state from patients with true BHSGA tonsillopharyngitis.Clinical assessment performed at day 5 of therapy may not identifY the rapid clinical improvement noted at 24 to 48 h after initiation of appropriate antibiotic therapy.In addition, acute or convalescent streptococcal serology to confirm the diagnosis was not obtained.The prevalence of BHSGA carrier status in the general population is, however, approximately 10% (13) and, because of randomization, should not influence results within treatment groups.
There is a large number of antibiotics available that are effective for the treatment of streptococcal pharyngotonsillitis.Symptomatic response for the acute clinical illness and prevention of acute rheumatic fever is achieved with antibiotics that can be given twice daily, including penicillin V (14,15).However, approximately every ftfth patient treated with penicillin for acute BHSGA pharyngotonsillitis continues to harbour the bacteria after treatment.While it has been questioned what additional significant benefit would result from the eradication of the carrier state, few epidemiological data are available to determine whether these patients can be considered a source of infection or whether they are at an increased risk of developing post-streptococcal sequelae.
There is a trend for decreasing dose intervals in antimicrobial therapy, potentially reducing adverse effects as well as improving cost, compliance and convenience for the patient.This study demonstrates that, for cefcanel, there is a point at which therapy becomes less effective.The lowest dose regimen was clearly inadequate.Conversely, the once-daily regimen was not of sufficient dosing frequency for the half-life of the study medication.Cefcanel daloxate 300 mg bid, however, was equivalent to PcV tid in outcomes.If an objective of treatment is to eradicate the carrier state, however, antibiotics with more favourable pharmacokinetics and therapeutic efficacy will need to be developed for treating this disease.
CAN j INFECT DIS VOL 5 No 3 MAY/JUNE 1994 Streptococcal pharyngotonsillitis

TABLE 1
Clinical response at short term (early) and last valid visit (late) for patients valid for efficacy Recurrences tended to be more frequ ent in all cefcanel daloxate groups compared with the PcV group.At lhe last valid visit the cure rate increased in the 300 mg cefcanel daloxate and the PcV groups by approximately 10% to a rate of 80% (Table

TABLE 2
Bacteriological outcomes at short term (early) and last valid visit (late) for patients valid for efficacy analysis C AN J INFECT DIS VOL 5 No 3 M AY/JUNE 1994