J Int MedRes(l978) 6, 271
Clinical Experience with Cefadroxil in Upper and Lower Respiratory Tract Infections F Flores Mercado, MD, Research and Teaching Laboratory, Army Hospital, Mexico City, Mexico P J Santella, MS, Associate Director Antibiotic Clinical Research, Bristol-Myers Company, International Division, New York, N.Y., U.SA. C A Fernandez, MD, Director Clinical Research-Latin America, Bristol-Myers Company, International Division, New York, N.Y., U.sA.
Cefadroxil is a new semisynthetic oral cephalosporin with a broad spectrum of activity against both Gram-positive and Gram-negative organisms. Absorption of cefadroxil is unaffected by food. its serum levels are prolonged and it is excreted in the urine at a relatively slow rate compared to cephalexin. In the treatment of 108 patients with upper or lower respiratory tract irfections, cefadroxil effected 93% complete cures. Fifty-five of the patients had upper respiratory tract infections and fifty-three had lower respiratory tract infections; among them cefadroxil achieved clinical success rates of 100% and 96%, respectively. Cefadroxil was clinically successful in eight (89%) out of nine patients whose infections were caused by mixed aetiologies. The principal causative agents were Staphylococcus aureus, p-haemolytic streptococci, Streptococcus pneumoniae and Klebsiella pneumoniae. Overall bacterial eradication produced by cefadroxil was 112 (91%) of 123 organisms isolated from 108 patients. Reports of mild and transient Side-effects in only 3·7% of the patients showed that the drug was well tolerated.
Introduction Cefadroxil is a new semisynthetic oral cephalosporin similar to other cephalosporins in its antibacterial spectrum which includes
coli, Klebsiella pneumoniae, Haemophilus inf/uenzae and Proteus mirabilis (Buck & Price 1977). Its pattern of resistance to fJ-lactamases is similar to that of cephalexin, Staphylococcus aureus, Streptococcus pneu- but it is distinguished from cephalexin as well as moniae, fJ -haemolytic streptococci, Escherichia from cephradine, by several pharmacokinetic properties which confer potential therapeutic advantage through extensive body distribution and longer duration of action. The absorption Requests for reprints to: P J Santella, Bristol-Myers Company, International Division, 345 Park Avenue, of cefadroxil is unaffected by food, serum levels are sustained and the rate of urinary exNew York, N.Y. 10022, U.S.A.
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The Journal ofInternational Medical Research
272
cretion is relatively slow (Hartstein et aI1977, Pfeffer et al 1977, Santella, Fernandez & Rondel 1977, Jolly, Henness & Richards 1977). These characteristics permit the administration of fewer daily doses and a convenient schedule which should improve patient compliance and consequently therapeutic efficacy. Objective v. A series of clinical trials by eight investigators in Mexico was conducted. to evaluate the efficacy and safety of cefadroxil in the treatment of upper and lower respiratory tract infections, of which several had mixed pathogenic origins. Materials and Methods Criteriafor Selection ofPatients Patients were admitted to the clinical trials on the basis of a diagnosis of bacterial infection of the upper or lower respiratory tract which could be treated with an oral cephalosporin. A specific pathogen or pathogens had to be isolated and identified from an appropriate : pre-treatment culture and susceptibility of all pathogens to cefadroxil proven by the .production of a ~ 18 mm zone of inhibition around a 30 f.Jg cefadroxil susceptibility test disc. In addition to these criteria, the diagnosis of lower respiratory tract infection required furthervconfirrnation byca ' positive pretreatment chest X-ray. Excluded from the trials were patients with a history of hypersensitivity to penicillins or cephalosporins, those who required concomitant antibacterial medication, those with renal insufficiency or hepatic disease, and pregnant patients. Prior to admission to the study, laboratory tests were performed on all patients to determine pre-treatment values for blood chemistry and for renal and hepatic function. Patients were considered evaluable for efficacy after they had received cefadroxil therapy for a minimum of 72 hours. All patients were evaluated for safety and reported side-effects were recorded. After therapy, laboratory tests were repeated for comparison with pre-treatment values. Chest X-rays were taken at a minimum of three weeks postfherapy in all cases of lower respiratory tract infection. I
Criteriafor Response Cure was considered complete if clinical signs and symptoms of infection had disappeared completely or improved markedly, the original pathogen(s) had been eradicated and no superinfection with a new pathogen occurred. Cure was considered clinical if clinical signs and symptoms of infection had disappeared completely or improved markedly but the causative bacteria were not eradicated. In lower respiratory tract infections, clinical improvement was verified by post-therapy chest X-ray. Treatment was considered a failure if there was no clinical improvement and no bacterial eradication. The sum of complete cures plus clinical cures constituted clinical success. Patient Population A total of 108 patients with infections of the upper or lower respiratory tract participated in the study. Among the fifty-five patients with upper respiratory tract infections, there were twentynine males and twenty-six females. The majority of these patients were between thirteen and twenty-five years of age. Forty-three of the upper respiratory tract infections were classified as moderate, three were mild and nine were severe. The fifty-three patients with lower respiratory tract infections were composed of twentythree males and thirty females. All were adults between thirteen and seventy years of age. Twenty-four patients were over fifty-one years of age. Among the lower respiratory tract infections, two were mild, thirty-five moderate and sixteen were severe infections. Dosage Cefadroxil was administered orally at either 12-hour intervals (forty-eight patients) or 8hour intervals (sixty patients). All patients received a total daily dosage between 1500 and 2000 mg. The mean duration of therapy for most patients was 10 days with. the exception of two patients with infected bronchiectasis whose treatment period averaged 40 days. Results Cefadroxil treatment of 108 patients with upper or lower respiratory tract infections
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F Flores Mercado. P J Santella and C A Fernandez produced 101 (93%) complete cures. Five patients had clinical cures and two patients did not respond to therapy. Thus, the overall rate of clinical success achieved with cefadroxil treatment was 98% (Table I). There were 123 pathogens isolated from the 108 patients. Cefadroxil eradicated ninety-six of 10 I Gram-positive and sixteenof twenty-two Gramnegative bacteria, resulting in an overall bacterial eradication rate of 91%. Bacterial eradication was accomplished in ninety-five of the ninety-nine patients with infections due to single pathogens (Tables 2 and 3). Infections in nine patients (two with upper and seven with lower respiratory tract infections) were caused by mixed pathogens. Cefadroxil effected complete cures in six of these nine patients and clinical cures without bacterial eradication in two patients. Only one patient with an infection caused by mixed pathogens did not respond to cefadroxil treatment.
Upper Respiratory Tract Infections Fifty-five patients were diagnosed as having infections of the upper respiratory tract and
273
among them cefadroxil effected fifty-four (98%) complete cures and one clinical cure, equivalent to 100% clinical success (Table I). Bacterial eradication in the fifty-five patients was 96% (Table 2); the use of cefadroxil produced bacterial eradication in one of the two cases of upper respiratory tract infections caused by mixed pathogens. Among upper respiratory tract infections the most common diagnosis was tonsillitispharyngitis. There were forty-six patients with these infections, of whom the majority were between the ages of thirteen and twenty-five years and had a moderate form of the infection. Single pathogens, primarily Staphylococcus aureus or P-haemolytic streptococci, were the cause of forty-five infections and cefadroxil treatment completely cured all forty-five patients. In the only tonsillitispharyngitis infection caused by mixed pathogens, the patient was clinically cured but the bacteria persisted (Table 2). The other upper respiratory tract infections were otitis media, which occurred in eight patients, and sinusitis in one patient. Cefadroxil
Tablel Cefadroxil - overall clinical response
Diagnosis Upper respiratory tract Tonsillitis-pharyngitis Otitis media Sinusitis Sub-total
Lower respiratory tract Bronchitis Broncho-pneumonia Lobar pneumonia Infected bronchiectasis Pulmonary abscess Empyema Sub-total Total Percentage
Number of patients
Complete cures
Clinical cures
Percentage clinical Failures
success"
46 8 1
45 8 I
0 0
0 0 0
100% 100% 100%
55
54
I
0
100%
25 14 8 2 2 2
24 II 6 2 2 2
0
I I
0 0 0 0
96% 93% 100% 100% 100% 100%
53
47
4
2
96%
108
101 93%
2 2%
98%
I
2 2
0 0 0 :
5 5%
·Percentage clinical success is based on complete cures plus clinical cures.
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*a. Klebsiella pneumoniae b. Enterobacter c. Pseudomonas aeruginosa
55 Patients 57 Pathogens isolated 55 Pathogens eradicated 96% Bacterial eradication
28
I
Sinusitis (l patient) I infection caused by single pathogen
Totals
I
I
28
I
3
23
3
23
5
4
I
4
4
0
19
I
18
18
0
18
Number eradicated
Total number
Number eradicated
Total number
Number eradicated
Total number
Otitis media (8 patients) 7 infections caused by single pathogens I infection caused by mixed pathogens
Tonsillitis-pharyngitis (46 patients) 45 infections caused by single pathogens I infection caused by mixed pathogens
Diagnosis
P-haemolytic streptococci
Streptococcus pneumoniae
Staphylococcus aureus
Causative pathogens
Cefadroxil bacteriological response in upper respiratory tract infections caused by single and mixed pathogens
Table 2
2
2
Total number
2
2
Number eradicated
Staphylococcus epidermidis
3
I'
2·'. b
Total number
Other"
3
I
2
Number eradicated
-
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b. Streptococcus faecalis c. Escherichia coli d. Pseudomonas aeruginosa
-8. Staphylococcus epidermidis
46 Patients 46 Pathogens isolated 42 Pathogens eradicated 91 % Bacterial eradication
Total
2 patients
Empyema
I patient
Infected bronchiectasis
8 patients
Lobar pneumonia
10 patients
Broncho-pneumonia
25 patients
Bronchitis
Diagnosis
12
I
1
3
7
Total number
11
I
1
3
6
Number eradicated
Staphylococcus aureus
13
6
1
6
Total number
12
5
I
6
Number eradicated
Streptococcus pneumoniae
9
1
8
Total number
streptococci
f3 -haemolytic
9
1
8
Number eradicated
Causativepathogens
CeraciroxH lIacteriolollic:al responle in lower res,iratory tract Infections caused by sinille pathollens
Table 3
8
1
1
3
3
Total number
3
3
Number eradicated
Id 4
7
2 b;c
.
Total number
Other-
1
0
Klebsiella pneumoniae
3
1
Ib
I
Number eradicated
-J V.
N
~
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l:l ;:s
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~
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§
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2
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~ ~ '"~
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1
·a. Enterobacter b. Escherichia coli c. Proteus mirabilis
7 Patients 20 Pathogens isolated 15 Pathogens eradicated 75% Bacterial eradication
Total
Pulmonary abscess (2 patients) 1 infection (5 pathogens) 1 infection (2 pathogens) 2
2 I
d. Staphylococcus epidermidis e. Haemophilus inftuenzae f. Klebsiella aerobacter
1
1
0
4
1
1
1
Infected bronchiectasis (/ patient) 1 infection (2 pathogens)
0
Total number
1 1
1
Number eradicated
Total number
Number eradicated
Total number
4
1
I
1 1
Number eradicated
p-haemolytic streptococci
1 infection (3 pathogens) 1 infection (3 pathogens) 1 infection (3 pathogens)
Broncho-pneumonia (4 patients) 1 infection (2 pathogens)
Diagnosis
Streptococcus pneumoniae
Staphylococcus aureus
Causativepathogens
Ceflldroxn bacteriological response in lower respirlltory tract infections cllused by mixed pllthogens
Table 4
Klebsiella
1
1
Total number
pneumoniae
0
0
Number eradicated
12
2d,e
3b,d,f
1" 2b,c 2b,d, 2 d.e
Total number
Other"
9
2
3
0 0 2 2
Number eradicated
...
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F Flores Mercado, P J Santella and C A Fernandez achieved complete cures in all nine patients with these diagnoses. One case of otitis media was due to multiple pathogens and total eradication of the bacteria was effected by cef'adroxil in this infection. Bacterial eradication was also accomplished in all infections caused by single pathogens (Table 2). i
Lower Respiratory Tract Infections There were fifty-three patients with infections of the lower respiratory tract. Cefadroxil therapy produced complete cures in fortyseven (89%) patients, clinical cures in four patients and was ineffective in two patients (Table 1). The rate of bacterial eradication was 91% among forty-six patients whose infections were caused by single pathogens and 75% among seven patients with infections due to multiple pathogens (Tables 3 and 4). All of the bronchitis infections were precipitated by single pathogens (Table 3), predominantly Staphylococcus aureus, Streptococcus pneumoniae and p-haemolytic streptococci. Eradication of the bacteria coupled with clinical cure (i.e., complete cure) was accomplished by cefadroxil treatment in twenty-four (96%) of these twenty-five patients. The remaining patient did not respond to a regimen of 1000 mg of cefadroxil administered every 12 hours for 7 days although the patients who were cured had received similar therapeutic courses. The number of infections caused by mixed pathogens was greater among patients with broncho-pneumonia than among those with any other diagnosis. Of fourteen patients with broncho-pneumonia, mixed pathogens were the causative agents in four patients, from whom a total of eleven micro-organisms were isolated. Cefadroxil produced bacterial eradication in four of five Gram-positive and in two of six Gram-negative organisms represented in the cultures (Table 4). The results of cefadroxil treatment in the four patients were two complete cures, one clinical cure and one failure. Among the ten patients with broncho-pneumonia caused by single pathogens, nine were completely cured; the tenth was clinically cured without eradication of the causative organism, Escherichia coli. Thus, the rate of clinical success of cefadroxil in the treatment of all patients with bronchopneumonia was 93% (Table 1).
277
Streptococcus pneumoniae was the most commonly encountered' pathogen (6/8) in lobar pneumonia and; was eradicated by cefadroxil in five' of sIX patients (Table 3). Overall, cefadroxil therapy in patients with lobar pneumonlaachieved six complete cures and two clinical cures, or a 100% clinical success rate. There were two cases of infected bronchiectasis, one due. to' Staphylococcus aureus (Table 3), and' the other to multiple pathogens (Table 4). Both patients were completely cured during an average of forty days treatment with cefadroxil, The mixed aetiologies which underlie the two cases of pulmonary abscess are shown in Table 4. While one of the infections was caused by a combination of one Gram-positive and one Gram-negative organism, a relatively common occurrence, the other was unique in being traceable to five infecting pathogens: Nevertheless, total eradication of the pathogens was accompfished bycefadroxil and the two patients with pulmonary abscesses were completely cured. . The final diagnostic category among the lower respiratory tract infections was empyema. There were two infections,' each caused by a Gram-negative organism (Table 3). Bacterial eradication was produced and complete cures effected by cefadroxil in both patients. Side-Effects Eight drug-related side-effects were experienced by four (3· 7%) of 108 patients in the studies. The effects consisted of nausea (three), abdominal pain (two), rash (two) and pruritus (one). These side-effects' were mild and transient and cefadroxil therapy was continued in all patients. Disseussion Cefadroxil achieved 98% clinical success in the treatment of 108 patients with upper or lower respiratory tract infections by effecting 101 complete cures and five clinical cures. Among fifty-five patients with upper respiratory tract infections, all were completely cured with the exception of one patient with tonsillitis-pharyngitis caused by multiple pathogens. A clinical cure was attained in this patient, but the bacteria were not eradicated.
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278
The Journal ofInternational Medical Research
The only other patient with an upper respiratory tract infection caused by mixed pathogens was completely cured. Of the forty-seven complete cures and four clinical cures produced by cefadroxil therapy in fifty-three patients with lower respiratory tract infections, five of the complete cures and one of the clinical cures occurred among patients with infections caused by mixed pathogens. Nine infections were caused by multiple organisms ~ a total of twenty-four (fourteen Gram-positive and ten Gram-negative) pathogens. There were five infections each caused by two pathogens, three infections each caused by three pathogens and one infection caused by five pathogens. The effect produced by cefadroxil treatment was such that, if one pathogen was eradicated, all the coexistent pathogens in the same patient were also eradicated. Cefadroxil was bactericidal for eleven Gram-positive and six Gram-negative organisms, with the clinical result of six complete cures, two clinical cures (89% clinical success) and one failure in these nine patients. These studies demonstrate the high rate of clinical success achieved by cefadroxil among patients with mild to severe infections of the upper or lower respiratory tract. Clinical success was, in part, the result of the notable effectiveness of cefadroxil as a bactericidal agent in the treatment of the generally more serious illnesses of the lower respiratory tract caused by multiple pathogens. The pharmacokinetic profile of cefadroxil includes a longer serum half-life, greater area under the serum level versus time curve, a slower rate of elimination and, hence, a longer duration of therapeutic action compared with cephalexin and cephradine. In addition, the peak serum levels of cefadroxil are reached without being affected by the presence offood. These pharmacokinetic properties permit the administration of fewer daily doses of cefadroxil, compared with cephalexin or cephradine, as well as a medication schedule that is convenient for all patients and may be tailored to suit the needs imposed on the individual patient by age or condition. We may assume the patient population who participated in these studies is fairly representative of any group of patients with infections of the upper or lower respiratory tract. In general, the majority of the patients with upper respiratory tract infections are between
childhood and middle age. They are usually ambulatory patients to whom the effectiveness of cefadroxil therapy means that relatively Jittlet~is.lostJJ;QJU,schooJ.9f ·WQfK. ·ijurther~ more, medication which can be taken on a schedule that neither conflicts with the busy patient's frequently erratic eating habits nor interrupts his night's sleep in order to take medication, provides a maximum of convenience which greatly improves patient compliance. Patients with lower respiratory tract infections generally comprise an older patient population suffering from infectious diseases of a more serious nature and often requiring a longer duration of treatment. An antibiotic which can be administered without interfering with either mealtime schedules or night-time sleep, would increase the probability that the medication will be taken precisely as prescribed and for as long as necessary, thus increasing the potential for a favourable therapeutic outcome. Similarly, the simplicity of taking two or three daily doses of cefadroxil, in contrast to the four daily doses required with cephalexin or cephradine, should be beneficial to patients of any age, but may be particularly appreciated by those geriatric patients who have difficulty remembering to take medication or have difficulty in swallowingcapsules or tablets. A final consideration of vital importance to all patients, regardless of age or condition, is the fact that no diarrhoea, and only a small percentage of other side-effects, was reported in these studies. This additional benefit carries the potential of improved patient compliance. Conclusion
The therapeutic efficacy of cefadroxil was confirmed in the treatment of a variety of upper and lower respiratory tract infections, mostly moderate and severe. Infection resulted from a single pathogenic origin to as many as five causative organisms. Clinical success was effected in 98% of the patients with the concomitant production of only a small number of side-effects, all mild and transient. Greater bioavailability provided by cefadroxil's pharmacokinetic properties justifies less frequent and more convenient dosage scheduling than cephalexin or cephradine and encourages better patient compliance, thereby enhancing the probability of clinical success.
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F Flores Mercado, P J Santella and C A Fernandez
Acknowledgements The authors wish to thank Ms. Rosemary Darmstadt and Ms. Annmarie Petraglia for the preparation of the manuscript. REFERENCES Buck R E & Price K E (1977) Cefadroxil, a new broad-spectrum cephalosporin. Antimicrobial Agents and Chemotherapy 11,324 Hartstein A I, Patrick K E, Jones S R, Miller M J & Bryant R E (1977) Comparison of pharmacological and antimicrobial properties of cefadroxil and cephalexin. Antimicrobial Agents and Chemotherapy 12,93
279
Jolly E R, Henness D M & Richards D Jr (1977) Human safety, tolerance, and pharmacokinetic studies of cefadroxil, a new cephalosporin antibiotic for oral administration. Current Therapeutic Research 22, 727 Pfeffer M, Jackson A, Ximenes J & De Menezes J P (I977) Comparative human oral clinical pharmacology of cefadroxil, cephalexin and cephradine. Antimicrobial Agents and Chemotherapy 11,331 Santella P J, Fernandez C A & Rondel R K (1977) The clinical evaluation of cefadroxil: a new oral cephalosporin. Presented at the 10th International Congress of Chemotherapy, 18-23 September, Zurich, Switzerland. To be published by the American Society for Microbiology in The Proceedings oj the 10th International Congress ofChemotherapy
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Clinical Experience with Cefadroxil in Upper and Lower Respiratory Tract Infections F Flores Mercado, MD, Research and Teaching Laboratory, Army Hospital, Mexico City, Mexico P J Santella, MS, Associate Director Antibiotic Clinical Research, Bristol-Myers Company, International Division, New York, N.Y., U.SA. C A Fernandez, MD, Director Clinical Research-Latin America, Bristol-Myers Company, International Division, New York, N.Y., U.sA.
Cefadroxil is a new semisynthetic oral cephalosporin with a broad spectrum of activity against both Gram-positive and Gram-negative organisms. Absorption of cefadroxil is unaffected by food. its serum levels are prolonged and it is excreted in the urine at a relatively slow rate compared to cephalexin. In the treatment of 108 patients with upper or lower respiratory tract irfections, cefadroxil effected 93% complete cures. Fifty-five of the patients had upper respiratory tract infections and fifty-three had lower respiratory tract infections; among them cefadroxil achieved clinical success rates of 100% and 96%, respectively. Cefadroxil was clinically successful in eight (89%) out of nine patients whose infections were caused by mixed aetiologies. The principal causative agents were Staphylococcus aureus, p-haemolytic streptococci, Streptococcus pneumoniae and Klebsiella pneumoniae. Overall bacterial eradication produced by cefadroxil was 112 (91%) of 123 organisms isolated from 108 patients. Reports of mild and transient Side-effects in only 3·7% of the patients showed that the drug was well tolerated.
Introduction Cefadroxil is a new semisynthetic oral cephalosporin similar to other cephalosporins in its antibacterial spectrum which includes
coli, Klebsiella pneumoniae, Haemophilus inf/uenzae and Proteus mirabilis (Buck & Price 1977). Its pattern of resistance to fJ-lactamases is similar to that of cephalexin, Staphylococcus aureus, Streptococcus pneu- but it is distinguished from cephalexin as well as moniae, fJ -haemolytic streptococci, Escherichia from cephradine, by several pharmacokinetic properties which confer potential therapeutic advantage through extensive body distribution and longer duration of action. The absorption Requests for reprints to: P J Santella, Bristol-Myers Company, International Division, 345 Park Avenue, of cefadroxil is unaffected by food, serum levels are sustained and the rate of urinary exNew York, N.Y. 10022, U.S.A.
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The Journal ofInternational Medical Research
272
cretion is relatively slow (Hartstein et aI1977, Pfeffer et al 1977, Santella, Fernandez & Rondel 1977, Jolly, Henness & Richards 1977). These characteristics permit the administration of fewer daily doses and a convenient schedule which should improve patient compliance and consequently therapeutic efficacy. Objective v. A series of clinical trials by eight investigators in Mexico was conducted. to evaluate the efficacy and safety of cefadroxil in the treatment of upper and lower respiratory tract infections, of which several had mixed pathogenic origins. Materials and Methods Criteriafor Selection ofPatients Patients were admitted to the clinical trials on the basis of a diagnosis of bacterial infection of the upper or lower respiratory tract which could be treated with an oral cephalosporin. A specific pathogen or pathogens had to be isolated and identified from an appropriate : pre-treatment culture and susceptibility of all pathogens to cefadroxil proven by the .production of a ~ 18 mm zone of inhibition around a 30 f.Jg cefadroxil susceptibility test disc. In addition to these criteria, the diagnosis of lower respiratory tract infection required furthervconfirrnation byca ' positive pretreatment chest X-ray. Excluded from the trials were patients with a history of hypersensitivity to penicillins or cephalosporins, those who required concomitant antibacterial medication, those with renal insufficiency or hepatic disease, and pregnant patients. Prior to admission to the study, laboratory tests were performed on all patients to determine pre-treatment values for blood chemistry and for renal and hepatic function. Patients were considered evaluable for efficacy after they had received cefadroxil therapy for a minimum of 72 hours. All patients were evaluated for safety and reported side-effects were recorded. After therapy, laboratory tests were repeated for comparison with pre-treatment values. Chest X-rays were taken at a minimum of three weeks postfherapy in all cases of lower respiratory tract infection. I
Criteriafor Response Cure was considered complete if clinical signs and symptoms of infection had disappeared completely or improved markedly, the original pathogen(s) had been eradicated and no superinfection with a new pathogen occurred. Cure was considered clinical if clinical signs and symptoms of infection had disappeared completely or improved markedly but the causative bacteria were not eradicated. In lower respiratory tract infections, clinical improvement was verified by post-therapy chest X-ray. Treatment was considered a failure if there was no clinical improvement and no bacterial eradication. The sum of complete cures plus clinical cures constituted clinical success. Patient Population A total of 108 patients with infections of the upper or lower respiratory tract participated in the study. Among the fifty-five patients with upper respiratory tract infections, there were twentynine males and twenty-six females. The majority of these patients were between thirteen and twenty-five years of age. Forty-three of the upper respiratory tract infections were classified as moderate, three were mild and nine were severe. The fifty-three patients with lower respiratory tract infections were composed of twentythree males and thirty females. All were adults between thirteen and seventy years of age. Twenty-four patients were over fifty-one years of age. Among the lower respiratory tract infections, two were mild, thirty-five moderate and sixteen were severe infections. Dosage Cefadroxil was administered orally at either 12-hour intervals (forty-eight patients) or 8hour intervals (sixty patients). All patients received a total daily dosage between 1500 and 2000 mg. The mean duration of therapy for most patients was 10 days with. the exception of two patients with infected bronchiectasis whose treatment period averaged 40 days. Results Cefadroxil treatment of 108 patients with upper or lower respiratory tract infections
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F Flores Mercado. P J Santella and C A Fernandez produced 101 (93%) complete cures. Five patients had clinical cures and two patients did not respond to therapy. Thus, the overall rate of clinical success achieved with cefadroxil treatment was 98% (Table I). There were 123 pathogens isolated from the 108 patients. Cefadroxil eradicated ninety-six of 10 I Gram-positive and sixteenof twenty-two Gramnegative bacteria, resulting in an overall bacterial eradication rate of 91%. Bacterial eradication was accomplished in ninety-five of the ninety-nine patients with infections due to single pathogens (Tables 2 and 3). Infections in nine patients (two with upper and seven with lower respiratory tract infections) were caused by mixed pathogens. Cefadroxil effected complete cures in six of these nine patients and clinical cures without bacterial eradication in two patients. Only one patient with an infection caused by mixed pathogens did not respond to cefadroxil treatment.
Upper Respiratory Tract Infections Fifty-five patients were diagnosed as having infections of the upper respiratory tract and
273
among them cefadroxil effected fifty-four (98%) complete cures and one clinical cure, equivalent to 100% clinical success (Table I). Bacterial eradication in the fifty-five patients was 96% (Table 2); the use of cefadroxil produced bacterial eradication in one of the two cases of upper respiratory tract infections caused by mixed pathogens. Among upper respiratory tract infections the most common diagnosis was tonsillitispharyngitis. There were forty-six patients with these infections, of whom the majority were between the ages of thirteen and twenty-five years and had a moderate form of the infection. Single pathogens, primarily Staphylococcus aureus or P-haemolytic streptococci, were the cause of forty-five infections and cefadroxil treatment completely cured all forty-five patients. In the only tonsillitispharyngitis infection caused by mixed pathogens, the patient was clinically cured but the bacteria persisted (Table 2). The other upper respiratory tract infections were otitis media, which occurred in eight patients, and sinusitis in one patient. Cefadroxil
Tablel Cefadroxil - overall clinical response
Diagnosis Upper respiratory tract Tonsillitis-pharyngitis Otitis media Sinusitis Sub-total
Lower respiratory tract Bronchitis Broncho-pneumonia Lobar pneumonia Infected bronchiectasis Pulmonary abscess Empyema Sub-total Total Percentage
Number of patients
Complete cures
Clinical cures
Percentage clinical Failures
success"
46 8 1
45 8 I
0 0
0 0 0
100% 100% 100%
55
54
I
0
100%
25 14 8 2 2 2
24 II 6 2 2 2
0
I I
0 0 0 0
96% 93% 100% 100% 100% 100%
53
47
4
2
96%
108
101 93%
2 2%
98%
I
2 2
0 0 0 :
5 5%
·Percentage clinical success is based on complete cures plus clinical cures.
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*a. Klebsiella pneumoniae b. Enterobacter c. Pseudomonas aeruginosa
55 Patients 57 Pathogens isolated 55 Pathogens eradicated 96% Bacterial eradication
28
I
Sinusitis (l patient) I infection caused by single pathogen
Totals
I
I
28
I
3
23
3
23
5
4
I
4
4
0
19
I
18
18
0
18
Number eradicated
Total number
Number eradicated
Total number
Number eradicated
Total number
Otitis media (8 patients) 7 infections caused by single pathogens I infection caused by mixed pathogens
Tonsillitis-pharyngitis (46 patients) 45 infections caused by single pathogens I infection caused by mixed pathogens
Diagnosis
P-haemolytic streptococci
Streptococcus pneumoniae
Staphylococcus aureus
Causative pathogens
Cefadroxil bacteriological response in upper respiratory tract infections caused by single and mixed pathogens
Table 2
2
2
Total number
2
2
Number eradicated
Staphylococcus epidermidis
3
I'
2·'. b
Total number
Other"
3
I
2
Number eradicated
-
;::s-
~
t%
~
~
-
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g.
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b. Streptococcus faecalis c. Escherichia coli d. Pseudomonas aeruginosa
-8. Staphylococcus epidermidis
46 Patients 46 Pathogens isolated 42 Pathogens eradicated 91 % Bacterial eradication
Total
2 patients
Empyema
I patient
Infected bronchiectasis
8 patients
Lobar pneumonia
10 patients
Broncho-pneumonia
25 patients
Bronchitis
Diagnosis
12
I
1
3
7
Total number
11
I
1
3
6
Number eradicated
Staphylococcus aureus
13
6
1
6
Total number
12
5
I
6
Number eradicated
Streptococcus pneumoniae
9
1
8
Total number
streptococci
f3 -haemolytic
9
1
8
Number eradicated
Causativepathogens
CeraciroxH lIacteriolollic:al responle in lower res,iratory tract Infections caused by sinille pathollens
Table 3
8
1
1
3
3
Total number
3
3
Number eradicated
Id 4
7
2 b;c
.
Total number
Other-
1
0
Klebsiella pneumoniae
3
1
Ib
I
Number eradicated
-J V.
N
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·a. Enterobacter b. Escherichia coli c. Proteus mirabilis
7 Patients 20 Pathogens isolated 15 Pathogens eradicated 75% Bacterial eradication
Total
Pulmonary abscess (2 patients) 1 infection (5 pathogens) 1 infection (2 pathogens) 2
2 I
d. Staphylococcus epidermidis e. Haemophilus inftuenzae f. Klebsiella aerobacter
1
1
0
4
1
1
1
Infected bronchiectasis (/ patient) 1 infection (2 pathogens)
0
Total number
1 1
1
Number eradicated
Total number
Number eradicated
Total number
4
1
I
1 1
Number eradicated
p-haemolytic streptococci
1 infection (3 pathogens) 1 infection (3 pathogens) 1 infection (3 pathogens)
Broncho-pneumonia (4 patients) 1 infection (2 pathogens)
Diagnosis
Streptococcus pneumoniae
Staphylococcus aureus
Causativepathogens
Ceflldroxn bacteriological response in lower respirlltory tract infections cllused by mixed pllthogens
Table 4
Klebsiella
1
1
Total number
pneumoniae
0
0
Number eradicated
12
2d,e
3b,d,f
1" 2b,c 2b,d, 2 d.e
Total number
Other"
9
2
3
0 0 2 2
Number eradicated
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F Flores Mercado, P J Santella and C A Fernandez achieved complete cures in all nine patients with these diagnoses. One case of otitis media was due to multiple pathogens and total eradication of the bacteria was effected by cef'adroxil in this infection. Bacterial eradication was also accomplished in all infections caused by single pathogens (Table 2). i
Lower Respiratory Tract Infections There were fifty-three patients with infections of the lower respiratory tract. Cefadroxil therapy produced complete cures in fortyseven (89%) patients, clinical cures in four patients and was ineffective in two patients (Table 1). The rate of bacterial eradication was 91% among forty-six patients whose infections were caused by single pathogens and 75% among seven patients with infections due to multiple pathogens (Tables 3 and 4). All of the bronchitis infections were precipitated by single pathogens (Table 3), predominantly Staphylococcus aureus, Streptococcus pneumoniae and p-haemolytic streptococci. Eradication of the bacteria coupled with clinical cure (i.e., complete cure) was accomplished by cefadroxil treatment in twenty-four (96%) of these twenty-five patients. The remaining patient did not respond to a regimen of 1000 mg of cefadroxil administered every 12 hours for 7 days although the patients who were cured had received similar therapeutic courses. The number of infections caused by mixed pathogens was greater among patients with broncho-pneumonia than among those with any other diagnosis. Of fourteen patients with broncho-pneumonia, mixed pathogens were the causative agents in four patients, from whom a total of eleven micro-organisms were isolated. Cefadroxil produced bacterial eradication in four of five Gram-positive and in two of six Gram-negative organisms represented in the cultures (Table 4). The results of cefadroxil treatment in the four patients were two complete cures, one clinical cure and one failure. Among the ten patients with broncho-pneumonia caused by single pathogens, nine were completely cured; the tenth was clinically cured without eradication of the causative organism, Escherichia coli. Thus, the rate of clinical success of cefadroxil in the treatment of all patients with bronchopneumonia was 93% (Table 1).
277
Streptococcus pneumoniae was the most commonly encountered' pathogen (6/8) in lobar pneumonia and; was eradicated by cefadroxil in five' of sIX patients (Table 3). Overall, cefadroxil therapy in patients with lobar pneumonlaachieved six complete cures and two clinical cures, or a 100% clinical success rate. There were two cases of infected bronchiectasis, one due. to' Staphylococcus aureus (Table 3), and' the other to multiple pathogens (Table 4). Both patients were completely cured during an average of forty days treatment with cefadroxil, The mixed aetiologies which underlie the two cases of pulmonary abscess are shown in Table 4. While one of the infections was caused by a combination of one Gram-positive and one Gram-negative organism, a relatively common occurrence, the other was unique in being traceable to five infecting pathogens: Nevertheless, total eradication of the pathogens was accompfished bycefadroxil and the two patients with pulmonary abscesses were completely cured. . The final diagnostic category among the lower respiratory tract infections was empyema. There were two infections,' each caused by a Gram-negative organism (Table 3). Bacterial eradication was produced and complete cures effected by cefadroxil in both patients. Side-Effects Eight drug-related side-effects were experienced by four (3· 7%) of 108 patients in the studies. The effects consisted of nausea (three), abdominal pain (two), rash (two) and pruritus (one). These side-effects' were mild and transient and cefadroxil therapy was continued in all patients. Disseussion Cefadroxil achieved 98% clinical success in the treatment of 108 patients with upper or lower respiratory tract infections by effecting 101 complete cures and five clinical cures. Among fifty-five patients with upper respiratory tract infections, all were completely cured with the exception of one patient with tonsillitis-pharyngitis caused by multiple pathogens. A clinical cure was attained in this patient, but the bacteria were not eradicated.
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278
The Journal ofInternational Medical Research
The only other patient with an upper respiratory tract infection caused by mixed pathogens was completely cured. Of the forty-seven complete cures and four clinical cures produced by cefadroxil therapy in fifty-three patients with lower respiratory tract infections, five of the complete cures and one of the clinical cures occurred among patients with infections caused by mixed pathogens. Nine infections were caused by multiple organisms ~ a total of twenty-four (fourteen Gram-positive and ten Gram-negative) pathogens. There were five infections each caused by two pathogens, three infections each caused by three pathogens and one infection caused by five pathogens. The effect produced by cefadroxil treatment was such that, if one pathogen was eradicated, all the coexistent pathogens in the same patient were also eradicated. Cefadroxil was bactericidal for eleven Gram-positive and six Gram-negative organisms, with the clinical result of six complete cures, two clinical cures (89% clinical success) and one failure in these nine patients. These studies demonstrate the high rate of clinical success achieved by cefadroxil among patients with mild to severe infections of the upper or lower respiratory tract. Clinical success was, in part, the result of the notable effectiveness of cefadroxil as a bactericidal agent in the treatment of the generally more serious illnesses of the lower respiratory tract caused by multiple pathogens. The pharmacokinetic profile of cefadroxil includes a longer serum half-life, greater area under the serum level versus time curve, a slower rate of elimination and, hence, a longer duration of therapeutic action compared with cephalexin and cephradine. In addition, the peak serum levels of cefadroxil are reached without being affected by the presence offood. These pharmacokinetic properties permit the administration of fewer daily doses of cefadroxil, compared with cephalexin or cephradine, as well as a medication schedule that is convenient for all patients and may be tailored to suit the needs imposed on the individual patient by age or condition. We may assume the patient population who participated in these studies is fairly representative of any group of patients with infections of the upper or lower respiratory tract. In general, the majority of the patients with upper respiratory tract infections are between
childhood and middle age. They are usually ambulatory patients to whom the effectiveness of cefadroxil therapy means that relatively Jittlet~is.lostJJ;QJU,schooJ.9f ·WQfK. ·ijurther~ more, medication which can be taken on a schedule that neither conflicts with the busy patient's frequently erratic eating habits nor interrupts his night's sleep in order to take medication, provides a maximum of convenience which greatly improves patient compliance. Patients with lower respiratory tract infections generally comprise an older patient population suffering from infectious diseases of a more serious nature and often requiring a longer duration of treatment. An antibiotic which can be administered without interfering with either mealtime schedules or night-time sleep, would increase the probability that the medication will be taken precisely as prescribed and for as long as necessary, thus increasing the potential for a favourable therapeutic outcome. Similarly, the simplicity of taking two or three daily doses of cefadroxil, in contrast to the four daily doses required with cephalexin or cephradine, should be beneficial to patients of any age, but may be particularly appreciated by those geriatric patients who have difficulty remembering to take medication or have difficulty in swallowingcapsules or tablets. A final consideration of vital importance to all patients, regardless of age or condition, is the fact that no diarrhoea, and only a small percentage of other side-effects, was reported in these studies. This additional benefit carries the potential of improved patient compliance. Conclusion
The therapeutic efficacy of cefadroxil was confirmed in the treatment of a variety of upper and lower respiratory tract infections, mostly moderate and severe. Infection resulted from a single pathogenic origin to as many as five causative organisms. Clinical success was effected in 98% of the patients with the concomitant production of only a small number of side-effects, all mild and transient. Greater bioavailability provided by cefadroxil's pharmacokinetic properties justifies less frequent and more convenient dosage scheduling than cephalexin or cephradine and encourages better patient compliance, thereby enhancing the probability of clinical success.
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F Flores Mercado, P J Santella and C A Fernandez
Acknowledgements The authors wish to thank Ms. Rosemary Darmstadt and Ms. Annmarie Petraglia for the preparation of the manuscript. REFERENCES Buck R E & Price K E (1977) Cefadroxil, a new broad-spectrum cephalosporin. Antimicrobial Agents and Chemotherapy 11,324 Hartstein A I, Patrick K E, Jones S R, Miller M J & Bryant R E (1977) Comparison of pharmacological and antimicrobial properties of cefadroxil and cephalexin. Antimicrobial Agents and Chemotherapy 12,93
279
Jolly E R, Henness D M & Richards D Jr (1977) Human safety, tolerance, and pharmacokinetic studies of cefadroxil, a new cephalosporin antibiotic for oral administration. Current Therapeutic Research 22, 727 Pfeffer M, Jackson A, Ximenes J & De Menezes J P (I977) Comparative human oral clinical pharmacology of cefadroxil, cephalexin and cephradine. Antimicrobial Agents and Chemotherapy 11,331 Santella P J, Fernandez C A & Rondel R K (1977) The clinical evaluation of cefadroxil: a new oral cephalosporin. Presented at the 10th International Congress of Chemotherapy, 18-23 September, Zurich, Switzerland. To be published by the American Society for Microbiology in The Proceedings oj the 10th International Congress ofChemotherapy
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