Topical and Oral Treatment of Chronic Otitis Media With Ciprofloxacin A
Preliminary Study
Silvano Esposito, MD; Gioacchino D'Errico, MD; Carmine Montanaro, MD
\s=b\ The clinical and bacteriological efficacy of ciprofloxacin was studied in three groups composed of 20 patients each, all of whom were affected by chronic otitis media in the acute stage. Ciprofloxacin was randomly administered according to the following schedules for 5 to 10 days: 250 mg orally twice a day (group A); 3 drops (250 \g=m\g/mL in saline solution) locally twice a day (group B); and both of the previous treatments twice a day (group C). A high percentage of favorable clinical response (100% and 95%) and bacteriological eradication (95% and 85%) was observed in groups B and C. A low percentage of patients (65% and 40%) were clinically and bacteriologically cured by the oral therapy (group A). No worsening of the audiometric and vestibular function was observed after local therapy. The results of this preliminary study suggest that the use of topical ciprofloxacin is effective in curing chronic otitis media, even when it is caused by Pseudomonas (47% of the total bacterial detections).
(Arch Otolaryngol Head Neck Surg. 1990;116:557-559)
Accepted for publication September 19,1989. From the Clinics of Infectious Diseases (Dr Esposito) and Otolaryngology (Drs D'Errico and Montanaro), University of Naples (Italy). Reprint requests to Clinic of Infectious Diseases, University of Naples, Ospedale Ges\l=u`\e Maria, Via D. Cotugno 1, 80135 Naples, Italy (Dr
Esposito).
Suppuratiby vpurulent e ized
PATIENTS AND METHODS Patients
processes character¬ otorrhea are very
frequently and recurrently observed in patients affected by chronic otitis me¬ dia (COM), and bacterial responsibil¬ ity in these processes is certain. Gram-positive and gram-negative aerobic, as well as anaerobic, bacteria are in fact involved in the etiology of suppurative COM, with different incidence.14 The frequent detection of
Pseudomonas and other multiresistant bacteria and the possible low con¬ centrations of antibiotics in the middle ear are probably responsible for the frequent failures following empirical therapy with conventional antibacte¬ rial agents. To date, the epidemiologi¬ ca! findings in suppurative otitis fre¬ quently suggest treatment with anti¬ biotics that also include Pseudomonas in their antibacterial spectrum, such as aminoglycosides. However, these antibiotics cannot be recommended, especially for local instillation, be¬ cause of the high risk of ototoxicity.57 The aim of the present preliminary study was to evaluate the therapeutic efficacy and tolerability of ciprofloxa¬ cin, which is a particularly active nontoxic drug against Pseudomonas, orally or topically administered in the treatment of COM in the acute stage.
Sixty adult patients (31 men, 29 women) affected by suppurative COM were included in the study. Data concerning the patients' demographic characteristics are reported in Table 1. All patients were affected by mild or moderate COM in the acute stage without choiesteatoma or mastoiditis. Table 1.—Patients' Demographic Characteristics Sex Mean
,-·-.
Group_M_F_Age, A
9 12
8
39
C
10
10
40
Total
31
29
38
Table 2.—Prior
Therapies
Drugs Cephalosporins Lincomycin
No. of Patients 13 6
Penicillins
5
Tetracycline Neomycin/colistin sulfate* Othersf
2
Total
y
36
11
7 5
38 (63%)
'Local drops. tGentamicin, netilmicin sulfate, erythromycin, miokamycin, and sulfamethoxazole/trlmethoprim.
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Pregnant women, patients with a history of previous allergy to quinolone derivatives, and patients younger than 18 years were excluded. All patients had given their in¬ formed consent before entering the study. No patient had any underlying diseases (such as diabetes), and none was taking any other drug during the study. Many of the patients (38 [63%] of 60) had been taking different systemic and local antibiotics at appropriate dosages for at least 5 days be¬ fore beginning the new therapy, without any significant improvement of the subjec¬ tive symptoms (Table 2). Antibiotic Treatments
Ciprofloxacin was randomly adminis¬ tered according to the following schedules:
patients), 250 mg orally twice a (20 patients), 3 drops contain¬ ing 250 ug/mL of ciprofloxacin in saline so¬ lution locally twice a day; and group C (20 patients), both the previous treatments twice a day. Ciprofloxacin solutions were prepared by dissolving the pure sterile ciprofloxacin powder in saline solution to obtain the final concentration of 250 ug/mL. Preliminary studies were performed using an agar dif¬ fusion method to evaluate a possible loss of activity of the solution stored either in the refrigerator or at room temperature. These tests were carried out for 10 days and did
group A (20 day; group
not show any decrease of
the in vitro anti¬
bacterial activity of the drug. Patients' Examination Patients were clinically examined before, during (every 2 to 3 days), and after the end of the therapy, and an accurate inquiry for side effects was carried out at each clinical control. Audiometrie measurement and vestibular tests were performed before and 24 hours after the end of the therapy in pa¬ tients receiving topical treatment only. Aerobic cultures of the middle ear effu¬ sions were always performed before the be¬ ginning of the therapy and, if the secretion was still present, at each clinical control. All bacteria were identified by the API sys¬ tem
(Bio-Herieux). Susceptibility
to
cipro¬
floxacin was studied by determining the minimal inhibitory concentrations by a mi¬ crodilution broth method. Treatments were carried out for at least 5 days. Patients who were not cured after this period of therapy continued the treat¬ ment until cure, or, in any case, not longer than 10 days. The clinical and bacteriolog¬ ical evaluation was stated 24 hours and 14 days (follow-up) after the interruption of treatment.
Statistical Analysis * 2 was calculated to compare the percent¬ ages of clinical and bacteriological re-
sponses in the three groups of patients ex¬ amined, to evaluate a possible statistical
Table 3.—Responsible Bacteria Isolated Before Treatment
difference.
Group,
RESULTS
Data concerning the isolation of the responsible bacteria from the middle ear effusion are reported in Table 3. We detected a single responsible bacteria in all cultures except one from one pa¬ tient in group B. This patient had a mixed culture consisting of Pseu¬ domonas aeruginosa and Staphylococcus aureus. The distribution of bacte¬ ria was homogeneous, especially in groups and C. Group A had a higher prevalence of Pseudomonas (60%); consequently, the number of grampositive cocci detected was lower, (25% ). Clinical and bacteriological re¬ sponses are reported in Tables 4 and 5,
respectively.
In group A, 13 (65%) of the 20 patients had a favorable clinical re¬ sponse to the oral ciprofloxacin ther¬ apy and 7 (35% ) showed no significant clinical improvement. These results corresponded to a high percentage of
bacteriological persistence or superin¬
fection. Of the 20 patients in group B, who received only locally administered drops of ciprofloxacin, a clinical cure was observed in 17 (85% ) and improve¬ ment was noted in 3 (15% ). Two of the patients who were clinically improved still had a very small ear secretion, which was sterile, and one was still in¬ fected by Escherichia coli. Of the 20 patients in group C, who received both oral and topical cipro¬ floxacin, 15 (75%) were clinically cured, 4 improved, and 1 failed. In two patients with significant clinical im¬ provement, there was persistence of a very small ear effusion, which was bacteriologically sterile. In two other patients, we observed a remarkable clinical improvement with a signifi¬ cant decrease of the ear effusion, which was still infected by S aureus and aeruginosa in one and superinfected by S aureus in the other. Finally, one pa¬ tient was not clinically or bacteriolog¬ ically cured, as there was persistence of S aureus in the culture of his middle ear effusion. Bacteria isolated from the cultures after the end of the treatment are reported for each patient group in Table 6.
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(%)
No.
C
Total
Pseudomonas* 12(60) 8(38) 8(49)28(46) Gram-positive coccif
5(25)10(48) 9(45)24(39)
Entero-
3(15) 3(14) 3(15) 9(15)
bacteriaf
21
20
Total
'Pseudomonas aeruginosa
61
20
and Pseudomas
puti¬
da.
t Staphylococcus aureus, Staphylococcus epider¬ midis, and Staphylococcus haemolyticus; Strepto¬ coccus
salivarius.
iEscherichia coli. Proteus mirabilis, Morganella morganii, Providencia stuartii, Enterobacter cloacae, and Klebsiella
ozaenae.
Table 4.—Clinical Results No.
Group
(%) Failure
C
Improvement 5 (25) 3(15) 17(85) 4 (20) 15 (75)
Table
5.—Bacteriological Results
A
Cure 8 (40)
7
(35)
1
(5)
No.(%) Eradi-
Group cation A 8 (40) 19(95) C 17(85)
Persistence
(40) (5) 1 (5)
8
Super-
infection 4
(20)
2
(10)
1
Table 6.—Responsible Bacteria Isolated 24 Hours After the End of
Therapy* Group Pseudomonas Pseudomonas ( 1 )
(7)
Staphylococcus aureus (3)
S
aureus
(3)
Morganella morganii ( 1 )
Streptococcus (1)
Escherchia The numbers in
co//(1) parentheses indicate the number
of bacteria.
Bacterial cultures of middle ear ef¬ fusion were performed 24 hours after the interruption of the therapy, and no ciprofloxacin resistance was detected. All patients who were clinically and
bacteriologically cured 24 hours after the interruption of the treatment con¬ firmed their clinical status 14 days af¬ ter the end of the therapy (follow-up).
of
activity. Sometimes, antibacterial agents such as neomycin are utilized for topical treatment, but their use is
The infectious processes of the mid¬ dle ear are usually difficult to cure, probably because of the low concen¬ trations of antibiotics at this site and because of the frequent etiologic role of Pseudomonas, which is resistant to several classes of antibiotics. Also, in the present study the frequency of de¬ tection of Pseudomonas was high (47% of the total number of isolated bacte¬
controversial because of the ototoxicity that can result, especially in case of tympanic membrane perforation. In our study, prior conventional treat¬ ments with parenteral, oral, or topical drugs had already failed in 38 of the 60 patients under examination. Few data concerning the treatment of bacterial otitis with oral ciproflox¬ acin are available in the literature at present, and our results are not in agreement with them. In 1985 Fujimaki et al8 and Mori et al9 in two dif¬ ferent studies performed in Japan re¬ ported a high frequency of clinical resolution and bacteriological eradica¬ tion following the oral administration of 200 mg of ciprofloxacin three times a day. Good results were also reported by Van de Heyning et al10 in 28 patients affected by suppurative COM, but at much higher dosages (750 mg twice a
ria).
day).
No side effect was recorded in any pa¬ tient, and no worsening of the audiometric function related to the local and C) was ob¬ therapy (groups served. The bacteriological and clinical cure rates observed in groups and C were statistically higher than those in group A
(P
Preliminary Study
Silvano Esposito, MD; Gioacchino D'Errico, MD; Carmine Montanaro, MD
\s=b\ The clinical and bacteriological efficacy of ciprofloxacin was studied in three groups composed of 20 patients each, all of whom were affected by chronic otitis media in the acute stage. Ciprofloxacin was randomly administered according to the following schedules for 5 to 10 days: 250 mg orally twice a day (group A); 3 drops (250 \g=m\g/mL in saline solution) locally twice a day (group B); and both of the previous treatments twice a day (group C). A high percentage of favorable clinical response (100% and 95%) and bacteriological eradication (95% and 85%) was observed in groups B and C. A low percentage of patients (65% and 40%) were clinically and bacteriologically cured by the oral therapy (group A). No worsening of the audiometric and vestibular function was observed after local therapy. The results of this preliminary study suggest that the use of topical ciprofloxacin is effective in curing chronic otitis media, even when it is caused by Pseudomonas (47% of the total bacterial detections).
(Arch Otolaryngol Head Neck Surg. 1990;116:557-559)
Accepted for publication September 19,1989. From the Clinics of Infectious Diseases (Dr Esposito) and Otolaryngology (Drs D'Errico and Montanaro), University of Naples (Italy). Reprint requests to Clinic of Infectious Diseases, University of Naples, Ospedale Ges\l=u`\e Maria, Via D. Cotugno 1, 80135 Naples, Italy (Dr
Esposito).
Suppuratiby vpurulent e ized
PATIENTS AND METHODS Patients
processes character¬ otorrhea are very
frequently and recurrently observed in patients affected by chronic otitis me¬ dia (COM), and bacterial responsibil¬ ity in these processes is certain. Gram-positive and gram-negative aerobic, as well as anaerobic, bacteria are in fact involved in the etiology of suppurative COM, with different incidence.14 The frequent detection of
Pseudomonas and other multiresistant bacteria and the possible low con¬ centrations of antibiotics in the middle ear are probably responsible for the frequent failures following empirical therapy with conventional antibacte¬ rial agents. To date, the epidemiologi¬ ca! findings in suppurative otitis fre¬ quently suggest treatment with anti¬ biotics that also include Pseudomonas in their antibacterial spectrum, such as aminoglycosides. However, these antibiotics cannot be recommended, especially for local instillation, be¬ cause of the high risk of ototoxicity.57 The aim of the present preliminary study was to evaluate the therapeutic efficacy and tolerability of ciprofloxa¬ cin, which is a particularly active nontoxic drug against Pseudomonas, orally or topically administered in the treatment of COM in the acute stage.
Sixty adult patients (31 men, 29 women) affected by suppurative COM were included in the study. Data concerning the patients' demographic characteristics are reported in Table 1. All patients were affected by mild or moderate COM in the acute stage without choiesteatoma or mastoiditis. Table 1.—Patients' Demographic Characteristics Sex Mean
,-·-.
Group_M_F_Age, A
9 12
8
39
C
10
10
40
Total
31
29
38
Table 2.—Prior
Therapies
Drugs Cephalosporins Lincomycin
No. of Patients 13 6
Penicillins
5
Tetracycline Neomycin/colistin sulfate* Othersf
2
Total
y
36
11
7 5
38 (63%)
'Local drops. tGentamicin, netilmicin sulfate, erythromycin, miokamycin, and sulfamethoxazole/trlmethoprim.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
Pregnant women, patients with a history of previous allergy to quinolone derivatives, and patients younger than 18 years were excluded. All patients had given their in¬ formed consent before entering the study. No patient had any underlying diseases (such as diabetes), and none was taking any other drug during the study. Many of the patients (38 [63%] of 60) had been taking different systemic and local antibiotics at appropriate dosages for at least 5 days be¬ fore beginning the new therapy, without any significant improvement of the subjec¬ tive symptoms (Table 2). Antibiotic Treatments
Ciprofloxacin was randomly adminis¬ tered according to the following schedules:
patients), 250 mg orally twice a (20 patients), 3 drops contain¬ ing 250 ug/mL of ciprofloxacin in saline so¬ lution locally twice a day; and group C (20 patients), both the previous treatments twice a day. Ciprofloxacin solutions were prepared by dissolving the pure sterile ciprofloxacin powder in saline solution to obtain the final concentration of 250 ug/mL. Preliminary studies were performed using an agar dif¬ fusion method to evaluate a possible loss of activity of the solution stored either in the refrigerator or at room temperature. These tests were carried out for 10 days and did
group A (20 day; group
not show any decrease of
the in vitro anti¬
bacterial activity of the drug. Patients' Examination Patients were clinically examined before, during (every 2 to 3 days), and after the end of the therapy, and an accurate inquiry for side effects was carried out at each clinical control. Audiometrie measurement and vestibular tests were performed before and 24 hours after the end of the therapy in pa¬ tients receiving topical treatment only. Aerobic cultures of the middle ear effu¬ sions were always performed before the be¬ ginning of the therapy and, if the secretion was still present, at each clinical control. All bacteria were identified by the API sys¬ tem
(Bio-Herieux). Susceptibility
to
cipro¬
floxacin was studied by determining the minimal inhibitory concentrations by a mi¬ crodilution broth method. Treatments were carried out for at least 5 days. Patients who were not cured after this period of therapy continued the treat¬ ment until cure, or, in any case, not longer than 10 days. The clinical and bacteriolog¬ ical evaluation was stated 24 hours and 14 days (follow-up) after the interruption of treatment.
Statistical Analysis * 2 was calculated to compare the percent¬ ages of clinical and bacteriological re-
sponses in the three groups of patients ex¬ amined, to evaluate a possible statistical
Table 3.—Responsible Bacteria Isolated Before Treatment
difference.
Group,
RESULTS
Data concerning the isolation of the responsible bacteria from the middle ear effusion are reported in Table 3. We detected a single responsible bacteria in all cultures except one from one pa¬ tient in group B. This patient had a mixed culture consisting of Pseu¬ domonas aeruginosa and Staphylococcus aureus. The distribution of bacte¬ ria was homogeneous, especially in groups and C. Group A had a higher prevalence of Pseudomonas (60%); consequently, the number of grampositive cocci detected was lower, (25% ). Clinical and bacteriological re¬ sponses are reported in Tables 4 and 5,
respectively.
In group A, 13 (65%) of the 20 patients had a favorable clinical re¬ sponse to the oral ciprofloxacin ther¬ apy and 7 (35% ) showed no significant clinical improvement. These results corresponded to a high percentage of
bacteriological persistence or superin¬
fection. Of the 20 patients in group B, who received only locally administered drops of ciprofloxacin, a clinical cure was observed in 17 (85% ) and improve¬ ment was noted in 3 (15% ). Two of the patients who were clinically improved still had a very small ear secretion, which was sterile, and one was still in¬ fected by Escherichia coli. Of the 20 patients in group C, who received both oral and topical cipro¬ floxacin, 15 (75%) were clinically cured, 4 improved, and 1 failed. In two patients with significant clinical im¬ provement, there was persistence of a very small ear effusion, which was bacteriologically sterile. In two other patients, we observed a remarkable clinical improvement with a signifi¬ cant decrease of the ear effusion, which was still infected by S aureus and aeruginosa in one and superinfected by S aureus in the other. Finally, one pa¬ tient was not clinically or bacteriolog¬ ically cured, as there was persistence of S aureus in the culture of his middle ear effusion. Bacteria isolated from the cultures after the end of the treatment are reported for each patient group in Table 6.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
(%)
No.
C
Total
Pseudomonas* 12(60) 8(38) 8(49)28(46) Gram-positive coccif
5(25)10(48) 9(45)24(39)
Entero-
3(15) 3(14) 3(15) 9(15)
bacteriaf
21
20
Total
'Pseudomonas aeruginosa
61
20
and Pseudomas
puti¬
da.
t Staphylococcus aureus, Staphylococcus epider¬ midis, and Staphylococcus haemolyticus; Strepto¬ coccus
salivarius.
iEscherichia coli. Proteus mirabilis, Morganella morganii, Providencia stuartii, Enterobacter cloacae, and Klebsiella
ozaenae.
Table 4.—Clinical Results No.
Group
(%) Failure
C
Improvement 5 (25) 3(15) 17(85) 4 (20) 15 (75)
Table
5.—Bacteriological Results
A
Cure 8 (40)
7
(35)
1
(5)
No.(%) Eradi-
Group cation A 8 (40) 19(95) C 17(85)
Persistence
(40) (5) 1 (5)
8
Super-
infection 4
(20)
2
(10)
1
Table 6.—Responsible Bacteria Isolated 24 Hours After the End of
Therapy* Group Pseudomonas Pseudomonas ( 1 )
(7)
Staphylococcus aureus (3)
S
aureus
(3)
Morganella morganii ( 1 )
Streptococcus (1)
Escherchia The numbers in
co//(1) parentheses indicate the number
of bacteria.
Bacterial cultures of middle ear ef¬ fusion were performed 24 hours after the interruption of the therapy, and no ciprofloxacin resistance was detected. All patients who were clinically and
bacteriologically cured 24 hours after the interruption of the treatment con¬ firmed their clinical status 14 days af¬ ter the end of the therapy (follow-up).
of
activity. Sometimes, antibacterial agents such as neomycin are utilized for topical treatment, but their use is
The infectious processes of the mid¬ dle ear are usually difficult to cure, probably because of the low concen¬ trations of antibiotics at this site and because of the frequent etiologic role of Pseudomonas, which is resistant to several classes of antibiotics. Also, in the present study the frequency of de¬ tection of Pseudomonas was high (47% of the total number of isolated bacte¬
controversial because of the ototoxicity that can result, especially in case of tympanic membrane perforation. In our study, prior conventional treat¬ ments with parenteral, oral, or topical drugs had already failed in 38 of the 60 patients under examination. Few data concerning the treatment of bacterial otitis with oral ciproflox¬ acin are available in the literature at present, and our results are not in agreement with them. In 1985 Fujimaki et al8 and Mori et al9 in two dif¬ ferent studies performed in Japan re¬ ported a high frequency of clinical resolution and bacteriological eradica¬ tion following the oral administration of 200 mg of ciprofloxacin three times a day. Good results were also reported by Van de Heyning et al10 in 28 patients affected by suppurative COM, but at much higher dosages (750 mg twice a
ria).
day).
No side effect was recorded in any pa¬ tient, and no worsening of the audiometric function related to the local and C) was ob¬ therapy (groups served. The bacteriological and clinical cure rates observed in groups and C were statistically higher than those in group A
(P
