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Sequential Intravenous-Oral Administration of Ciprofloxacin vs Ceftazidime in Serious Bacterial Respiratory Tract lnfections* Faroque A. Khan, MB., F.C.C.P;t and Riyad M.D4 Basir, The ethcacy and safety of sequential intravenous/oral ciprofloxacin in rnoderate to severe respiratory tract infections (RTI) were cornpared with those of ceftazidirne in a prospective clinical trial. Sixty-six patients received IN ciprofloxacin (200 to 300 rng twice daily), followed by oral rng twice daily). Fifty-six patients received intravenous ceftazidime (1 to 2 g two to three times daily). Ciprofloxacin was as effective as ceftazidime and produced a 91 percent clinical cure rate. Signfficantly more pretreatment bacterial isolates were susceptible to ciprofloxacin, and ciprofloxacin had a significantly higher rate of sputum bacterial eradication than did ceftazidime. Ciprofloxacin ciprofloxacin(500 T he recent introduction represents a major of advance potent in the antibiotics, allowing for the first therapy of serious infections caused tant bacteria. tive in terms compounds ciprofloxacin of its potency, rapidity RTlrespiratory available the most ofbacterial infections; tract of oral resis- MIC minimal inhibitory concentration PATIENTS development time effective by multiply currently is among broad minimal low 4-quinolones Four fluoroquinolones, as follow, are in various stages of approval and clinical investigation in the United States norfioxacin, ciprofloxacin, enoxacin, and ofloxacm.’ Of the investigation, in vitro antibacterial activity with particularly inhibitory concentrations for Gram-negative organisms. Ciprofloxacin was well tolerated; there were few adverse effects. Ciprofloxacin was an effective and welltolerated treatment for severe RTI that had the advantages of broad in vitro antibacterial activity, twice-daily dosing, and sequential availability in an intravenous and oral formulation. (Chest 1989; 96:528-37) showed AND METHODS Patients hospitalized at Nassau County Medical Center between and June 1988 for community-acquired, nursinghome-acquired, hospital-acquired (more than 72 hours of hospitalization) bacterial respiratory tract infections were enrolled in the study. Bacterial lower respiratory tract infection was defined as January 1987 presumedifpatients fever over hadcompatible 37.2#{176}C,total clinical white blood cell features count which over included 10,000/cu mm, and productive cough with purulent sputum, or proven if patients had, in addition, a positive sputum culture from a sputum which on Cram stain had less than 25 squamous epithelial cells and 25 or under attrac- more killing neutrophils considered per to be low-power suitable field. All for intravenous these patients antimicrobial were treatment. of the 140 patients had normal chest roentgenogram; remaining 129 patients had roentgenographic findings ranging bronchopneumonia to multilobar pneumonia. All patients the from Eleven For and that editorial see page 453 In vitro pharmacokinetics. ciprofloxacin Gram-negative, well as organisms comment is active studies have shown against Gram-positive, and multi-drug-resistant such as Chlamydia, and Legionella.25 We have previously results of a prospective, double-blind, assess the safety and efficacy of oral bacteria, Mycobacteria, this study, we report our results with the informed clinical features as dl, group. ofage, Antibiotic comparison of sequential intravenous/oral ciprofloxacin with intravenous ceftazidime in the treatment of hospitalized patients with lower respiratory tract infections. venous 528 were excluded findings) included if they were if their was more condition was gave compatible were value psychiatric had x-ray result creatinine and an in the under 18 2 mg/ than hemodynanii- disease. administered ceftazidime, minimum in randomized a sequential code. One manner group with received a intra- a day, except for five patients day; and the control group received 1 to 2 g two to three times a day intravenously. A of five days of therapy was required for evaluation. No ciprofloxacin, 200 300 mg mg twice other patient received as the control drug that ofciprofloxacin. antibiotics parenteral community-acquired twice a chosen prescribed Medical had who Administration received matched 0From the Department of Medicine, Nassau County Center, East Meadow, NY. tProfessor of Medicine. fllesearch Fellow. Manuscript received July 5; revision accepted January 4. Reprint requests: Dt Khan, Department of Medicine, County Medical Center, East Meadou NY 11554 were and or they computer-generated, who stain serum to quinolones, cally unstable Antibiotics In Patients patients abnormal Cram pregnant, allergic Those cough, sputum presumed years consent. (fever, unsatisfactory reported on the clinical trial to ciprofloxacin in comparison with those of ampicillin in the treatment of mild to moderate respiratory tract infections.6 written concomitanfly. because In addition, antimicrobial and its agent hospital-acquired in Ceftazidime vitro it was spectrum the for the lower most was closely commonly treatment of both respiratory tract infections. Clinical Monitoring Nassau Laboratory complete tests, blood Treatment cell including count, of Serious liver were Bacterial Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 and performed renal before function and after tests and therapy. Respiratory Tract Infections (Khan, Besir) and Pre-enroliment patients. Serum receiving that drug reaction; fever, cough, follow-up drug. a daily done in 21 were monitored daily ofthe physical examination production on all suction were Only specimens and 25 or more mented was performed for adverse sputum or sputum obtained from all on all expectorated containing less than per low-power obtained patients. sputum 25 squamous were hours. incubated Isolates Disk inoculated blood, identified isolates, pretive zone using criteria for Kirby-Bauer ciprofloxacin inhibitory resistant susceptible, 21 mm concentrations 1-In of pneumoniae E Coil Enterobacter Citrobacter 1 5 3 2 13 12 6 6 9 5 5 Bacterial (p.g/ml) Range Mean S .008-.5 (.059) 38 17 .06-1 (.378) 23 - 5 .015-. (.04) 5 - - - 2 .015-25 (.133) 4 - - 15 - 10 .25-1 .5-2 (.55) (1.75) 11 12 - 10 .25-2 (1.1) 10 - 4 .015-1 (.269) 5 - - - 2 .03-06 (.045) 4 - - 3 .25-4 (1.58) 3 - - (.076) 1 - 1 1 - 1 2 - 5 - - 2 2 - - 2 .03-. Morganella 2 2 - - 2 .008-125 2 2 - - 1 .25 (.067) (.25) 5 4 - - 3 .06-4 (1.52) 1 0Total number of isolates. of MICs. number One strain liquifaciens. ofeach ofthe following: 125 4 1 2 - (.257) (.103) (7.3) (2.03) (21.33) (.238) (.475) (.405) (.5) 4-8 . (6.67) 125-64 1-32 (32.06) (16.5) 16 - 1 (16) 8-16 (13.33) 118t 170* tTotal (49) - 2 Mean (3.4) - 9 Range 4-64 .06-.5 .006-125 .25-32 .06-4 8-64 .006-1 .125-2 .06-1 .5 6 3 Diffusion 3 (.018) Acinetobacter anitratus Serratia marceseus Inhibitory (.804) .008-03 - 2 (g/ml) .06-8 3 5 or .06-8 - 1 was 1 - 1 - 4 Pseudomonas stutzeri 9Other Gram-negatives - R - 4 morgani I 26 125 failure . - - to of infection by Agar - 12 - isolates Concentration (Kirby-Bauer) . . 5 stuarti as Stan- of previously Clinical MIC (.057) 6 of Minimum .015-125 5 criteria Ceftazidime 9 12 mirabilis MIC Strains 1 - p.g/ml Laboratory and symptoms - 3 Providencia of signs - 9 1.0 intermediate disappearance 2 22 than interpretive of infection. (1.67) 12 Ivteus and as the symptoms 1-2 22 1.0 p.g/ml for resistant susceptibility 4 aureus more Clinical - pneumoniae sp and No.of R - jig/mI MIC Therapy as the continuation Testing-Ciprofloxacin - Strep strep and the were 2.0 was tentative considered on categorize was defined cure signs defined MIC - Staph 3-Hemolytic breakpoints Sensitivity 23 were were Committee ofAntibiotic A clinical were . 9 to Ciprofloxacin The than values p.g/ml Sensitivity 38 sp MIC National used more MIC to 2.0 The the and CEFF 25 sp which growth. plates. of antibiotic with ciprofloxacin therapy Antibiotic 38 maltophilia were Evaluation zone antibiotics I inoculated of antibiotic powder. CIPRO S were concentration ofvisible Antibiotic Isolates the with ftaz’ inter- (Kirby-Bauer) Hemophilus sp PS aeruginosa for series lowest standard isolates or equal documented No.of by and inter- or less, Vitro by dards or more. (MICs) Strains detailed in each as the for systemic for susceptible in susceptibility. performed Interpretive 15 mm outlined Plates 3 included defined a laboratory but less than 18 to 24 Standard 2 ofthe was no evidence as or less methods.#{176}’#{176} was was there breakpoints for were value supplied supple- for described technique.” were and dioxide were Table Kieb bacteria MIC at which cells agar dilutions as Standards. The agar, and MacConkey carbon for ceftazidime for ceftazidime 16 to 20 mm, Minimal testing the criteria soy chocolate by previously susceptibility on all mediate, sheep trypticase at 35#{176}C in 5 percent were diffusion onto technique Laboratory by isolates. were dilution Clinical with a multipoint replicator designed to deliver a 1 p.1 inoculum containing approximately 10 organisms. The plates were read at 24 and 48 hours. A control plate without antibiotics was inoculated before and after each antibiotic series, and appropriate quality Gram accepted agar for the use oftwofold specimens. epithelial field the Committee of and was maintained. neutrophils with 5 percent and by National analysis.’ Specimens Ps determined patients control expectorated smears size were monitored Methods tracheal-bronchial agar films were record and sputum Spontaneously culture x-ray levels All patients and Microbiologic stain chest theophylline CDC-M6, Achroinohacter xylosoxidaris. Pseudonzonas pseudoakaligenes. Bordetella Serratia bronchosepta, lnterpretatu)n: 1. Three 2. The 3. Eight 4. Three 5. Four strains shoved in vitro resistance MICc of Cipro for Gram negatives, OUt often out offour out of five strains strains strains to Cipro ofpneumococci of Pseudonionas of enterohacter 6. Two strains of Staph aureus S = sensitive; I intermediate; were R (1.77%) were tested ofintermediate were maltophilia aerogenes resistant compared in general, to Ceft lower tested were (MIC resistant more to 14 strains than those sensitivity were resistant in the for Gram to Cipro to Ceft Ceft positive (MIC (8.24%). group bacteria. (MIC of2 g/ml). more than 64). to Ceft. than 64) and nine strains were of intermediate sensitivity (MIC 16). resistant. CHEST Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 I 96 I 3 I SEPTEMBER, 1989 529 Table 2-Characteristics ofIztiente with in Whom Pneumonia Ciprofloxacin Regimen Failed Cipro, Dose, Severity Patient of No. Age/Sex Diagnosis 38 55/M Pneumonia Underlying Disease Infecting Infection Chronic Cipro MIC pg/ml Route and Duration Not 200 Organisms Severe No pathogens schizophrenia done isolated mg Comments IV Continuing x 2 x 3 #{189} and days fever, respiratory symptoms. Outcome: responded to benzyl penicillin. 46 43/M Pneumonia Alcohol abuse, addiction, in ‘85, Staph aureus Moderate .5/S drug intravenous HIV+ 200 mg IV x 2 x 3 Worsening days and cryptococcal meningitis of clinical signs of infection switched to Bactrim, in ‘85 erytliromycin, nafacillin and B amphotericin Outcome: 128 73/F Pneumonia Recurrent Enterobacter P aeruginosa Severe episodes ofpneumonia, CVA, aemgenes .03/S .25/S died. 200 g IV Patient deteriorated x 2 x 3 #{189}and WBC increased days to 28.9; switched to meziocillin and seizure disorder, urinary tract infection gentamycin. Outcome: died patient day of on 4th therapy. 133 34/M Pneumonia . Severe . . No pathogens isolated Not done 200 g IV Persistence x 2x 5 days of signs and symptoms infection. Pneumocystis of carnii pneumonia diagnosed by bronchoscopy and switched to IV No risk for AIDS. Bactrim. factors Outcome: recovered. worsening defined of signs as the Bacteriologic pathogen sputum analysis, and symptoms. elimination failure Bacteriologic ofpretreatment was defined eradication pathogens as persistence of was from sputum. the original of a new pathogen on posttreatment cultures. The chi-square test was used in the statistical and a p value ofless than 0.05 was considered statistically and/or isolation significant. RESULTS Ofthe 140 patients treated, 87 of these patients produced listed in Table 1. The 18 ciprofloxacin who were following five days group and ten in the ceftazidime not evaluable were eliminated reasons: failure (14), confirmation (two), endocarditis this report is based patients There with documented were 68 men and of 58 years (range 21 group) for the to take the drug for at least ofother diagnosis-tuber- culosis Thus, 530 122 were evaluable and 170 bacterial isolates as patients (eight in the (one), meningitis on the remaining respiratory 54 women to 95 years). (one). 122 tract infections. with a mean age Sixty-six patients received ciprofloxacin idime for a mean and five intravenous days and duration 56 patients received of six days of oral ciprofloxacin, ceftazidime, respectively. significant difference groups in age, gender, between admission and therapy. In the 11 patients seven in ciprofloxacin and group, the bacterial isolates rable and Pseudomonas included species one and no pathogens were ing of no in five, aureus isolated in three isolates was found Efficacy A clinical cure was achieved in the proven group (91 percent) group days was with acute four in the were compa- Hemophilus influenza in two, Staphylococcus patients. Similar pattern ofbacterial in the patients with pneumonia. Clinical seven There these two patient diagnosis, or length of antibiotic bronchitis, ceftazidime in ceftaz- of intravenous ciprofloxacin (90 percent). aid This in 42 of the 46 patients with patients receiv- 18 of the 20 in the was not statistically Treatment of Serious Bacterial Respiratory Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 presumed significant Tract Infections (Khan, Basir) Table 3-Characterietica ofPatients with in Whom Pneumonia Ceftazidime Regimen Failed Cell, Severity Dose, of Patient No. 14 Age/Sex Diagnosis 34i’M Pneumonia Underlying Disease Infecting Infection None Severe Cell Organisms Strep MIC Route g/ml pneumoniae and Duration .25/S ig X Comments 3 x 1 day Worsening fever constitutional chest and and symptoms. Outcome: responded to erythromycin. 23 36,’M Pneumonia Seizure disorder, IVDA, Severe No pathogens isolated alcohol 2g x 3 x 6 Persistence days and of fever signs and symptoms abuse of chest infection. Responded to and penicillin gentamycin. 58 95/M Pneumonia COPD, colon cancer, Alzheimer’s disease, Severe partial Strep pneumoniae, Staph aureus .25/S ig x 3 x Worsening 10 days signs of clinical and symptoms with increasing superinfection WBC; colectomy changed penicillin to and gentamycin. Outcome: pneumonia resolved. 139 79fF Pneumonia UT! Recurrent Severe Ps aeruginosa 8/S ig After with indwelling IV x 3 x response catheter, 14 days ofceftazidime, Mzheimers to 14 days she deteriorated disease, clinically and with switched to in ‘77 naficillin, dementia, breast initial cancer mastectomy was and mezlocillin gentamycin. Outcome: 2 days 140 861M Pneumonia Colonic polyps colonoscopy Severe with Hemophilus influenzae . 125/S and polypectomy barium died ig Worsening signs IV x 3 x 6 symptoms with days fever, by diverticulosis She later. enema and increased WBC and worsening chest x-ray. Died while on protocol. Presumed death: cause of acute myocardial infarction. from the clinical cure rate obtained with 38 out of 42 in the proven group (90 out of 14 in the presumed group (85 of the patients enrolled were adult to a tertiary care county hospital respiratory tract infection considered severity antibiotic elderly necessitating therapy. who also hospitalization A majority had significant ceftazidime- marizes percent) and 12 percent). All 122 patients referred for treatment of to be of a and parenteral of the patients comorbidities-dia- were betes, hypertension, ethanol abuse, etc. A clinical and bacteriologic response of over 90 percent in both ciprofloxacin and ceftazidime treated patients in this group of patients is impressive. Tables 2 and 3 sum- the clinical patients in whom total of 66 patients and bacteriologic features either regimen failed. in the ciprofloxacin-treated Four of the out of a group failed therapy. Two patients (46 and 133) had respiratory infection in a background of HIV disease. One patient (128) was a failure. This 73-year-old man had seizure disorder, recurrent episodes of pneumonia, and a polymicrobial Gram-negative tion. A fourth patient responded to penicillin (38) had therapy. respiratory in the ceftazidime group failed therapy. (14 and 58) had S pneumonia which penicillin. One (23) had no pathogens CHEST Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 infec- no pathogens and he Five ofthe 56 patients I 96 I 3 I Two patients responded to and he re- SEPTEMBER, 1989 531 sponded to alternate 140), failed therapy. both elderly ceftazidime with therapy. Two patients multiple (139 medical and ation of the received Bacteriologic A total Susceptibility of 170 bacterial isolates were recovered from pretreatment sputum cultures. All these isolates showed in vitro sensitivity to ciprofloxacin, except for four isolates (one Pseudomonas aeruginosa, one Acinetobacter, 3-hemolytic xylosoxidans one Achromobacter strep sp which diffusion, but was was sensitive the isolates, ceftazidime except (three Pseudomonas aeruginosa, by the for 13, MIC showed Pseudomonas four two and by resistant one disc method). All sensitivity to maltophilia, one Enterobacter aero genes, morganii, one S mar- S aureus, one Morganella one Citrobacter diversus). Twenty-two patients in the ciprofloxacin and 18 patients in the ceftazidime treatment group had more than one isolate in their sputum culture . This sterilization of sputums Microbiologic Results in one patient; ceftazidime, not observe any tween ciprofloxacin who received following patient adverse clinically significant and theophylline both effects drugs in this interaction bein the 21 patients therapy. Superinfrctions Three of developed tiple 66 patients underlying three in superinfection. medical eventually died 56 patients the remaining patients are the ciprofloxacin All three patients problems and from the group had two mulof the superinfection. in the ceftazidime one died from this superinfection; did not appear to in either group. the another cramps and diarrhea Of the 56 patients who were noted: seizures (one), hallucinations (one), progressive decrease in WBC (one). Ceftazidime was not discontinued in any of these three patients. We did the cescens, pretreatment influence the drug developed transient abdominal while receiving ciprofloxacin. problems, of Six group developed superinfection and five recovered. The summarized in Tables highlights 4 and 5. of these DISCUSSION Table Oral 1 summarizes recovered in the the 87 type and patients, number as of isolates well as the disk tory susceptibility for these isolates and the available values of 118 isolates. Significantly more isolates MIC were results susceptible determined as MIC tory values to ciprofloxacin by the diffusion reveal that than to ceftazidime technique. The ciprofloxacin vitro than ceftazidime negative bacteria tested. was more active in against the strains of GramAll nine of the Enterobacter isolates were susceptible to ciprofloxacin at a concentration equal to or less than 0.06 pg/ml, while four of these nine isolates were resistant to ceftazidime. The MIC values aeruginosa Ciprofloxacin isolates of ciprofloxacin species range was more MIC of Streptococcus isolates susceptible susceptible to ciprofloxacin. in the ciprofloxacin group in the ceftazidime group the end of the treatment. antibiotic ated by both encountered who 532 All the isolates were with ceftazidime 12 of 12 of the and nine of 12 Three of the 46 patients and three of the 41 patients had organisms persisting at Reactions Both received regimens patient were groups. skin rash ciprofloxacin, were of the generally well-toler- The common in five of the side effects 66 patients necessitating discontinu- been found of various infection. to be forms Contrary to quite of respira- the favorable problems were due to resistance or recurrence of streptococcal pneumonia infection or failure to eradicate Pseudomonas. We also reported on a large, prospective, double-blind, we compared ciprofloxacin, ampicillin in the treatment tract randomized study where 750 mg twice a day, with of bacterial respiratory Eight-seven clinical bacterial (p value against has treatment found by Gleedhill et al and Kobayashi,’’5 16 in his study of oral ciprofloxacin for respiratract infection, reported several problems; most ceftazidime isolates of Staphylococcus aureus to ciprofloxacin. Ceftazidime was ciprofloxacin against the 12 isolates to tract ciprofloxacin (MIC less than 1 pg/ml), to or less than .008 pg/ml pneumoniae, in the the Pseudomonas .06 to 1 .0 jig/ml. than influenzae. to ciprofloxacin range equal to 0.5 p.g/ml. The tested were sensitive more effective than Adverse from active ofHemophilus susceptible with an for ciprofloxacin effective effective as or oral ampicillin patients cure rate . Significantly isolates were susceptible of less than 0.05), and significantly tion than higher ampicillin Ciprofloxacin tivity with showed particularly trations for was well tolerated; received ampicillin. Ciprofloxacin and produced a 98 rate either was as percent more pretreatment to ciprofloxacin ciprofloxacin had a of sputum bacterial eradica(p values of less than 0.05). broad in vitro antibacterial aclow minimal inhibitory concen- Gram-negative there organisms. were few adverse Ciprofloxacin effects, and patients had a significantly lower incidence of diarrhea with ciprofloxacin than with ampicillin (p value of less than and that 0.05). We felt that ciprofloxacin was an effective well tolerated treatment for bacterial bronchitis had the advantage of broad in vitro antibacterial activity and ciprofloxacin, twice we daily dosing.6 did encounter ciprofloxacin and theophylline, larly seen in elderly patients term theophylline, and who and this was particuwho had been on longreceived the total dose of Treatment of Serious Bacterial Respiratory Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 In the study of oral interaction between Tract Infections (Khan, Basir) Table 4-Characteristics with ofPatients on Ceftazidime Pneumonia Who Developed Superinfection Cell, Severity Patient No. Age/Sex Diagnosis Underlying Disease 43 86/F Pneumonia Carcinoma aureus Staph of Infecting Infection Organisms of P Dose, Cell MIC Severe uterus, aeruginosa hysterectomy Route p.g/ml and Duration Comments 8/S lg IVQ8 Developed 21S 10 days bacteremic 1965, anemia, chronic diarrhea of unknown etiology 41 66/M Acute Chronic superinfection. Outcome: Severe bronchitis, H parainfluenzae .03/S lg IVPBQ8 emphysema exacerbation Strep frcalLs in died. Improvement. 8 days Developed of COPD with superinfection Pseudomonas aeruginosa, PS maltophila. Outcome: recovered. 48 23/M Pneumonia None Severe No pathogens 2g IVPBQ8 5 days - Improvement. Developed superinfection with influenzae. H Outcome: recovered. 52 56t’M 47/F 32 S/P aortofemoral Pneumonia Pneumonia bypass graft, alcohol abuse Sarcoidosis No pathogens Moderate H - Parainfluenzae .008/S during diagnosed current Moderate ig IVPQ8 6 days Improvement. Superinfection with E coli. Outcome: recovered. ig IVPBQ8 Improvement. Candida 4 days albicans superinfection. admission for pneumonia 58 95/M Pneumonia COPD, cancer colon with Severe pneumonia Strep 10 days lg IVPBQ6 Worsening right signs symptoms with increased hemicolectomy, Alzheimer’s of clinical and disease WBC, Staph aureus superinfection sputum. in Switched to and penicillin gentamycin. Outcome: pneumonia resolved. 1 ,500 mg ciprofloxacin a We have on the effectiveness ment of 14 adult of oral ciprofloxacin patients with bacterial These received 14 patients also reported treatment bronchitis in the treatpneumonia. 750 mg of ciprofloxacin for a duration of 11.5 days. Thirteen had underlying lung disease, and 12 of the 14 (86 percent) were cured. All the isolates, which included streptococcal pneumonia in five, Hemophilus floxacin and only in four, two were pathogens sensitive persisted this of whom 19 had bacterial isolates from sputum blood, and all patients improved in this study. Based evident on an analysis of the that oral ciprofloxacin or reported studies, it is is effective in the infection, both Fibrosis ment ciprofloxacin of patients floxacin’s special nosa, S aureus, Ernst et al also reported on the effectiveness mg twice a day in 25 patients with pneumonia, 19 of 750 tract A number of studies have reported on the effectiveness of oral ciprofloxacin in the treatment of bacterial infection in cystic fibrosis.21 Oral to ciproin Cystic of bacterial respiratory as well as pneumonia. is of special with cystic activity against and Hemophilus pathogens which, tions in patients lies in safety, oral tient use. Some not with interest fibrosis influenzae, bioavailability, studies show Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 I 96 I 3 I and the cause The treat- of cipro- Pseudomonas uncommonly, cystic fibrosis. CHEST in the in view the aerugithree exacerbaattraction possible outpaemergence of SEPTEMBER, 1989 533 Sequential Intravenous-Oral Administration of Ciprofloxacin vs Ceftazidime in Serious Bacterial Respiratory Tract lnfections* Faroque A. Khan, MB., F.C.C.P;t and Riyad M.D4 Basir, The ethcacy and safety of sequential intravenous/oral ciprofloxacin in rnoderate to severe respiratory tract infections (RTI) were cornpared with those of ceftazidirne in a prospective clinical trial. Sixty-six patients received IN ciprofloxacin (200 to 300 rng twice daily), followed by oral rng twice daily). Fifty-six patients received intravenous ceftazidime (1 to 2 g two to three times daily). Ciprofloxacin was as effective as ceftazidime and produced a 91 percent clinical cure rate. Signfficantly more pretreatment bacterial isolates were susceptible to ciprofloxacin, and ciprofloxacin had a significantly higher rate of sputum bacterial eradication than did ceftazidime. Ciprofloxacin ciprofloxacin(500 T he recent introduction represents a major of advance potent in the antibiotics, allowing for the first therapy of serious infections caused tant bacteria. tive in terms compounds ciprofloxacin of its potency, rapidity RTlrespiratory available the most ofbacterial infections; tract of oral resis- MIC minimal inhibitory concentration PATIENTS development time effective by multiply currently is among broad minimal low 4-quinolones Four fluoroquinolones, as follow, are in various stages of approval and clinical investigation in the United States norfioxacin, ciprofloxacin, enoxacin, and ofloxacm.’ Of the investigation, in vitro antibacterial activity with particularly inhibitory concentrations for Gram-negative organisms. Ciprofloxacin was well tolerated; there were few adverse effects. Ciprofloxacin was an effective and welltolerated treatment for severe RTI that had the advantages of broad in vitro antibacterial activity, twice-daily dosing, and sequential availability in an intravenous and oral formulation. (Chest 1989; 96:528-37) showed AND METHODS Patients hospitalized at Nassau County Medical Center between and June 1988 for community-acquired, nursinghome-acquired, hospital-acquired (more than 72 hours of hospitalization) bacterial respiratory tract infections were enrolled in the study. Bacterial lower respiratory tract infection was defined as January 1987 presumedifpatients fever over hadcompatible 37.2#{176}C,total clinical white blood cell features count which over included 10,000/cu mm, and productive cough with purulent sputum, or proven if patients had, in addition, a positive sputum culture from a sputum which on Cram stain had less than 25 squamous epithelial cells and 25 or under attrac- more killing neutrophils considered per to be low-power suitable field. All for intravenous these patients antimicrobial were treatment. of the 140 patients had normal chest roentgenogram; remaining 129 patients had roentgenographic findings ranging bronchopneumonia to multilobar pneumonia. All patients the from Eleven For and that editorial see page 453 In vitro pharmacokinetics. ciprofloxacin Gram-negative, well as organisms comment is active studies have shown against Gram-positive, and multi-drug-resistant such as Chlamydia, and Legionella.25 We have previously results of a prospective, double-blind, assess the safety and efficacy of oral bacteria, Mycobacteria, this study, we report our results with the informed clinical features as dl, group. ofage, Antibiotic comparison of sequential intravenous/oral ciprofloxacin with intravenous ceftazidime in the treatment of hospitalized patients with lower respiratory tract infections. venous 528 were excluded findings) included if they were if their was more condition was gave compatible were value psychiatric had x-ray result creatinine and an in the under 18 2 mg/ than hemodynanii- disease. administered ceftazidime, minimum in randomized a sequential code. One manner group with received a intra- a day, except for five patients day; and the control group received 1 to 2 g two to three times a day intravenously. A of five days of therapy was required for evaluation. No ciprofloxacin, 200 300 mg mg twice other patient received as the control drug that ofciprofloxacin. antibiotics parenteral community-acquired twice a chosen prescribed Medical had who Administration received matched 0From the Department of Medicine, Nassau County Center, East Meadow, NY. tProfessor of Medicine. fllesearch Fellow. Manuscript received July 5; revision accepted January 4. Reprint requests: Dt Khan, Department of Medicine, County Medical Center, East Meadou NY 11554 were and or they computer-generated, who stain serum to quinolones, cally unstable Antibiotics In Patients patients abnormal Cram pregnant, allergic Those cough, sputum presumed years consent. (fever, unsatisfactory reported on the clinical trial to ciprofloxacin in comparison with those of ampicillin in the treatment of mild to moderate respiratory tract infections.6 written concomitanfly. because In addition, antimicrobial and its agent hospital-acquired in Ceftazidime vitro it was spectrum the for the lower most was closely commonly treatment of both respiratory tract infections. Clinical Monitoring Nassau Laboratory complete tests, blood Treatment cell including count, of Serious liver were Bacterial Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 and performed renal before function and after tests and therapy. Respiratory Tract Infections (Khan, Besir) not encounter and theophylline. any dose-related 1,000 interaction We now and feel encountered mg ofciprofloxacin The in the ciprofloxacin that this interaction only when observed group and group more is not in the three the six patients surprising. Potent bial therapy in elderly, debilitated, been associated with superinfection ganisms, and the present study finding.27 The role of ciprofloxacin infections by Gram-positive than antimicrohas orthis treatment particularly Streptococcus pneumonia, had not been fully lished, the doubt arising from the laboratory vation of high MICs. We have also observed of estabobserhigh are perhaps related to the ciprofloxacin in penetrating four quinolones, enoxacin, ofloxacin, have the bronchial in the lung, sputum. received Ten over unique properties successive et oral period. 2.2 ± 1 .3 mg(L at two mgfL .6 ± 0.4 The hours ratio was the same ciprofloxacin al dose samples a 12-hour of penetrating studied of 500 of the 21 mg sputum The serum hours and at six hours. into The the patients who ciprofloxacin. were levels collected peaked decreased slowly corresponding to bronchial author into fluid at six hours. reported the lung distribution also achieved on the parenchymal a peaked ratio of 300 to 900 a high concentration pleural level administration ofciprofloxacin after 24 hours.m Schlenkhoff levels In another penetration tissue. to nine hours at two study, of Intra- hours before tissue showed that the penetration lung tissue is marked with sampling and the 1. 1 to 17.32 mg/g. into bronchial to be quite mucosa variable. low, the The bronchial studied plasma 500 mg each, average mucosa mg The bronchial levels. limed after the final penetration levels equilibrium dose ofthe are very ratio mucosa was absolute drug was found levels are high. Marlin of enoxacin in patients established. bronchial of enoxacin mucosal at three, and the high-pressure beafter They mucosal also concentra- was given biopsies and four, or five samples liquid were samples were in six patients assayed for chromatography. patients was 117 (47.8 pg/g); tration was 3. 1 (1 . 1 pg/ml), 46.8. These data suggest into the enoxacin Marlin respiratory mucosa, tract. These and by et al32 mucosa of dose. for all the mean plasma and the mean the possibility bronchial of 400 a to all 18 patients. plasma hours concluded that equilibrium between bronchial and plasma is achieved within three hours The mean bronchial mucosal concentration concenratio was of active avid tissue may account for quinolones in the findings support the use ofciprofloxacin in severe chest infections and help to dispel the earlier apprehension about the use of the medication, particularly in patients who have streptococcal pneumonia infections. It thus appears that the quinolones far exceed all the other known and studied antibiotics in their unique property of tissue penetration, particularly into the respiratory tract. This unique feature helps to understand with the apparent ciprofloxacin infection exceeding the corresponding serum concentration. These authors found a lung-serum ratio of 195 to 753 percent at one hour, 545 to 1044 percent in two hours, bron- 500 was 161 percent but Although the sputum the distribution and bronchial the Bronchial obtained infection. results received tion achieved with the in vitro bacterial activity enoxacin. Eighteen patients received enoxacin, mg twice daily, for four days; on the fifth morning, after of ciprofloxacin into the the tissue level significantly percent the dose. In the 15 patients, the serum levels ranged from 1 to 9 .Lg/L while the bronchial levels ranged between pg/ml on 14 patients who had been premedicated with 100 mg intravenous ciprofloxacin prior to thoracic surgery. Four groups received injections one, two, three, and four had ciprofloxacin twice daily for four days. biopsy samples were assayed for the biopsies and venipunctures were done bronchial given and surgical The lung tissue serum level with a and averages 0.9 et al#{176} reported who binding to the tissue macromolecules the extensive accumulation of the percent. Ciprofloxacin in the pleural fluid six 15 patients transport bron- to 1000 800 et ala’ studied at .5 mg(L at two hours and they stayed six hours with a range of 0.5 to 0.8 mgfL. 0. 19 to 0.95 and to were of serum in compared of the high concentrations mucosa, and in venous 100 mg ciprofloxacin was samples of the lung were obtained. level exceeded the corresponding with property level hours, Honeybourne distribution tissue compartments. The pefloxacin, ciprofloxacin, lining and achieving in the bronchial Bergogne a single chial levels stable until unique in three hours. et al32 tween MICs in our previous study and the study being reported here. However, our clinical results in the seven patients who received ciprofloiacin indicated that the high MICs did not interfere with the action of the drug. The reasons for this interesting observation in four chial patients in the sick people with various also confirms and the bacteria, percent 675 is is used. superinfection ciprofloxacin ceftazidime between Almost have paradox in the in the treatment 100 been patients treated results obtained of S pneumonia with with S pneumonia ciprofloxacin, a clinical cure rate of over 95 percent the relatively high MICs in these patients. high lung achieved marginal explain parenchymal with MIC the and ciprofloxacin level against excellent results bronchial apparently S pneumonia reported in with spite of The very tissue levels overcome the and help to by several au- Cost Analysis Intravenous ciprofloxacin CHEST Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21600/ on 05/12/2017 or another I 96 I 3 I SEPTEMBER, comparable 1989 535 intravenous quinolone by federal drug the intravenous However, has, agency, preparation comparable as yet, not and thus, is not cost analysis been approved the market available. oforal cost of IV every eight hours. Ciprofloxacin was mg orally in both mately rable clinical results The daily cost in 11.5 days and both groups. the given every groups to 24 mise with ciprofloxacin, have been realized in clinical to the ofparenteral therapy would storage!preparation/administration, have the on mg ceftazidime an average, followed by twice daily. at seven various The Nassau daily costs etc), and ther that ciprofloxacin found useful in the will play would also respiratory tract infections abusers who have a higher be of use in the in diabetics propensity treatment floxacin 536 After becomes the intravenous available, it will be an attractive Chemother 1986; N, potential significant. like to would quinolones. Mayo thank Clin Antimicrob Proc the 1987; of ciprofioxa- piperazinylAgents Chemo- apy. Kyoto, Japan: 6 Wollschlager CM, Q. V, Afzal J Am S, Khan Raoof Med SM. quantitative Bacteriology culture aspirates. RC. Am Medical New ofciprofloxacin respiratory of bacterial Finegold transtracheal JJ, LaBombardi Guarneri study versus tract infections. 82:164-68 1987; JC, FA, comparative in treatment Bartlett activity of LegiOnelIa. In: of Chemother- vitro 1985:37-74 Controlled, ampicihin 29:386-88 Pangon B, et al. in pefloxacin and ofloxacin against of the 14th International Congress Proceedings wash technique Rev Respir Dis and Sons, microbiology: York: John ofexpectorated and 1978; quality, Wiley sputum compared 10 Lennette E, clinical ofClinical 11 Balows cost and clinical 1974:27 WH, Shadom 4th ed. Washington, DC: AW, Kirby susceptibility testing J 1966; Pathol YH. of the of Manual American of Society 1985 Microbiology, Bauer Clin A, Hausler microbiology. to 117:1019-27 9 Goldstein J, Cuarneri JJ, DellaLatta P, Scherer J. Use auto microbic and enteric-tek systems for identification Enterobacteriaceae. J Clin Microbiol 1982; 15:654-59 of than the use in the anaerobic of cipro- The are 25:518-21 relevance. and alcohol for developing formulation authors derivatives. A, Desplaces 8 Bartlett of bacterial Gram-negative respiratory tract infections general population. Ciprofloxacin has no treatment of aspiration pneumonia and infections. Agents a exacerbations ofpatients with COPD and cystic fibrosis, and the agent will play a particularly useful role in the treatment of respiratory tract infections in the elderly patients who often have Gram-negative organisms and Staphylococcus respiratory tract infections. Ciprofloxacin less. regimen AJ. The quinolone 1984; 5 Bure is respiratory tract oral ciprofloxacin treatment costs The available. 3 Heessen FWA, Muytjens L. in vitro activities of ciprofloxacin, norfioxacin, pipemidic acid, cinoxacin, and nalidixic acid against Chlamydia trachomatis. Antimicrob Agents Chemother 1984; 25:123-24 4 Fenlon CH, Cynamon MH. Comparative in vitro activities of ciprofloxacin and other 4-quinolones against Mycobacterium tuberculosis and Mycobacterium intraceilulare. Antimicrob intravenous Center formulation this type of a regimen third-generation ceph- County Medical Center for their help in Drs. K. Szabo, J. J. Cuarneri and S. Chadda Wright ciprofloxacin, 500 mg twice daily in the ceftazidime one extra day of cost was $4, 144 (56 major role in the treatment ofvarious infections in the years to come. The been of regimen oral REFERENCES RC, with we feel an oral sequential thepatients, substituted patients Medical the of this to the 62:1007-12 2 Van Caekenberghe DL, Pattyn SR. in vitro activity cia compared with those of other new fluorinated saved as wellsupplies (solu- cost County and over and, thus, this would be would have both a se- for the microbiologic evaluations, and Ms. A. Borg for preparation ofthe manuscript. Miles Pharmaceuticals supplied the ciprofloxacin; ceftazidime was supplied by U.S. Pharmacopeial Convention, Inc. 7 patients X $74). In conclusion, and savings enrolling days of intravenous currently available approximately $78i’day while oral ciprofloxacin costs $4/day. Thus, group of 56 patients who received intravenous ceftazidime , the extra has intravenous ACKNOWLEDGMENTS: house staff of Nassau broad spectrum oral antibiotics for a variable period of time. The 66 ciprofloxacin-treated patients, on an average, received six days ofintravenous ciprofloxacin, followed by an average offive days oforal ciprofloxacin, 500 quential infection S aureus and clinical condition be switched alosporin “hidden” been can were compaof cefotaxime tions, tubing, etc), complications (phlebitis, inconvenience (nurse, patient, fami1y). In our study, the 56 ceftazidime-treated received, ceftazidime, the patients ofthe same drug antimicrobial which cost tract organisms, After the Our study demonstrates that works as effectively as a potent a total savings of without any compro- saved, respiratory formulation the first 1 Walker dollars for Gram-negative infections. improves, for those hospitalized suitable for parenteral 12 hours. The was approxi- efficacy. In addition therapy considered therapy, by polymicrobial caused totaled $59 per day compared to approximately $9.00 per day for ciprofloxacin, and the cost savings of $50! day or $579!total course oftherapy could be achieved. If the 32 patients who had received cefotaxime had been treated $18,000 could antimicrobial who are antimicrobial ciprofloxa- cm with other conventional therapies is available. In one study, IV cefotaxime was compared with oral ciprofloxacin in the treatment of soft-tissue infections. 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