Treatment of serious infections with intravenous ciprofloxacin

Treatment of Serious Infections with Intravenous Ciprofloxacin JACQUES MODAI,

M.D., THE

FRENCH MULTICENTER STUDY GROUP*

Paris, France

lthough the efficacy of oral ciprofloxacin in the A treatment of a variety of infections caused by &am-negative bacilli and staphylococci has previously

Ninetv-four uatients. 61 men and 33 women with a me& age 6f 54 ye&, were treated with intravenous ciprofloxacin. Eighty-one patients (86 percent) were in serious or fair condition. Pathogens included Enterobacteriaceae (74 patients), Pseudomonas sp. (23 patients), other gram-negative bacilli (five patients), staphylococci (19 patients), other gram-positive cocci (seven patients), and Rickettsia conorii (five patients). Thirty-eight patients were ,given parenteral therapy (ciprofloxacin at a mean daily dose of 200 mg every 12 hours, mean duration of therapy, nine days). Fifty-six patients were also given ciprofloxacin orally after initial intravenous therapy at a dose of either 500 or 750 mg every 12 hours (mean duration of therapy, 36 days). Another antibiotic was given concomitantly in 25 cases (27 percent). The overall clinical response was 93 percent and the bacteriologic response rate was 84 percent. There was no difference between patients treated by intravenous ciprofloxacin and those treated by intravenous ciprofloxacin followed by oral ciprofloxacin. Favorable responses (resolution of improveme@) were ,observed in 39 of 42 patients (93 percent) with bacteremia, 28 of 30 (93 percent) with uritiary tract infection, 10 of 13 (77 percent) with respiratory tract infection, 11 of 12 (92 percent) with bone and joint infection, three of three (100 percent) with skin and soft-tissue infection, nine of nine (100 percent) with intraabdominal infection, three of three (100 percent) with typhoid fever, and two of two (100 percent) with meningitis. All five patients with R. conorii infections had a response to therapy. The adverse effects were minor and transient. Seven patients experienced clinical adverse effects: pain at the inject& site (three patients), rash (two patients), and headache (2 patients). Serum transaminase levels were increased in 11 patients. Intravenously administered ciprofldxacin or intravenous ciprofloxacin followed by oral ciprofloxacin is a safe and effective therapy for serious infections.

I

been demon.strated, there are situations, such as suspected septicemia, in which it would be preferable to begin therapy with an intravenous agent. This study determined the efficacy and safety of intravenous ciprofloxacin in the treatment of patients hospitalized with serious infection in which the parenteral route is required.

I From the Department of Infectious Diseases, Saint Louis Hospital, Paw, France, Requests for reprints should be addressed to Prof. Jacques Modal, Saint Louis Hospi*A list of the Centers participating in this study ISprovided at the end of this article.

PATIENTS AND METHODS Ten centers (a list of which is provided at the end of this article) participated in the study. There were 114 infections occurring in 94 patients: 61 men and 33 women aged 18 to 83 years (mean age, 54 years). Eighty-one patients (86 percent) were in serious or &itical condition. The clinical diagnosis was confirmed in each case by cultures, radiographic examination, and diagnostic tests appropriate to the infection. One hundred thirty-three pathogens were isolated, but the minimal inhibitory concentration (Table I) was determined in 123 strains only (Figure 1). Thirty-eight patients were treated with ciprofloxatin intravenously (200 mg every 12 hours over 30 minutes). In 56 subsequent patients, therapy was switched to the oral route after seven to 12 days of intravenous therapy, depending on the clinical condition. For oral administration, 500 or 750 mg of ciprofloxacin was given every 12 hours for nine to 90 days, depending on the site of infection. In 25 cases, ciprofloxacin was combined with another antibiotic to increase the bactericidal effect and/or to prevent the emergence of resistant strains: Pseudomonas aeruginosa (11 patients), Stu~hylococcus aureus (five patients)? Serratia marcescens (two patients), Enterobactemaceae (three patients), Escherichia coli (two patients), Klebsiella sp. (one patient), and Citrobacter sp. (one patient). The bacteriologic examination, performed before treatment? consisted of isolation and identification of the organisms and antibiotic sensitivity tests using disks containing 5 pg of ciprofloxacin. The criteria of sensitivity based on the diameters of inhibition were as follows: sensitive, at least 20 mm; intermediate, 19 to 15 mm; resistant, less than 15 mm. The minimal inhibitory concentrations were determined on liquid media and the critical values were: sensitive, less than or equal to 1 pg/ml; resistant, more than 2 pg/ml. Some infections, mainly skin and soft-tissue infections, were polymicrobial; thus, 133 pathogens were isolated, mainly Enterobactemaceae, Pseudomonas, and staphylococci. Most pathogens were inhibited by 1 pgiml or less of ciprofloxacin (Table II). The minimal inhibitory concentration of the two strains of pneumococci isolated was 2 Fglml. Two strains of Enterococcus were resistant (minimal inhibitory concentration, 4 and 8 pg/ml, respectively).

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TABLE I Minimal Inhibitory Concentrations Ciprofloxacin

of Infecting Bacteria and

Number of Isolates Enterobacteriaceae E co/i Proteussp. Klebsiella Enterobacter Serratia Other Pseudomonas sp. Other gramnegative bacilli Staphylococcus sp. Other gram-positive cocci Rickettsia conori I

Ran~;ofJCs

:i

Total

0.008-0.5 0.008-0.25 0.008-0.5 0.008-0.12 0.06-2 0.008-0.5 0.008-l 0.016-0.5 0.12-l 0.124 ND

133*

= minimal inhibitory concentration *Some infections were polymicrobial

MIC

ND

= not determined.

Response to therapy was evaluated from clinical, radiologic, and bacteriologic aspects. The clinical response was evaluated in terms of the improvement in the signs and symptoms of the infection treated and, in every case, in terms of resolution of fever. Bacteriologic cure required elimination of organisms from culture sites during treatment and at follow-up, more than 24 hours after therapy for infections outside the urinary tract.

RESULTS Ten centers participated in the study. Eighty-one patients (86 percent) were in serious or critical condition (52 patients hospitalized in the intensive care unit). There were 114 infections caused by pathogens expected or known to be susceptible to ciprofloxacin. The infections treated (Table II) were predominantly septicemia; urinary tract infections, including 11 complicated infections of the lower urinary tract, 13 cases of pyelonephritis, five cases of prostatitis, and one case of epididymitislorchitis; respiratory tract infections, including 10 cases of bronchopneumonia; osteo-

0.007

O.Olrj

0.03

0.06

0.12

0.25

0.50

1

articular infections, including five cases of osteomyelitis, three cases of septic arthritis, three cases of mediastinitis, and one case of spondylodiscitis; and intraabdominal infections, including five cases of peritonitis, two hepatic abscesses, and two pancreatic fistulae. Initially, ciprofloxacin was administered to all patients by the intravenous route (200 mg every 12 hours over 30 minutes). Thirty-eight patients received the drug only parenterally and continued treatment for a period of seven to 12 days (mean, 8.6 t 5.9 days), depending on the clinical situation and on the site of infection. These patients were the most seriously ill, with one or several organ failures, and all were hospitalized in an intensive care unit. Parenteral therapy was switched to the oral route in 56 patients at a mean dose of ‘750 mg ciprofloxacin given every 12 hours and administered for a mean duration of nine days (respiratory tract and intra-abdominal infections) to three months (prostatitis and osteoarticular infections). The majority (56 patients, i.e., 60 percent) were treated with ciprofloxacin as first-line treatment. The other patients had received another antibiotic prior to administration of ciprofloxacin, which was ineffective due to primary resistance or resistance acquired during treatment. The clinical results observed in 93 evaluable patients are listed in Table III, according to the site of infection. Clinical cure was achieved in 83 eases (74 percent) and improvement occurred in 22 cases (19 percent). The best results were noted in patients with bone and joint infections, urinary tract infections, and septicemia. The differences between patients receiving ciprofloxacin only and those taking ciprofloxacin combined with another antibiotic were not statistically significant, nor were the differences between patients receiving ciprofloxacin by parenteral route only and those in whom therapy was switched to the oral route.

BACTERIOLOGIC RESULTS Ciprofloxacin was administered as a single agent in 69 patients (60 percent). In 25 cases, ciprofloxacin was combined with another antibiotic in order to increase the bactericidal activity, particularly in immunode-

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Figure 1. Number of bacterial strains categorized by minimal inhibitory concentration (ME).

MIC (pg/mL)

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pressed patients, and/or to prevent the emergence of resistant strains: P. aeruginosa (11 cases), S. aurew (five cases), Enterobacter cZoacae (three cases), 5’. marcexens (two cases),,E. coli (two cases), Klebsiella sp. (one case), and Cztrobacter freundii (one case). The choice of the combination antibiotic was made on the basis of the bacteriologic data: aminoglycoside (16 cases), beta-la&am (four cases), vancomycin (three cases), fosfomycin, and rifampin (one case each). The bacteriologic results are listed in Tables IV and V. Eradication was noted in 89 cases (67 percent), with the mean time to sterilization of the specimens being nine days; eradication with reinfection occurred in 22 cases (17 percent); relapse occurred in three cases; and persistence occurred in 11 cases. In eight cases, the bacteriologic results were not determined. The differences between patients receiving ciprofloxaein by parenteral route only and those in whom therapy was switched to the oral route were not statistically significant. Persistence and relapse were noted mainly with P. aeruginosa and S. aureus, but in most cases they were still sensitive to ciprofloxacin, except in six cases (three S. aureus, two P. aeruginosa, one Sewatia). The rate of eradication in septicemia is remarkable in view of the resistance of the responsible micro-organisms to the antibiotics available in this indication. Persistence and reinfection observed in respiratory tract infections are due mainly to grampositive cocci.

ADVERSEEFFECTS Adverse effects considered to be possibly or probably related to intravenous ciprofloxacin were ob-

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TABLE II Infections Treated Infection

Number of Infection Sites

Septicemia Urinary tract infections Respiratory tract infections Osteoarbcular infections Intraabdominal infectrons Skin and sofLtissue infectrons Typhoid fever Meningitis Total

114*

*Some oatients had more than one site of infectlon.

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Clinical Results According to the Site of infection

Septicemia Urinary tract infection Respiratory tract infection Osteoarticular infection SkinisofLtissue infection Intra.abdominal infection Typhoid fever Meningitis

Total (percent)

3 ;i

i 1 -

6

11 2 :

-

2 83(74)

22(19)

8(7)

42 29* I’; i 3 2 113

‘Not evaluable in one case.

TABLE IV Bacteriologic

Results According to the Responsible Pathogen

Microorganism

Total Number of Patients

Eradication

Reinfection

Relapse

54

14 2

3

12

5 -

I!

Enterobacteriaceae Pseudomonas sp. Other gramnegative bacilli Gram.positwe cocci R. conoti

265 5

1: 5

Total (percent)

133

89(67)

22(17)

-

3 (21

Persistence

ND

i-

3 5

i-

-

ll@l

-

8 (6)

1D = not determined.

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TABLE V Bacteriologic

Results According to the Site of Infection

Type of Infection Septicemia Unnary tract Respiratory tract* Osteoaliicular* Skin/soft&sue* Intra.abdominal* Typhoid fever Meningibs Total

Total Number of Patients

42 30 ii

Eradication

Reinfection

32 23

s

i

i

;

i

;

;

114

93

-

Relapse

Persistence

1

12

4

1

1

3

-

-i

T -

2 -

3

11

1

ND

i

-i -

8

ND = Not determined. *Polymicrobial infections.

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treatment, 90 percent of the patients receiving ciprofloxacin had sterile urine as compared with 74 percent Adverse Effects of those receiving mezlocillin; these values were 88 percent and 57 percent, respectively, four weeks Adverse Effect Number (percent) of Patients later. The differences were statistically significant. Helfer et aZ [4] treated 21 patients with urinary tract Patientstreated 94 infections (nine upper urinary tract infections and 11 Patients with adverse effects 1; g,y lower urinary tract infections) with intravenous ciproPatientswith clinical adverse effects Pain at the injection site floxacin 200 mg every 12 hours for at least five days, Skin eruption : followed by 500 mg orally every 12 hours for an addlHeadache tionall0 days: all patients were cured. In 62 evaluable Patients with increased transaminase 1:(11.7, reports of patients with urinary tract infections serum levels treated with intravenous ciprofloxacin (data on file, Bayer AG), a clinically favorable response was noted served in 15 of 94 patients (16 percent). These effects, in 90.3 percent of cases and a bacteriologically favoraconsisting of seven clinical adverse effects and 11 labo- ble response was found in 88.5 percent. ratory abnormalities, are listed in Table VI. TreatIn bone and joint infections (12 cases), the clinical ment was discontinued in only one patient before its response rate was 91 percent and the bacteriologic efficacy could be evaluated, because of an erythema response was 70 percent. Scully and Neu [5] treated and a general feeling of malaise. Mild renal failure oc- six patients who had subacute or chronic osteomyelitis curring during treatment could not be formally attriband three who had septic arthritis. The dosage of uted to ciprofloxacin, and the good renal tolerance of ciprofloxacin was 200 mg intravenously every 12 intravenous ciprofloxacin should be stressed. In most hours for nine to 56 days or 300 mg intravenously cases, these adverse effects occurred at the beginning every 12 hours for seven to 42 days, usually followed of treatment, i.e., during the intravenous phase, and by 750 mg orally every 12 hours for another 21 to 80 they all resolved after discontinuing therapy. Adverse days. Seven patients had complete cure and two treateffects did not appear to be related to the dose admin- ments failed (one patient had a superinfection with istered. No hematologic toxicity was noted. ciprofloxacin-resistant Pseudomonas). In the series reported by Giamarellou and Galanakis [2], nine paCOMMENTS tients with chronic osteomyelitis were treated with In this study the clinical response rate (cure and the dosages described earlier. The pathogen was P. improvement) and the bacteriologic response rate aeruginosa in seven patients and a member of the En(eradication and eradication followed by reinfection) of terobacteriaceae in three. Six patients had clinical ciprofloxacin therapy compared favorably with cure cure and three experienced improvement. Pathogens rates reported in other studies. were eradicated in seven patients and persisted in two In respiratory tract infections (13 cases), the clinical (one was a superinfection with ciprofloxacin-resistant response rate was 7’7 percent and the bacteriologic Pseudomonas). A clinically and a bacteriologically response was 67 percent. The largest series of respirafavorable response was noted in 10 of 11 case reports tory tract infections treated with intravenous cipro- of bone and joint infections (data on file, Bayer AG). floxacin was reported by Chrysanthopoulos et al ill, In septicemia (42 cases), the clinical response rate was who treated 78 patients with pneumonia (mostly com- 92 percent and the bacteriologic response was 88 permunity-acquired) with ciprofloxacin 200 mg intravecent. Many investigators [1,2,4,5] have treated panously every 12 hours for about four days, followed by tients who had various infections and produced posi500 mg orally every 12 hours, usually for another five tive blood culture specimens, as well as bacteremia of unknown infection site. Fifty-four valid case reports days. The pathogen had been isolated from 18 patients only (8. pneumoniae from 12 patients, gram-negative from patients treated for septicemia (data on file, strains from six patients). Seventy-three patients (94 Bayer AG) show 88.9 percent clinical success and 90.2 percent) had complete cure. The bacteriologic re- percent bacteriologic success. sponse is not known. Giamarellou and Galanakis [21 The overall clinical response rate of 93 percent (cure treated 15 cases of serious nosocomial pneumonia with and improvement) and the bacteriologic response rate the dosage described earlier. Pathogens were P. aeru- of 84 percent (eradication and eradication followed by ginosa, Acinetobacter calcoaceticus, and E. cloacae. reinfection) compared favorably with cure rates reNine of the 15 patients had cure and six experienced ported previously. These results are comparable with improvement. Nine pathogens were eradicated and those that have been found with ceftazidime [6] and six (four P. aeruginosa and two A. calcoaceticus) per- aztreonam [7] in the treatment of infections caused by sisted. In 144 valid reports of cases of respiratory P. aeruginosa and other resistant bacteria in seriously tract infections treated with intravenous ciprofloxacin ill patients. In a prospective, randomized, controlled (data on file, Bayer AG), a favorable clinical response study of 66 patients with serious clinical infections, 67 was noted in 85.5 percent of cases and a favorable bac- percent of the causative pathogens (mainly Enteroteriologic response was found in 70.2 percent. bacteriaceae, P. aeruginosa, S. aureas, Haemophilus In urinary tract infections (30 cases), the clinical iq‘luenxae, and streptococci) were eradicated by response rate was 93 percent and the bacteriologic ciprofloxacin treatment and 79 percent were eradiresponse was 87 percent. Peters [31 treated 40 pa- cated by imipenem therapy [S]. In terms of clinical and tients hospitalized with complicated urinary tract in- bacteriologic efficacy and safety, there was no statistifections in a randomized study comparing intravenous cal difference between the two groups. Giamarellou administration of ciprofloxacin 100 mg every 12 hours and Galanakis [23 treated 54 patients with “difficultwith mezlocillin 2 g every 12 hours. At the end of to-treat” infections using intravenous ciprofloxacin TABLE VI

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200 mg every 12 hours: a successful clinical response was observed in 49 patients (91 percent) and eradication of pathogen was observed in 33 patients (61 percent). Adverse reactions were minimal and transient in nature. The most frequent reactions seen were transient abnormalities in liver function results. All of the abnormal liver function results returned to normal when ciprofloxacin therapy was stopped. In this series, there was no major hematopoietic, renal, or neurologic toxicity due to ciprofloxacin. The pattern and frequency of side effects are similar to those of oral ciprofloxacin. In conclusion, this multicenter study demonstrated that ciprofloxacin administered intravenously is an effective and safe therapy for serious infections caused by multi-drug-resistant bacteria such as P. aeruginosa. The possibility of starting ciprofloxacin treatment intravenously and switching to oral therapy as soon as possible results in rapid removal of intravenous lines, lowers the rate of nosocomial infections, lessens patient discomfort, and reduces hospitalization length and cost, allowing ciprofloxacin to be a convenient and cost-effective alternative to current therapies that require continued use of the intravenous route.

November

ON ClPROFLOXAClN/MODAl

THE FRENCHMULTICENTER STUDYGROUP The following is a list of the 10 participants and centers in this study: Professors Carbon (Paris), Cartier (Rennes), Casanova (Marseille), Dellamonica (Nice), Gauthier-Lafaye (Strasbourg), Modai (Paris), Motin (Lyon), Mouton (Lille), Rapin (Paris), and Vachon (Paris).

REFERENCES 1. Chrysanthopoulos CJ Skoutelis AT, Stakaris JC, Anastassiou ED, Bassaris HP: Use of intravenous ciprofloxacin in respiratory tract infections and blliary sepsis. Am J Med 1987: 82 (suppl 4A): 357-359. 2. Giamareliou H, Galanakis N: Use of intravenous ciprofloxacin in diffrcult.totreat infec. tions. Am J Med 1987; 82 (suppl 4A): 346-351. 3. Peters HJ: Comparison of intravenous ciprofloxacln and mezlocillin in treatment of complicated urinary tract Infections. Eur J Clin Mlcrobiol 1986; 5: 253-255. 4. Helfer C, Auckenthaler R, Waldvogel FA: Efficacy and safety of ciprofloxacin in severe infections caused by susceptible organisms. In: Neu HC, Weuta H, eds. Proceedings of the 1st International Ciprofloxacin Workshop, Amsterdam: Excerpta Medlca, 1986; 405-410, 5. Scully BE, Neu HC: Treatment of serious infections with intravenous clprofloxacln. Am J Med 1987; 82 (suppl 4A): 369-375. 6. Scully BE, Neu HC: Clinical efficacy of ceftazidime. Treatment of serious infections due to Pseudomonas aeruginosa and hepatic failure. Arch Intern Med 1984; 144: 57-62. 7. Scully BE, Neu HC: Use of aztreonam in the treatment of serious infections due to multiresistant gramnegative organisms, including Pseudomonas aeruginosa. Am J Med 1984; 78: 251-261. 8. Lode H, Wiley R, Hoffken G, Wagner J, Borner K: Prospective randomized controlled study of ciprofloxacin versus imipenem”ciiastatln in severe clinical infections. Antimlcrob Agents Chemother 1987; 31: 1491-1496.

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