Parenteral ofloxacin in treatment of pyelonephritis

PARENTERAL

OFLOXACIN

IN TREATMENT

OF PYELONEPHRITIS

CLAIR E. COX, M.D. From the Department of Urology, University of Tennessee, Memphis, Tennessee

ABSTRACT--The interim findings of two studies of intravenous ofloxacin .[or the treatment 6~ pyelonephritis are presented. The findings are ?from one center o?f a muIticenter trial. In the fir~ l study intravenous (IV) ofloxacin was given to 34 patients with urine-culture-positive pyelonep~ ritis. After three days of intravenous therapy patients could be switched to oral ofloxacin. Micr~ biologic eradication occurred in 97 percent and clinical cures in 97 percent of the patients treat~ with ofloxacin. There were three probable drug-related adverse events. In the second comparati~ study 38 patients with pyelonephritis were randomized to receive IV ofloxacin with the option i switching to oral ofloxacin after three days. IV ceftazidime was given to 30 patients with pyeli nephritis with the option of switching to trimethoprim/sul?famethoxazole (TMP/SMX) after thri days. Microbiologic cures were experienced by 97 percent o?f the ofloxacin patients and by 1i percent of the ceftazidime patients. Probable drug-related adverse reactions were experienced by:~ 28 ofloxacin patients and by none of the ceftazidime patients. These interim study ?findings indical that the intravenous preparation of ofloxacin is efficacious in the treatment of pyelonephritis a,i that it is safe. In addition, 1V ofloxacin is as efficacious as 1V ce3~azidime ?for the treatment i pyelonephritis.

Transitional therapy of acute pyelonephritis has ineluded hospitalization and the administration of parenteral antibiotics. Currently, the availability of broad-spectrum oral antibiotics has provided alternative treatment options. However, intravenous antibiotic therapy remains an element of treatment for many patients with pyelonephritis, including the initial course of therapy, underlying medical conditions, potential pathogens, and the patient's ability to comply with outpatient therapy. It appears clear that there is today a role for both oral and intravenous therapy of pyelonephritis. Drugs available in both oral and parenteral forms could prove to be advantageous since ff a patient were improving on a parenteral regimen and was then switched to an oral regimen, the ability to maintain therapy with the same drug should provide the best opportunity for continued improvement combined with possible cost savings and reduce length of stay. Additional factors to consider when selecting an antibiotic for pyelonephritis inelude the antimicrobial aetivity against suspected 16

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pathogens, achieving adequate blood, tissue, urine levels, adverse effects profile, relationshi~[i~ renal function, and clinical experience w i t h ~ drug. Ofloxacin, a new fluoroquinolone with oral i!~ii parenteral formulations, is particularly well s ~ to the treatment of urinary tract infections, in ing those infections involving the kidney. T h e ~ form has been shown to have similar e f f i c a 0 ~ parenteral agents including aminoglycosides, c e p ~ losporins, and extended-spectrum penieilli Pharmacokineties of the oral and parenteral f of ofl0xacin are nearly identical. Ofloxacin m ~ talus serum and urine concentrations a b o v ~ minimal inhibitory concentrations for the m a j ~ of pathogens responsible for urinary tract i n f e c t ~ it is excreted by the kidney primarily as u n m e t ~ . 0 :~ lized drug; and it can be dosed once daily. The worldwide clinical experience has s h o ~ ~ ofloxacin to be highly effective in the t r e a t m e ~ urinary tract infections.7-12 Current research is ~ conducted to evaluate the efficacy and safety o ~ [ ~

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Evaluation schedule

TABLE I. Evaluation Medical history Physical examination U~ine culture Blood culture (if :s~pticemia suspected) ~matology Se~um chemistry Urinalysis i~hest x-ray film ~r~gnancy test (childbearing potential) ~ e s s adverse experience

Hospital Admission*

Therapy (Days 2-4)

x x x

x

x x x x x

Prior to Oral Therapy

Posthospital Discharge Contact

x

X X X

X X

x

x

Post-therapy (Days 5-9)

x x

x

x

x x

be monitored daffy for signs/symptoms (including daffy temperature), adverse experiences, and concurrent events.

of ofloxacin for the treatment of ~ctions and pyelonephritis. This re,rim clinical data from two studies Floxacin therapy of pyelonephritis. one center of a multicenter trial. xamines the efficacy and safety of te second study compares ofloxacin ?ectrum, third-generation cephalole.

'reliminary Results

veatment o] pyelonephritis sented herein are preliminary find~ter of a multicenter trial studying ofloxacin in patients with pyeloudy was conducted to gain expeV preparation of ofloxacin and to ~cy and safety in the treatment of atients were eligible for enrollment T were hospitalized with a diagno,itis confirmed with urine culture .05 organisms/mL. Other inclusion ients eighteen years of age or older ad of child-bearing potential, the ired to have a negative pregnancy e had normal menses within thirty dy entry, and to use a recognized .ontrol. Patients who came into the welling catheters were eligible for d the catheter was removed within nitiation of antibiotic therapy. Papartial, but not total, urinary tract lusion criteria included patients :nown to be resistant to the study psychiatric disorders, history of history of allergic or serious ad:o the study drug or any quinolone,

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weight less than 40 kg, necessity of a second antimicrobial agent, pregnancy, or lactation. Ofloxacin was given for between seven and fourteen days. The initial dose was 400 mg IV followed by 200 mg every twelve hours for a minimum of three days. After three days of intravenous therapy patients could be switched to 200 mg orally bid and either be kept as inpatients or followed as outpatients. The majority of patients were kept on the intravenous regimen as their clinical condition warranted continuing hospitalization. The evaluation schedule is provided in Table I and included urine cultures on admission, at days 2-4 of therapy, at days 5-9 post-therapy, and blood cultures. Microbiologic evaluation was based on urine culture results obtained five to nine days posttherapy. Cure was defined as eradication of the initial pathogen. Clinical evaluation was also performed one week following therapy. Clinical criteria included cure, complete resolution of signs and symptoms; improved, partial resolution of signs and symptoms; failure, no response, or deterioration. Patient demographics reflect the inner-city Memphis, Tennessee, population (Table II). Both males

TABLE II.

Patient demographics (study 1)

Variable Race Black White Sex Male Female Age (years) Mean Range

VOLUME XXXVII, NUMBER 3

Ofloxacin 30 4 19 14 54.7 24-88

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TABLE III.

Microbiologic response

-Ofloxacin (n = 34)-Pathogen Cured* % Citrobacter diversus 1/1 100 Citrobacter freundii 1/1 100 Enterobacter aerogenes 2/2 100 Enterobacter cloacae 4/4 100 Escherichia eoli 14/15 93 Klebsiella pneumoniae 2/2 100 Providencia stuartii 1/1 100 Proteus mirabilis 2/2 100 Serratia marcescens 1/1 100 Providencia rcttgeri 1/1 100 Pseudomonas aeruginosa 4/4 100 TOTAL (pathogen) 33/34 97 *Pathogens isolated/pathogenseradicated. and females were included, and the majority of males in the study had urinary tract strictures or prostatic disease. The average age of the patients was 54.7 years.

Ofloxacin was given to 34 patients with pyelonephritis. Thirty-one remained on intravenous therapy, and 3 patients were switched to oral ofloxacin. The microbiologie eradication rate at one week post-therapy was 33/34 (97 %) (Table III). The most common pathogen isolated was Escherichia coli, followed by Pseudomonas aeruginosa and Enterobaeter cloacae. All the P. aeruginosa and E. cloacae isolates were eradicated from the urine by ofloxacin. Clinical cures were obtained in 33 (97 % ) of the patients with 1 patient (3 %) failing treatment. Adverse events were reported to the investigators who determined their relationship to the study drug. Probable drug-related adverse effects were experienced by 3 patients and included two infiltrated intravenous lines and one episode of pruritus (Table IV). Possible drug-related adverse effects were experienced by 7 patients with four central nervous system events, three gastrointestinal events, and two episodes of pruritus. Preliminary Results

IV ofloxacin vs ceftazidime-TMP/SMX .for pyelonephritis After obtaining preliminary data from the first study regarding the safety and efficacy of ofloxacin in pyelonephritis, a comparative study on patients with pyelonephritis was begun. As in the first study, the results presented here are interim results from one center of a multicenter trial. The inclusion and exclusion criteria were exactly the same as in the

Adverse events by body system for IV ofloxacin Not Related

System CNS Headache Nervousness Lightheadedness Seizure Skin Pruritus GI Vomiting Nausea Diarrhea Ileus Other Peritonitis Abdominal abscess Infiltrated IV TOTALS/pt.

TABLE V.

Results

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TABLE IV.

Variable Race Black White Sex Male Female Age (years) Mean Range

2

Possibly

Probabl:

1 1 1 1 2

1

1

1 1 1

1 1 1 2 3/3

9/7

Patient demographics (study 2)' ::i Ofloxacin (n = 38)

Ceftazidil TMP/SM] (n = 30i

33 5

26 4

9 29

12 18

56.7 20-105

52.6 25-74

first study. Patients randomized to receive oflox~ were given 400 mg IV initially, followed by 200 IV every twelve hours for a minimum of three 4 with the option of then switching to 200 mg ori bid. Patients randomized to the eeftazidime gr~ were given 1 g every twelve hours IV for three with the option of then switching to trimethop$i sulfamethoxazole 160/800 mg orally bid. The eVi ation schedule was identical to the first study (Ta I). The patients were primarily black, with mor~ males than males, and average ages of 56.7 and years for the ofloxacin and ceftazidime groups,:: spectively (Table V). Results

: :-i

In this study 8 of the 38 ofloxacin patients switched from IV to outpatient oral oflox.~ therapy, and 4 of the 30 ceftazidime patients switched to oral TMP/SMX. Microbiologic C~ (evaluated 5-9 days after discontinuatiOfi

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TABLE VI.

Microbiologic response Ofloxacin

--(n Pathogen Citrobacter diversus Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella oxytoca Morganella morganii Proteus mirab ilis Serratia marcescens Providencia rettgeri Pseudomonas aeruginosa Acinetobacter anitratus K1ebsiell a p ne um o ni a e Providentia stuartii TOTALS (pathogen)

= 38)--

Cured*

%

1/1 3/3 2/2 3/3 10/10

100 100 100 100 100

2/2 1/1 4/4 1/1 3/4

10b 100 100 100 75

6/6 1/1 37/38

100 100 97

CeftazidimeTMP/SMX (n = 30) Cured* % 2/2 . .

100 .

.

3/3 9/9~ 1/1

1'00 100 100

i/i 4/4 1/1 3/3 1/1 4/4 2/2 31/31

i00 100 100 100 100 100 100 100

*Pathogens isolated/pathogens eradicated. tOne patient had E. eoli isolated from blood and urine.

TABLE V I I .

System CNS Headache Insomnia Nervousness Anxiety Dizziness Lethargy Skin Urticaria Pruritus GI Vomiting Nausea Gas Stomach ache Diarrhea Special senses Eye pain Other Back pain Elbow pain Neck pain Chest pain Nasal congestion

- NR 1

Adverse events by body system

Relationship to Study DrugCeftaz'idimeOfloxacin (n = 3 8 ) - - - TMP/SMX (n = 3 0 ) Poss. * Prob. * NR Poss. ~ Prob. 2 2

3 3

1 1 1 1 1 1 1

1 1

2 4

1 1 1 1

1 1 1

KEY: NR = not related; Poss. = possible; Prob. = probable. *Fifteen adverse events in 14 patients. ~Ten adverse events in 8 patients.

~'~*~py) were experienced b y 37/38 (97 %) of the ~N~ie~ receiving ofloxacin (Table V I

~ e

T h e micro-

failure was due to a R aeru)nosa isolate.

~ ' i 6 f ! the 31 patients receiving eeftazidime T M P / ~,,~v~expenenced mierobiolo~ic cures T h e most

c o m m o n organisms isolated w e r e E. coli, Klebsiella p n e u m o n i a e , Serratia mareescens, a n d P. aeruginosa. Clinical cure rates w e r e 95 p e r c e n t (36/38) for the ofloxaein g r o u p w i t h 2.5 p e r c e n t (1/38) imp r o v e d a n d 2.5 p e r c e n t (1/38) failed. A m o n g the

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patients receiving ceftazidime-TMP/SMX, 100 percent (30/30) experienced clinical cures. Patients' complaints while taking the study drug were registered as adverse events, and investigators determined their relationship to the study drugs. Probable drug-related adverse events were experienced by 2 of the 38 ofloxaein patients, and 13 possible drug-related events were experienced (Table VII). Among patients receiving ceftazidime-TMP/ SMX, there were 14 possible drug-related adverse events. The distribution of adverse events was similar in the treatment groups with the most common events being headache, insomnia, and nausea. Comment These interim study results provide preliminary information regarding the intravenous preparation of ofloxacin and its use in pyelonephritis. In the first study, IV ofloxacin was effective in the treatment of pyelonephritis and provided microbiologic and clinical cures in patients with the typical spectrum of uropathogens. Cure rates for the intravenous form are similar to those observed with oral ofloxacin therapy. ~ Importantly, ofloxacin was effective in eradicating all the E aeruginosa isolates from the patients with pyelonephritis. The second study compared IV ofloxacin with IV ceftazidime with the option of switching to oral ofloxacin or TMP/SMX after three days of IV therapy. Bacteriologic and clinical cure rates were high and similar for both treatment groups. Both ofloxacin and ceftazidime were effective against the spectrum of urinary pathogens found in this study, eradicating all the isolates of E. eoli, S. marcescens, and K. pneumoniae. In both studies the results of relapse and reinfection are not available and, therefore, long-term cure rates are sure to be somewhat less than those reported. Information regarding side effects found a low incidence of possibly drug-related side effects and an even lower incidence of probable drug-related side effects with IV ofloxaein. The incidence of adverse events was similar for patients treated with ofloxacin or eeftazidime. No patients receiving ofloxacin had serious central nervous system disturbances. This is significant in light of earlier concerns that some fluoroquinolones have been shown to be central nervous system excitors. ~3

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Conclusion These interim study findings indicate that the ini travenous preparation of ofloxacin is efficacious i~ the treatment of pyelonephritis, and that it is safe. Ii has the bacteriologic efficacy against typical ur0! pathogens of the currently available oral quino lones, norfloxacin and ciprofloxacin, with a goo~ safety profile. L~3 It is anticipated that ofloxaci will be available in both oral and parenteral forrn~ lations. This will eventually make it possible for p! tients who require initial intravenous therapy an improve clinically on parenteral ofloxacin to bl switched to oral therapy with the same drug with ni loss of efficacy. University of Tennessee Hospifd! 956 Court Avenue, Room H2I~ Memphis, Tennessee 3816~ References 1. ScheffeRT, et al: Norfloxacinvs. best parenteral theral~:~d treatment of moderate to serious, multiply-resistant, nosoco-mi~ urinary tract infectious: a pharmacoeeonomie analysis, Urol0~ (Suppl 3) 32:24-30 (1988). ~~:::i 2. Corrado ML, Cherubin CE, and Shulman M: The coi parative activity of norfloxaein with other antimierobial ag6~ against gram-positive and gram-negative bacteria, J Antimicf~ Chemother I1:369-376 (1983). 3. Hooper DC, and WolfsouJS: The fluoroquinolones: phi macology, clinical uses, and toxicities in humans, Antimicri Agents Chemother 28:716-721 (1985). f:', 4. Wolfson JS, and Hooper DC: The fluoroquinolones: stru/~ ture, mechanisms of action and resistance, and spectra of a c t i ~ in vitro, Antimicrob Agents Chemother 28: 581-586. (1985). ~ 5. Marble DA, and Bosso JA: Norfloxacin: a qumolone a ~ biotic, Drug InteU Clin Pharm 20:261-266 (1986). "~ 6. Cox CE: Ofloxacin in the management of complic : ~ urinary tract infectious, including prostatitls, Am J Med ( S ~ 6C) 6C: 61S-68S (1989). 7. Mont JP, and Campoli-Richards DM: of its antibacterial activity, pharmacokinetic peutic use, Drugs 33:346-391 (1987). 8. Tanphaichitra D, Shaaphong S, and Si a new quinolone in the treatment of genit infectious, Infection (Suppl 4) 14:$321-S32 9. Grassi GG: A multicenter study on elir acin in respiratory and urinary tract infecti 4) 14:$300-$302 (1986). 1O. Cox CE, Callery SV, and Tack KJ: Cli ofloxacin in urinary tract infection, Infectio: $304 (1986). 11. Kromann-Andersen B, et al: Clinica acin versus ciprofloxacin in complicated uri Infection (Suppl 4) 14:S305-8306 (1986). 12. Rugendorff EW: Open randomised acin and norfloxacin in the treatment of tract infectious Drugs (Suppl 1) 34:91-94 (1987). 13. Poppel HV, et al: Clinical experience with eiprofloxacila~!i~',~, the treatment of urinary tract infections: a review, Infecti0~ ~ 337-344 (1988).

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