Piperacillin or ticarcillin plus amikacin: A double-blind prospective comparison of empiric...

Piperacillin or Ticarcillin Plus Amikacin

A Double-Blind Prospective Comparison of Empiric Antibiotic Therapy for

Febrile Granulocytopenic Cancer Patients

JAMES C. WADE, M.D.

STEPHEN C. SCHIMPFF, M.D.

KATHRYN A. NEWMAN, R.N.

CLARENCE L. FORTNER, M.S.

HAROLD C. STANDIFORD, M.D.

PETER H. WIERNIK, M.D.

Baltimore, Maryland

From the Baltimore Cancer Research Center, University of Maryland School of Medicine, Balti- more, Maryland. Reprint requests should be ad- dressed to Dr. James C. Wade, Baltimore Cancer Research Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, Maryland 2120 1. Manuscript accepted August 12, 1981.

Piperacillin plus amikacin was compared in a prospective randomized double-blind trial with our standard regimen of ticarcillin plus amikacin as empiric therapy of fever in patients with granulocytopenia. Profound persistent granulocytopenia (fewer than lOO/pl polymorphonuclear leukocytes without a rise during therapy) was present in 60 percent of the patient trials in both treatment groups. Of 38 microbiologically and clinically documented infections treated with piperacillin plus amikacin, 22 (58 percent) showed improvement. Of 34 microbiologically and clinically documented infections treated with ticarcillin plus amlkacin, 19 (56 percent) showed improvement. There was no difference in response between groups according to the site of infection or infecting pathogen. Toxicity was minimal, with an equivalent incidence of immediate reactions, nephrotoxicity and superinfection. Patients receiving ticarcillin plus amikacin became colonized with more resistant gram-negative bacilli (17) than did those receiving piperacillin plus amikacin (3). Despite the monosodium structure of piperacillin, hypokalemia was not reduced for patients who received piperacillin plus amikacin. Although piperacillin has a wider in vitro antibacterial spectrum than ticarcillin, the clinical efficacy and toxicity of the combination of piperacillin plus amikacin were similar to those of ticarcillin plus amikacin as empiric therapy.

The empiric administration of broad-spectrum antibiotics at the onset

of fever is the accepted therapy for patients who are granulocytopenic.

The frequently used two- or three-drug combinations of an aminoglycoside, a semisynthetic penicillin such as ticarcillin or carbenicillin

and a cephalosporin are generally effective but potentially toxic [l-5]. The appearance of antibiotic-resistant gram-negative bacilli in many

centers has fostered the search for new, more effective antibiotics

that hopefully would have a decreased potential for side effects. Piperacillin, a new monosodium, semisynthetic penicillin has broad

in vitro activity including greater activity than carbenicillin or ticarcillin

against Pseudomonas aeruginosa plus activity against Klebsiella pneumoniae and Serratia marcescens, which are usually resistant to

carbenicillin and ticarcillin. Piperacillin also has excellent activity against anaerobes including Bacteroides fragilis and most gram-

positive cocci (except beta-lactamase producing Staphylococcus aureus) [6-lo]. The monosodium structure of piperacillin theoretically

should decrease the hypokalemia observed with ticarcillin or carbenicillin [ 111. Early studies have shown piperacillin to be an effective,

nontoxic antibiotic when utilized as a single agent for treatment of

December 1981 The American Journal of Medicine Volume 71 983

PIPERACILLIN OR TICARCILLIN PLUS AMIKACIN-WADE ET AL.

serious bacterial infections [ 121, while in vitro synergy against gram-negative bacilli has been demonstrated

with the combination of piperacillin and amikacin

[ 131. The broad antibacterial activity, the demonstrated in

vitro synergy and low potential toxicity led us to combine

piperacillin with amikacin and compare this antibiotic

combination, in a prospective randomized double-blind

trial of empiric antibiotic therapy for febrile granulo-

cyfopenic patients with cancer, with our current stan-

dard regimen of ticarcillin plus amikacin.

METHODS

Patients at the Baltimore Cancer Research Center with an absolute granulocyte count below l,OOO/pl and a tempera- ture of 10 l°F (38.3’(Z) or more in the absence of an obvious noninfectious cause of fever, e.g., administration of blood products just prior to the fever, were candidates for the protocol. Patients who had a record of penicillin allergy or who in the previous 72 hours had received therapeutic sys- temic antibiotics were excluded from the study.

The pretherapy evaluation included: (1) a complete history and physical examination with specific reference to the subtle findings of inflammation [ 141; (2) at least two separate blood cultures; (3) cultures from any clinically suspicious lesion: (4) culture and analysis of catheterized or clean-caught voided urine specimen: (5) chest x-ray; (6) surveillance cultures of nose, gingiva and rectum [ 151; and (7) complete blood cell count, liver and renal function tests, leukocyte differential and determination of serum electrolyte and chemistry values. If a pneumonia was present, and no contraindications were present, transtracheal aspiration was performed.

Antibiotic therapy was initiated after informed consent was obtained. The randomization was performed using a previously generated table of random numbers, known only to the Baltimore Cancer Research Center Pharmacy. The study blinding remained in effect until patient accrual and case analyses were complete. Patients received amikacin plus either ticarcillin or piperacillin. the latter supplied by S. Sathe, M.D., Ph.D., of Lederle Laboratories, Pearl River, New York. The semisynthetic penicillins (ticarcillin or piperacillin) were labelled as “beta-lactam study drug”, given at a dosage of 306 mg/kg per day divided into four equal doses and administered intravenously over 15 minutes. Amikacin was given at the manufacturer’s recommended dosage of 600 mg/m* per day, divided into four equal doses and given intravenously over 15 minutes. The amikacin was administered prior to but separately from the “beta-k&am study drug” so as to avoid any potential inactivation, and to facilitate the determination of serum drug levels. Blood specimens were obtained 30 minutes after infusion of the “beta-lactam study drug” (1 hour after infusion of amikacin) and immediately before the next amikacin dose. Serum samples were promptly frozen and maintained at -7O’C until the drug assay was performed. To avoid inactivation, the serum specimen, once unfrozen, was concomitantly assayed for both beta- lactam and amikacin levels. Amikacin serum levels were determined by a radioimmunoassay with a range of 2.5 to 40.0 pg/ml. The beta-la&m assay was performed (following

amikacin inactivation with sodium polyanethol sulfonate) by an agar well method that utilized P. aeruginosa NCTC # 1070 1 as the test organism for the ticarcillin and piperacillin studies [ 161. The dosages of both amikacin and beta-lactam study drug were not adjusted according to serum levels obtained except in patients with renal failure.

Hematologic and chemical studies and urinalysis were repeated two or three times each week and within 48 hours after discontinuation of study drugs. Blood culture specimens were obtained on days one, two, seven and every seventh day thereafter and within 48 hours after termination of therapy. Culture specimens from the site of infection were obtained on a similar schedule whenever possible. Suveillance culture specimens of the nose, gingiva and rectum were obtained weekly and reviewed for the presence of organisms resistant to amikacin. ticarcillin or piperacillin.

Febrile episodes were classified as: (1) microbiologically documented, with and without bacteremia (site and pathogen identified); (2) clinically documented (site but no pathogen identified); (3) possible (equivocal); and (4) doubtful (fever without signs of infection) [ 1,5]. Patients were studied for at least three days unless a change in therapy was required by a worsening of the clinical status. Patients who responded to therapy remained on the study drugs for at least five days after all signs of infection had disappeared. Antibiotics were discontinued after four days in patients believed to be unin- fected.

Study investigators examined all protocol patients regularly and participated in all clinical decisions regarding a change in the antibiotic regimen or the initiation of therapeutic granulocyte transfusions. Therapeutic response was classified as: (1) improvement (disappearance of fever and other clinical evidence of infection); (2) failure (poor response to the antibiotics, or the pathogen was resistant to the “beta- lactam study drug”): (3) nonevaluable (possible or doubtful infection, nonbacterial infection or a protocol violation) [ 1,171. Granulocyte transfusions were given only when the infection clinically progressed, the patient was not alloim- munized. and a suitable donor was available. All patients who required granulocytes therapeutically were considered to have an infection that failed to respond to the antibiotic regimen.

Antibiotic toxicity was evaluated in all patients who received at least 12 doses of the beta-lactam study drug (i.e., three days of therapy). Antibiotic-related hypokalemia was defined as a drop of 1 meq/liter or more in the serum potassium level from baseline when other potassium-depleting factors were excluded, e.g., amphotericin B or diarrhea [ 171. Potassium supplementation was computed on a meq-perday basis, and recorded as the highest dosage per day administered for at least two consecutive days. Hyperbilirubinemia was defined as a two-fold or greater rise in the level of serum bilirubin over baseline [ 171. Antibiotic-related nephrotoxicity was defined as an increase in the serum creatinine level of more than 0.4 meq/lOO ml when other possible causes of nephrotoxicity (e.g., hypotension. other nephrotoxic drugs) had been excluded [ 181. Colonization was defined as a new organism isolated from the infection site cr from surveillance cultures. When this colonization occurred at the initial site of infection, accompanied by fever and clinical signs of in-

984 December 1991 The American Journal of Medicine Volume 71

PIPERACILLIN OR TICARCILLIN PLUS AMIKACIN-WADE ET AL

TABLE I Patient Characteristics

Trials (patients) Age (yr)

(Range) Males/Females Diagnosis

Leukemia Acute nonlymphocytic leukemia Acute lymphocytic leukemia Chronic myelocytic leukemia-

blast crisis Solid tumor

Granulocyte count Pretherapy < 1 OOll.~l Rise during therapy to > lOO/yl No rise or rise to <5OO/yl

during therapy Days of therapy

(Range) Shock at presentation (bacteremia)

Ticarcillin Piperacillin t t

Amikacin Amikacin

62 (47) 59 (45) 43 43

(18 to 72) (19 to 69) 26136 30129

43 49 36 40

4 5

3 5 19 10

45 50 20 18

25 32 9 9

(1 to 32) (1 to 21)

3 (2) 4 (3)

fection, it was deemed a superinfection. Colonization at other

sites, accompanied by fever and clinical signs of infection, was deemed a further infection.

Minimal inhibitory concentrations (MIC) for piperacillin, ticarcillin and amikacin were determined for all pathogens and colonizing organisms by a serial dilution microtiter technique [ IQ].

RESULTS

Patient Characteristics. Of 12 1 trials completed (Table I), 62 received ticarcillin plus amikacin (Ti-A) and

59 received piperacillin plus amikacin (P-IA). Both

treatment groups were similar with regard to mean

patient age and sex. Most patients had a diagnosis of

acute leukemia with acute nonlymphocytic leukemia

being the most frequent disease. Forty-five (73 percent)

of 62 T-IA patients and 50 (85 percent) of 59 P-i-A pa-

tients had a pretherapy granulocyte count below lOO/pl.

Of these patients with severe initial granulocytopenia

(below lOO/pl), only 20 of 45 T+A, and 18 of 50 P-i-A

patients had a rise in circulating granulocyte count to

more than lOO/pl during therapy. The median duration

of therapy for both groups was nine days. Shock at presentation occurred in three patients treated with

T-IA; two had documented bacteremia, one patient

died. Four episodes of shock at presentation occurred

in patients treated with P+A; three had documented

bacteremia, one patient died. Serum Antibiotic Concentrations. The mean antibiotic concentrations for the beta-lactam antibiotics were

similar between groups, although the ranges for both groups were wide. For patients receiving piperacillin, the 30-minute postinfusion and immediately preinfusion

levels (range) were 173 (63 to 378) and 23 (less than

5 to 79) pg/ml. For patients receiving ticarcillin, the

levels were 202 (89 to 588) and 25 (less than 5 to 148)

yglml, respectively. Amikacin levels were sampled

immediately preinfusion (trough) and 60 minutes postinfusion. The median levels were 9.1 (2.5 to 23) pg/ml

and 15.7 (7.7 to 40) pg/ml, respectively, for the P+A

trials and 5.2 (2.5 to 15.8) pg/ml and 11.3 (5.6 to 27.2) pg/ml for the T-i-A group (p = 0.29).

Response. Ticarcillin plus amlkacin: There were 36 microbiologically and clinically documented infections,

two of which were not evaluable for efficacy-one in

a patient with Aspergillus flavus pneumonia and sinusitis

and the other in a patient with Escherichia coli bacter-

emia who received only one dose of ticarcillin because of an allergic reaction (rash). Nineteen of the remaining 34 infections (56 percent) improved. These 34 infections included 11 cases of bacteremia, of which six improved; nine nonbacteremic microbiologically documented cases, of which five improved; and 14 clinically documented cases, of which eight improved. Ten of 12 infections that originated in the skin or urinary tract or that were labeled bacteremia of unknown origin

improved (Table II), whereas only nine of 22 infections originating in the sinuses, lower respiratory tree or alimentary tract improved.

The microbiologically documented pathogens (Table Ill) included: eight gram-negative bacilli of which six responded, eight gram-positive cocci of which four responded, and one nonresponding infection caused by Propionibacterium acnes. Three cases of mixed-organism infection occurred: Listeria monocytogenes plus

December 1981 The American Journal of Medicine Volume 71 9B5

PIPERACILLIN OR TICARGILLIN PLUS AMIKACIN-WADE ET AL

TABLE II Microbiologically and Clinically Documented Infection: Response to Therapy by Site

Site ol Infection

Lower respiratory tract Sinus Alimentary canal

Pharynx, esophagus Colon, rectum

Skin Urine Bacteremia of unknown origin Total

l Improved/Total.

licarcitlin Piperacillin $ t

Amikacin Amikacin

O/3’ l/5’ l/l O/l

417 8/12 4/11 3/8 416 517 212 l/l 414 4/4

19134 (56%) 22138 (58%)

TABLE IV Initial Antibiotic Susceptlbillty and Response to Therapy in Gram-Negative Infections

Ticarciliin Piperacilttn Hal Anttbiotic t t Susceptibility Amikacln Amtkacin Total

No antibiotics* - - -

One antibiotic O/l (O/l) l/6 (O/4) l/7 (O/5) + Two antibiotics 3/4 (O/l) 315 (l/3) 6/9 (l/4)

( ) = Gram-negative bacteremia. l Initial granulocyte count below 100/j& without subsequent rise. + p = 0.047 Antibiotic resistance: amikacin >16 gglml; ticarcillin >64 pg/ml; Piperacillin >64 pg/ml.

TABLE Ill Mlcrobiologically and Clinically Documented Infection: Response to Therapy by Pathogen (Improved/Total)

Ttcarcillin Piperacillin t t

Amtkacin Amikacin

Gram-negative bacilli P. aeruginosa 011 l (1) l/3” (2)+ Klebsiella species 011 (1) 213 (2) E. coli 2/2 (1) l/4” (3)+ S. marcescens l/l l/l Other 3/3 (1) l/l Total 6/8 (75%) 6/12 (50%)

Gram-positive cocci Staph. aureus 3r3 (2) 215’ (2) Staph. epidermidis O/2’ (l)+ O/4’ (2)+ Other l/3 (2) 212 (2) Total 4/8 (50 %) 4/11(36%)

Other (Corynebacterium species) 011 (1) Mixed l/3’ (1) l/3 (2) Grand total 11/20(55%) 11/26(43%)

( ) = bacteremic organisms. l Deaths (each asterisk indicates one death). + Therapeutic granulocytes.

Staphylococcus epidermidis, improved; Corynebac-

terium species plus Clostridium perfringens, failed; and

Streptococcus enteromedius plus Bifidobacterium

adolescents, failed. Three infection-related deaths

occurred in the T+A group: in a patient with P. aerugi-

nosa pneumonia and bacteremia; in one with Staph.

epidermidis enterocolitis; and in another with Coryne-

bacterium species and Clostridium perfringens ab- dominal abscess.

Six of the eight gram-negative bacilli were susceptible to ticarcillin (MIC <64 pg/ml), and five responded; one of the two infections caused by ticarcillin-resistant gram-negative bacilli improved. All eight gram-negative bacilli were amikacin-susceptible (MIC < 16 pg/ml).

Piperacillin plus amikacin: There were 40 microbiologically and clinically documented infections, two of which were not evaluable for efficacy-one in a patient with Candida albicans pharyngitis and the other in a patient with a clinically documented cellulitis who received only one dose of piperacillin because of an allergic reaction (urticaria). Twenty-two of the remaining 38 infections (58 percent) improved. These 38 infections included 15 cases of bacteremia, of which five improved; 11 nonbacteremic microbiologically documented cases, of which six improved; and 12 clinically documented infections, of which 11 improved. Ten of the 12 infections that originated in the skin or urinary tract or that were labeled bacteremia of unknown origin improved (Table Ill). while only 12 of 26 infections originating in the sinuses, lower respiratory tract or alimentary tract improved.

The microbiologically documented pathogens (Table IV) included 12 gram-negative bacilli of which six improved, and 11 gram-positive cocci of which four improved. There were three mixed-organism infections documented; one caused by P. aeruginosa plus Staph. aureus improved, whereas one case of Staph. epidermidis plus Flavobacterium infection and a case of Streptococcus bovis plus Moraxella infection failed to improve. Six infection-related deaths occurred among patients who received P+A. Two deaths were secon- dary to P. aeruginosa bacteremia that originated from perirectal cellulitis; one each from pneumonia caused by E. coli and by Staph. aureus, respectively, and one each from a bacteremic E. coli cellulitis and a bacteremic Staph. epidermidis pharyngitis.

There were 14 gram-negative pathogens (including mixed infections); 10 were susceptible to piperacillin (MIC <64 pg/ml), of which five responded to therapy. Only one of the four gram-negative bacilli resistant to piperacillin improved. Three of the 14 gram-negative bacilli were resistant to amikacin (MIC > 16 pg/ml), and one of three improved.

Granulocyte transfusions: Therapeutic granulocyte transfusions were employed in only four infections while



TABLE V Antibiotic-Related Side Effects

Ticarcillin Pipsracillin t t

Amlkacln Amikacln

Immediate reactions Total trials Evaluable for allergic reactions

Rashlurticaria Fever

Evaluable for other Toxicities* Hypokalemia

Mean decrease serum potassium Range

Patients requiring supplementation Mean potassium supplement

Range Nephrotoxicity Hyperbilirubinemia Superinfection

62 59 62 59 2 2/l

60 56 9 9

0.6 meq/liter 0.5 meqlliter o-2.4 o-2.2

36 35 57 meqlday 46 meqlday

20-300 25-160 2 3 4 6 3 2

l Greater than 12 doses (three days) of empiric antibiotics.

study antibiotics were being used. Three of these patients received P-FA, and two ultimately died despite granulocyte transfusions. The one infection (Staph. epidermidis enterocolitis) treated with T-FA and therapeutic granulocytes subsequently resolved when in- travenous vancomycin was added to the regimen.

Granulocytopenia: The granulocyte count was evaluated before, during and at the completion of therapy. Initial granulocyte levels were categorized into one of four groups: below lOO/pl, 100 to 499/pl, 500 to 999/yl and above l,OOO/~l. Thirty-one of 34 (91 percent) T-i-A-treated microbiologically and clinically documented infections and 33 of 38 (87 percent) P+A-treated microbiologically and clinically documented infections occurred at a pretherapy granulocyte count below lOO/& with 56 granulocyte counts in these patients remaining at a level below lbO/~l throughout the study period. The therapeutic response was low for those infections in which the granulocyte count persisted throughout therapy below lOO/~l; with T-l-A, eight of 19 (42 percent) improved, and with Pi-A, eight of 21 (38 percent) improved. The response rate in- creased when there was a rise in the granulocyte count to more than lOO/~l during therapy; with T+A, eight of 12 (75 percent) improved, and with P-FA, 10 of 12 (83 percent) improved. All but one infection in both groups responded to the antibiotic treatment regimen if the pretherapy granulocyte count was above lOO/~l, except for a K. pneumoniae bacteremia (perirectal cellulitis) treated with P-l-A.

Antibiotic susceptibility and response: Further analysis of the therapeutic response and the susceptibility of the infecting organism to the initial antibiotic combination for infections caused by gram-negative bacilli in patients with a pretherapy granulocyte count

below lOO/pl and without a rise to more than lOO/@ during therapy reveals an improved outcome for both treatment groups when the infecting organism was susceptible to both initial antibiotics. None of the gram-negative infections in either group was treated initially with therapy to which the pathogen(s) was doubly resistant (Table IV). When the infecting organism was susceptible to only one of the initial antibiotics, one of seven infections improved. When the pathogen was susceptible to both initial antibiotics, six of nine infections responded (p = 0.047).

Toxicity: Drug-related fever occurred in one patient in each study arm while immediate hypersensitivity reactions occurred in two T+A-treated patients (rash) and three Pi-A-treated patients (rash in two and urticaria and chill in one) (Table V). Evaluation for other toxicity was possible in 60 T-FA trials and 56 Pi-A trials. Study antibiotic-related hypokalemia occurred in nine patients in each group, with a mean decrease in serum potassium of 0.6 meq/liter for the T-FA group and 0.5 meq/ liter for the P+A group. Thirty-eight of 60 (63 percent) T-f-A-treated patients and 35 of 56 (63 percent) Pi-A- treated patients required potassium supplementation, with a mean requirement of 57 meq/day for Ti-A trials and 46 meq/day for Pi-A trials. The lowest recorded serum potassium for both groups was 1.6 meq/liter.

Definite antibiotic-related nephrotoxicity occurred in two (3 percent) T-FA-treated patients and three (5 percent) P-FA-treated patients. The peak rise in creatinine levels in these patients was 0.7, 1. I, and 0.6, 0.9, 1.3 mg/dl, respectively. Asymptomatic hyperbilirubinemia (direct), unrelated to septicemia, occurred in four T-f-A-treated and six P-l-A-treated patients. The hyperbilirubinemia for both groups occurred by day two to three and spontaneously resolved by day seven, with



or without discontinuation of the study antibiotics. Liver

enzyme elevations did not occur in either group. Antimicrobial susceptibilities of organisms recov-

ered from surveillance cultures: Serial surveillance cultures revealed that 16 T+A-treated patients had ti-

carcillin-resistant (MIC >64 pg/ml) organisms. K.

pneumoniae was the resistant organism isolated from

nine of the trials, five of these organisms were sensitive

to piperacillin. Ticarcillin-resistant E. coli was isolated

from patients in five T-l-A trials: four were susceptible

to piperacillin. One T-l-A patient had a ticarciilin-re-

sistant S. marcescens that was also piperacillin-re-

sistant, and one patient each had a ticarcillin-resistant

E. coli and P. aeruginosa, both of which were pipera-

cillin-susceptible. Two patients acquired yeasts.

Piperacillin-resistant organisms were acquired by five

P+A-treated patients: all were uniformly ticarcillin-

resistant: S. marcescens in two, E. coli in one and

yeasts in two. Superinfection and further infection: Superinfection

(same site, new organism) occurred in three T+A trials:

Staph. aureus enterocolitis, C. albicans enterocoiitis

and a bacteremic enterocolitis caused by an alpha-

hemolytic Streptococcus plus B. fragilis. There were

two superinfections in the P+A trials: P. aeruginosa

perirectal cellulitis and Staph. aureus cellulitis. Four

further infections (new site) occurred in patients treated with T+A: A. fiavus pneumonia, A. flavus sinusitis,

clinically documented esophagitis and clinically docu-

mented pneumonia. Three further infections occurred

among P+A-treated patients: Staph. epidermidis

pneumonia, A. flavus sinusitis and A. flavus sinusitis and

pneumonia.

COMMENTS

Empiric antibiotic therapy with ticarcillin plus amikacin

or with piperacillin plus amikacin in febrile granulocy-

topenic cancer patients was effective in 57 percent of

microbiologically and clinically documented infections.

This prospective randomized double-blind trial showed

no statistically significant differences in efficacy or antibiotic-related side effects between the studied

regimens.

The overall response rate for this study was disap-

pointing and substantially lower than that previously

reported from our center as well as others [l-5,20-22]. The reasons for this are likely three. The patients studied were mainly those with acute leukemia, with approxi-

mately 75 percent beginning therapy with an initial granulocyte count below loo//11 and only 40 percent

of these patients subsequently had a rise in granulocyte count to more than lOO/pl. This study like others

[ 2,3,5,21] has pointed out the improved response to appropriate antimicrobiais when the granulocyte count

concomitantly rises. The mean serum amikacin levels

obtained were low, although equivalent to previous studies from this institution [ 3,5]. Generally, levels after

infusion of 18 to 30 pg/mi are considered desirable. We

elected to observe the manufacturer’s recommendation

for dosage (15 mg/kg or 600 mg/m* per day). The timing of administration was modified to every six hours

so as to take advantage of the observation of Longstreth

and Leitman [ 231 that high peak concentrations are no

more bactericidal but that maintaining levels in excess

of the MIC maintains growth inhibition. Keating et al. [2]

suggested a relationship between aminoglycoside levels

and ultimate infection response among granulocyto-

penic patients. Consequently, because of the profound

granulocytopenia and the manufacturer’s dosage recommendation providing insufficient serum levels in this

patient population, the potential importance of the low

amikacin levels was perhaps accentuated [3]. Ap-

proximately 45 percent of the infecting pathogens were

gram-positive cocci, with Staph. epidermidis infections

being frequent in both treatment regimens and uniformly

unresponsive to either empiric regimen. This occur-

rence of less frequently encountered gram-positive

organisms is different from that usually reported. The

Baltimore Cancer Research Center has recently been

plagued by Staph. epidermidis infections, which cer-

tainly were a major factor in our lower reported re-

sponse rates [ 241. In vitro testing of piperacillin has shown a wide range

of activity against most gram-negative bacilli with ac-

tivity against Klebsiella species and improved activity

against P. aeruginosa when compared with ticarcillin

[lo]. The absolute number of infections caused by

Klebsiella species and P. aeruginosa were too few to

be able to draw significant conclusions regarding rel-

ative efficacy, although two of three Klebsielia species

infections improved when treated with P+A, whereas the one treated with T+A was a failure.

The occurrence of gram-negative bacilli resistant to

the study beta- lactam as initial pathogen was similar

in both groups: two of eight in the Ti-A group (one im-

proved), and four of 14 in the Pi-A group (one improved). Thus, despite piperacillin’s broader in vitro

spectrum, the frequency of resistant clinical isolates

was equivalent. In both study groups, the single patient

with a beta-lactam-resistant pathogen and infection

improvement with antibiotics had a rise in granulocyte

count during therapy: in the other cases, severe gran- uiocytopenia persisted and the antibiotic therapy was

a failure. There was a substantial difference, however, in the

acquisition of resistant gram-negative bacilli during

therapy as revealed by routine surveillance cultures. Cram-negative bacilli resistant to the study beta-la&m were acquired during 16 of 42 T-l-A courses but only three of 45 P-l-A courses of therapy. Among the T+A-


PIPERACILLIN OR TICARCILLIN PLUS AMIKACIN--- WADE ET AL.

treated patients, 11 of 16 acquired gram-negative bacilli

that, although resistant to ticarcillin, were susceptible

to piperacillin. Each of the three piperacillin-resistant

acquired gram-negative bacilli among the P+A-treated patients was also resistant to ticarcillin. This difference

in recovery of resistant organisms may be of impor-

tance and deserves further observation.

In evaluating the group of patients with profound,

persistent granulocytopenia and gram-negative bacillus

infections, it would appear that for most infections there

is an improved outcome if the pathogen is sensitive to

both initial antibiotics. This relationship has been es-

tablished in previous reports [2,22,25.26] and em-

phasizes the importance of appropriate initial therapy

with two active agents, preferably a synergistic com-

bination.

The use of piperacillin plus amikacin, like ticarcillin

plus amikacin, was accompanied by minimal antibi-

otic-related toxicity. These findings are consistent with

all of our previous studies evaluating a semisynthetic

penicillin plus an aminoglycoside [3,4,21]. Our hope

prior to instituting this study was that with the decreased

2

3

4

5.

10.

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Greene WH. Schimpff SC, Young VM. Wiernik PH: Empiric carbenicillin, gentamicin and cephalothin therapy for pre- sumed infection in patients with granulocytopenia and cancer. Ann Intern Med 1973; 78: 825.

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White WG. Malow JB. Zimelis VM. Pahlavanzadeh H. Pan- walker AP. Jackson GG: Comparative in vitro activity of azlocillin. ampicillin. mezlocillin. piperacillin, and ticarcillin alone and in combination with an aminoglycoside. Antim-

sodium content of piperacillin (1.98 meq/g) compared

with that of ticarcillin (5.2 meq/g). there would be less

antibiotic-related hypokalemia [ 111. Hewitt et al. [ 271

have reported that the combination of piperacillin plus

amikacin causes less hypokalemia than the combination of carbenicillin plus amikacin. However, in our study

utilizing ticarcillin instead of carbenicillin, the incidence

of hypokalemia, mean drop in potassium and required

potassium supplement per patient were equivalent between groups.

In this double-blind prospective randomized study,

the combination of piperacillin plus amikacin provided

excellent efficacy and safety as compared with ticar-

cillin plus amikacin when used as empiric therapy for

fever. The use of piperacillin did not lessen the degree

of hypokalemia.

ACKNOWLEDGMENT

We wish to thank Paula Salvatore, Rebecca Finley and

Thomas Hornick for their expert assistance in con-

ducting this evaluation.

REFERENCES

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