Vol. 16, No. 5
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1979, p. 605-610 0066-4804/79/11-0605/06$02.00/0
Clinical Evaluation of Mezlocillin HARAGOPAL THADEPALLI*
AND
BHAVANI RAO
Division of Infectious Diseases, Martin Luther King, Jr. General Hospital, Charles R. Drew Postgraduate School of Medicine and University of Southern California School of Medicine, Los Angeles, California 90059 Received for publication 15 March 1979
The safety and efficacy of intravenous mezlocillin were determined in 25 patients with aerobic, anaerobic, and mixed infections. Included were pleuropulmonary, urinary tract, skin, and soft-tissue infections, osteomyelitis, and abdominal and breast abscess. Nineteen patients (76%) were cured without recurrence as determined by clinical and bacteriological parameters. In three, the infection recurred (12%); two patients failed (8%), and in one, it was indeterminate (4%). No serious adverse effects were noted except for severe thrombophlebitis in three (12%) patients. Our preliminary data suggest that mezlocillin is a safe (except for thrombophlebitis) and effective antibiotic in the treatment of aerobic, anaerobic, and mixed infections. counts, liver and renal function tests, and urine analysis done before, during, and after treatment. In some patients, these tests were repeated more often if clinically indicated. A clinical response was graded as "cure" when there was evidence of total resolution of the signs of infection and no recurrence within 12 weeks after discharge. When the pathogens were not eradicated from the site of infection or no improvement in clinical status was noted, or both, such patients were considered as "failures" of therapy. When the infection reappeared due to the same pathogens after their eradication, it was classified as a "recurrence." When neither the microbiological nor the clinical efficacy of the antibiotic could be determined, it was called "indeterminate." Cultures. Transtracheal aspirates or thoracentesis specimens were obtained in pleuropulmonary infections. Pus was collected at the time of surgery in abdominal abscess, breast abscess, and bone, skin, and soft-tissue infections. Midstream clean-catch urine specimens were obtained in urinary tract infections. When the infected site was accessible for culture, a set of follow-up cultures was obtained during treatment MATERIALS AND METHODS and at the end of therapy. Urine cultures were rePatients. Twenty-five patients were treated with peated 6 to 8 weeks after the termination of therapy. Anaerobic cultures were collected in sterile tubes mezlocillin after obtaining signed, informed consent. Pregnant women and those with penicillin allergy were filled with oxygen-free carbon dioxide (002) and excluded. All these patients had positive cultures be- brought to the infectious disease laboratory. The aerofore therapy. Mezlocillin (Delbay Pharmaceuticals, bic bacteria were cultured and identified by convenFlorham Park, N.J.) was reconstituted by adding 5% tional schema, and their antimicrobial susceptibility dextrose in water and administered intravenously (i.v.) was tested, either by the Kirby-Bauer method (2) or in piggyback over a period of 15 to 20 min. Twenty- by determining the minimal inhibitory concentration three patients received 20 g (5 g every 6 h) and two (MIC) by the agar dilution method (5), using a Steers patients with renal failure received 8 g (2 g every 6 h) multiple replicator apparatus. Anaerobic cultures were per day. All of these patients were treated for at least processed and identified by Virginia Polytechnic In5 days, the average being 12 (5 to 27) days. Clinical stitute Anaerobe Laboratory methods (4). The MICs evaluation of these patients consisted of a daily check for the isolates were determined by serial agar dilution of temperature and pulse in addition to periodic blood methods in the anaerobic glove box, the details of 605
Newer penicillins, such as mezlocillin and piperacillin, are improvements over carbenicillin in that they provide additional coverage against Klebsiella pneumoniae (3, 6). Like carbenicillin, mezlocillin and piperacllin are effective against Escherichia coli, Pseudomonas aeruginosa, and anaerobic bacteria, including Bacteroides fragilis (6). None of these three antibiotics is effective against penicillinase-producing Staphylococcus aureus. Because of its known efficacy against most of the aerobic and anaerobic bacteria, we evaluated the overall therapeutic safety and efficacy of mezlocillin in aerobic, anaerobic, and mixed infections. (This work was presented in part at the Annual Meeting of the American Society for Microbiology, Los Angeles, Calif. [B. Rao, I. Roy, and H. Thadepalli, Abstr. Annu. Meet. Am. Soc. Microbiol. 1979, A13, p. 3].)
606
THADEPALLI AND RAO
which were reported before (1). The serum antibiotic levels were measured by the agar well diffusion
method, utilizing Bacillus subtilis ATCC 6633 as the test organism with appropriate controls.
RESULTS Clinical results. Eight women and 17 men of an average age of 40 (20 to 90) years were treated with mezlocillin. Included were pleuropulmonary infections (five patients), osteomyelitis (five), urinary tract infections (four), abdominal abscess (four), skin and soft-tissue infection (six), and breast abscess (one). (See Table 1 for details.) Pleuropulmonary infections. Five patients (no. 1-5, Table 1) were treated with mezlocillin for an average duration of 14 (7 to 27) days. They became afebrile within 3 to 7 days. Three had exclusively aerobic infections. One had pure anaerobic infection and the other had both aerobic and anaerobic bacteria. Three patients were cured. A patient with postoperative anaerobic empyema (no. 5) failed to respond to mezlocillin therapy. She had refractory P. aeruguwsa infection, although the associated anaerobe, Fusobacterium bullosum, was eradicated. One patient with B. fragilis lung abscess (no. 4) improved on therapy but had a recurrence 6 months after mezlocillin therapy was discontinued. Bronchoscopy revealed no explanation for the recurrence of the lung abscess. A repeat transtracheal aspiration also yielded B. fragilis on culture. Osteomyelitis. Five patients (no. 6-10) with osteomyelitis were treated for an average duration of 9 (6 to 13) days, of which four patients had post-traumatic osteomyelitis of the mandible and one had spontaneous osteomyelitis of the femur. Sequestrectomy was done before or during mezlocillin therapy in all patients. All four patients with mandibular osteomyelitis had anaerobic bacteria; they responded well to therapy, but one due to S. aureus (MIC of mezlocillin, 64 ug/ml) infection had recurrence 4 weeks after discontiuing therapy. The fifth patient, with femoral osteomyelitis, failed. She had relatively resistant organisms. No improvement was noted even after 14 days of therapy. Urinary tract infection. Four patients (no. 11-14) were treated for an average period of 9 (6 to 14) days. One of them hiad pyelonephritis; prostatic hypertrophy was noted in one patient, carcinoma of the prostate was found in one, and the other had carcinoma of the urinary bladder. Associated renal failure was noted in one patient (no. 13). He received a reduced dose of mezlocillm (2 g every 6 h). All patients had satisfactory clinical and bacteriological improvement, and no
ANTimICROB. AGENTS CHEMOTHER.
recurrences were noted during the 6- to 12-week follow-up. Abdominal and perineal abscess. Four patients (no. 15-18) were treated for an average duration of 10 days (5 to 20 days). One patient had liver abscess secondary to a gunshot injury and one had subdiaphragmatic abscess; two others had perirectal abscess. All of these patients underwent surgical drainage of the pus. Good clinical response was noted in all four patients, and there were no recurrences. Skin and soft-tissue infections. Six patients (no. 19-24) were treated for an average duration of 11 (5 to 25) days. One patient (no. 21) with a giant stasis ulcer failed earlier on several antibiotic regimens but showed remarkable improvement on mezlocillin therapy, followed by excellent "take" of skin grafts. One patient with Fournier's gangrene of the penis and scrotum complicated by renal failure was treated with 2 g of mezlocillin every 6 h. He showed bacteriological and clinical cure. One patient had B. fragilis septicemia associated with Pseudomonas urinary tract infection (no. 23). In this patient, B. fragilis septicemia was eradicated, but the overall response could not be evaluated due to his death during therapy. At autopsy, he was found to have had an acute myocardial infarction. One patient with S. aureus scalded skin syndrome (no. 20) initially responded well to mezlocillin therapy, but the infection recurred 4 to 6 weeks after the discontinuation of mezlocillin. Breast abscess. One patient (no. 25) with breast abscess was treated for 12 days after surgical drainage. She responded well to mezlocillin and had no recurrence. Microbiological results. Fourteen patients had pure aerobic infections, five had exclusive anaerobic infections, and six had mixed aerobic and anaerobic infections. In all, 58 isolates were recovered from these patients; included were 45 aerobic and 13 anaerobic bacteria. All but two isolates were susceptible to mezlocillin at 128 yg/ml or less. The exceptions were one strain of E. coli (MIC, 1024 ,g/ml) and one strain of K. pneumoniae (MIC, 256 yg/ml). In spite of resistant strains, these two patients responded to mezlocilHin therapy. In contrast, persistent infection occurred in two patients with mezlocillinsusceptible bacteria, P. aeruginosa (MIC of mezlocillin, 128 tig/ml) in one and E. coli (MIC, 128 ug/ml) in the other. The infections recurred in three patients with mezlocillin-susceptible bacteria; one had anaerobic lung abscess (no. 4) and the other two (no. 6 and 20) had S. aureus (MICs 64 and 128 IAg/ml) infections. Seruih specimens were studied m lb patuents
VOL. 16, 1979
CLINICAL EVALUATION OF MEZLOCILLIN
at different time intervals. The average serum levels were 370 (100 to 1,200 ,Lg/ml) at 1 h, 350 (110 to 600) ,ug/ml at 2 h, 300 (50 to 600) ug/ml at 3 h, 63 (55 to 72) ,ug/ml at 4 h and 14 (6 to 35) ,tg/ml at 6 h after infusing 5 g of i.v. mezlocillin over a period of 15 to 20 min. Two patients with renal failure on a dose of 2 g every 6 h had higher serum mezlocillin levels (see no. 13 and 24, Table 1). One patient with severe renal failure inadvertently received 5 g of i.v. mezlocillin, after which the serum levels were up to 1,200 ,ug/ml 1 h after the infusion. Adverse effects. Thrombophlebitis was noted in most of the patients receiving the therapy for 7 days or more. It was severe in three patients but it did not require change in therapy. No hematological, renal, or hepatic dysfunction related to mezlocillin was noted in any of these patients. DISCUSSION The in vivo efficacy of mezlocillin is not established. In our study of 25 patients, 14 had aerobic infections, of which 12 were cured without recurrence, 1 failed, and 1 recurred. Seven patients in our study were infected with K. pneumoniae, of which six patients responded to mezlocillin therapy and one patient associated with Pseudomonas and Fusobacterium failed. Four of these Klebsiella isolates were resistant to carbenicillin. Pseudomonas infection is another indication for broad-spectrum penicillin therapy. Mezlocillin, in our laboratory, was more effective than carbenicillin, ticarcillin, and piperacillin against P. aeruginosa (7). Nine patients in our study were infected with P. aeruginosa, of which one of these isolates was resistant to carbenicillin (MIC, 256 ,g/ml). In eight patients, the organism was eradicated, the infected site clinically improved, and the infection did not recur. In one patient, the infection persisted, although this strain was susceptible to mezlocillin at 128 ,g/ ml. Inclusion of nine patients with S. aureus infections in this study was purely serendipitous. We were unaware of the culture results on initiation of antibiotic therapy, and, interestingly, in all nine instances there was rapid clinical improvement; therefore, no change in therapy was made. The fact that two of these patients had recurrences of their infection suggests that alternate antibiotic therapy should be considered in cases of penicillin-resistant S. aureus infection. There was a reasonably good correlation between the MICs of the pathogens and the final clinical response. For example, patients 4, 5, 6, 10, and 20 (Table 1) harbored bacteria at MICs
607
close to 128 ,ug/ml, and they had either failed or recurred. The exceptions were patients 13 and 24, who had renal failure. They had bacteria resistant to mezlocillin, but these bacteria were eradicated from the site of infection. The discrepancy between in vitro and in vivo bacterial susceptibility to antibiotics is well known. The clinical efficacy of mezlocillin in the treatment of anaerobic infections is unknown. In our study, 11 patients with anaerobic infections were treated with mezlocillin, of which 7 were cured and had no recurrences. The infection recurred after eradication in two patients and persisted in one, and one patient expired due to myocardial infarction. Five patients had Bacteroides infections, of which three were due to B. fragilis. All three patients clinically improved and B. fragilis was eradicated on mezlocillin therapy. Six months later, the infection recurred in one patient due to B. fragilis associated with other anaerobic bacteria, and in one patient the B. fragilis septicemia was promptly eradicated within 2 days, but he died of an unrelated cause 1 week later. Mezlocillin therapy for anaerobic infections, though, appears satisfactory, but more patients with B. fragilis infections should be evaluated in future studies. Mezlocillin at 64 ,ug/ml was effective against 85% of the isolates of P. aeruginosa, Klebsiella, Proteus, E. coli, and B. fragilis (6, 7). In our study, the serum mezlocillin levels were at least 300 ,tg/ml at 3 h after an i.v. infusion of 5 g of mezlocillin. With similar doses, Bodey and Pan (3) observed serum levels of 426 ± 61.3 ILg/ml after 1 h. Therefore, satisfactory serum antibiotic levels against most of the common aerobic and anaerobic bacterial pathogens can be easily achieved with i.v. mezlocillin when given in a dose of 20 g/day. At this dosage, no major adverse effects were noted. In our experience, severe thrombophlebitis requiring frequent change in the infusing site was common with i.v. mezlocillin therapy, and it occurred in almost all
patients. Our study suggests that i.v. mezlocillin may be a satisfactory form of therapy for aerobic gram-negative infections such as Klebsiella and Pseudomonas and in infections associated with anaerobic bacteria. Further studies are needed to evaluate its efficacy in B. fragilis infections (6). Perhaps by further dilution and slow i.v. drip the incidence of thrombophlebitis could have been decreased. With the exception of thrombophlebitis, mezlocillin appears to be a safe and well-tolerated antibiotic. Our previous in vitro results and the present in vivo results suggest that mezlocillin can be used as a single antibiotic even in mixed aerobic and anaerobic
ANTIMICROB. AGENTS CHEMOTHER.
THADEPALLI AND RAO
608
0
CD
0~~00
0 0
0
d0
~ -~~ C 00
ade00
030
Od "0
~~~~
cq cq
00 ~~ c'~ ~ ~ bQ ~~~~~
0
o~~~~~~~~~~~~~0
0
cis~
"e
0d
~
'0
'0
0
0
~
' 0(' '0 ..
~ -6 c~~~ c~~~~Ci -
0.-0 0~~~~~~~~~~~~~~~~~4
0
U~~~~~~~~~~~~~~~~~~~~ N~~~~~~~
0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
A
U~~~~O U~~~~~~~~
0
z Z Z ~~~~~~~A4-o~ 0 ~~~~
Z4 Z
P
0
.0>
0 0 ~~ ~~~~0
0
0 0~
S'~~~~ ~ ~
~0
0.
cq m ~
~
~
o
0
0
t-
S0
~
~ 0
0
42
4
0
Z
Z
VOL. 16, 1979
CLINICAL EVALUATION OF MEZLOCILLIN
609
I
C)
00
'b
=C
10C
0
C)
0a
0
10
0
C)
C)
+a *1
la
0
0
10
C)
C)
C)
C)
-4~~~~.4
.4j
-62
C
0
0
*0
C)0S 0
Q
$14
14
C)
1.4
cw
ad
w
t
1
w
Y
-~~~~e
-
c11
CD
$i
CL
C)
U)
_ 0S 0
a
~
0 C.)
1..
)
co C) C)
1_
CU
0
0
0
0
q00
~
00~~~
CA _ _
0-^
_
oD
* :
w
'Ilr-E
S C4 C
0
C)
0s
"0
S3F3
I
Do
,
go
a
w'
0o
^p
F
A4
0
LO
X
wco 3
)
00 -4a
CD
r-
0
Om r-4
0
c'
Cq4
Cq
m e
c~1
10l
cq1
610
THADEPALLI AND RAO
infections caused by mezlocilhin-susceptible bacteria. LITERATURE CITED 1. Aranki, A., S. A. Syed, E. B. Kenny, and R. Freter. 1969. Isolation of anaerobic bacteria from gingiva and mouse cecum by means of a simplified glove box procedure. Appl. Microbiol. 17:568-572. 2. Bauer, A. W., W. M. M. Kirby, J. C. Sherris, and M. Turck. 1966. Antibiotic testing by a standardized single disc melthod. Am. J. Clin. Pathol. 45:493-496. 3. Bodey, G. P., and T. Pan. 1977. In vitro studies of a new broad-spectrum penicillin. Antimicrob. Agents Chemother. 11:74-79.
ANTIMICROB. AGENTS CHEMOTHER. 4. Holdeman, L. V., and W. E. C. Moore. 1977. Anaerobe laboratory manual. Virginia Polytechnic Institute Anaerobe Laboratory, Virginia Polytechnic Institute and State University, Blacksburg. 5. Steers, E., E. L. Foltz, and B. S. Graves. 1959. An inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother. 9:307-311. 6. Sutter, V. L., and S. M. Finegold. 1976. Susceptibility of anaerobic bacteria to 23 antimicrobial agents. Antimicrob. Agents Chemother. 10:736-752. 7. Thadepalli, H., L. Roy, V. T. Bach, and D. Webb. 1979. In vitro activity of mezlocillin and its related compounds against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 15:487-490.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1979, p. 605-610 0066-4804/79/11-0605/06$02.00/0
Clinical Evaluation of Mezlocillin HARAGOPAL THADEPALLI*
AND
BHAVANI RAO
Division of Infectious Diseases, Martin Luther King, Jr. General Hospital, Charles R. Drew Postgraduate School of Medicine and University of Southern California School of Medicine, Los Angeles, California 90059 Received for publication 15 March 1979
The safety and efficacy of intravenous mezlocillin were determined in 25 patients with aerobic, anaerobic, and mixed infections. Included were pleuropulmonary, urinary tract, skin, and soft-tissue infections, osteomyelitis, and abdominal and breast abscess. Nineteen patients (76%) were cured without recurrence as determined by clinical and bacteriological parameters. In three, the infection recurred (12%); two patients failed (8%), and in one, it was indeterminate (4%). No serious adverse effects were noted except for severe thrombophlebitis in three (12%) patients. Our preliminary data suggest that mezlocillin is a safe (except for thrombophlebitis) and effective antibiotic in the treatment of aerobic, anaerobic, and mixed infections. counts, liver and renal function tests, and urine analysis done before, during, and after treatment. In some patients, these tests were repeated more often if clinically indicated. A clinical response was graded as "cure" when there was evidence of total resolution of the signs of infection and no recurrence within 12 weeks after discharge. When the pathogens were not eradicated from the site of infection or no improvement in clinical status was noted, or both, such patients were considered as "failures" of therapy. When the infection reappeared due to the same pathogens after their eradication, it was classified as a "recurrence." When neither the microbiological nor the clinical efficacy of the antibiotic could be determined, it was called "indeterminate." Cultures. Transtracheal aspirates or thoracentesis specimens were obtained in pleuropulmonary infections. Pus was collected at the time of surgery in abdominal abscess, breast abscess, and bone, skin, and soft-tissue infections. Midstream clean-catch urine specimens were obtained in urinary tract infections. When the infected site was accessible for culture, a set of follow-up cultures was obtained during treatment MATERIALS AND METHODS and at the end of therapy. Urine cultures were rePatients. Twenty-five patients were treated with peated 6 to 8 weeks after the termination of therapy. Anaerobic cultures were collected in sterile tubes mezlocillin after obtaining signed, informed consent. Pregnant women and those with penicillin allergy were filled with oxygen-free carbon dioxide (002) and excluded. All these patients had positive cultures be- brought to the infectious disease laboratory. The aerofore therapy. Mezlocillin (Delbay Pharmaceuticals, bic bacteria were cultured and identified by convenFlorham Park, N.J.) was reconstituted by adding 5% tional schema, and their antimicrobial susceptibility dextrose in water and administered intravenously (i.v.) was tested, either by the Kirby-Bauer method (2) or in piggyback over a period of 15 to 20 min. Twenty- by determining the minimal inhibitory concentration three patients received 20 g (5 g every 6 h) and two (MIC) by the agar dilution method (5), using a Steers patients with renal failure received 8 g (2 g every 6 h) multiple replicator apparatus. Anaerobic cultures were per day. All of these patients were treated for at least processed and identified by Virginia Polytechnic In5 days, the average being 12 (5 to 27) days. Clinical stitute Anaerobe Laboratory methods (4). The MICs evaluation of these patients consisted of a daily check for the isolates were determined by serial agar dilution of temperature and pulse in addition to periodic blood methods in the anaerobic glove box, the details of 605
Newer penicillins, such as mezlocillin and piperacillin, are improvements over carbenicillin in that they provide additional coverage against Klebsiella pneumoniae (3, 6). Like carbenicillin, mezlocillin and piperacllin are effective against Escherichia coli, Pseudomonas aeruginosa, and anaerobic bacteria, including Bacteroides fragilis (6). None of these three antibiotics is effective against penicillinase-producing Staphylococcus aureus. Because of its known efficacy against most of the aerobic and anaerobic bacteria, we evaluated the overall therapeutic safety and efficacy of mezlocillin in aerobic, anaerobic, and mixed infections. (This work was presented in part at the Annual Meeting of the American Society for Microbiology, Los Angeles, Calif. [B. Rao, I. Roy, and H. Thadepalli, Abstr. Annu. Meet. Am. Soc. Microbiol. 1979, A13, p. 3].)
606
THADEPALLI AND RAO
which were reported before (1). The serum antibiotic levels were measured by the agar well diffusion
method, utilizing Bacillus subtilis ATCC 6633 as the test organism with appropriate controls.
RESULTS Clinical results. Eight women and 17 men of an average age of 40 (20 to 90) years were treated with mezlocillin. Included were pleuropulmonary infections (five patients), osteomyelitis (five), urinary tract infections (four), abdominal abscess (four), skin and soft-tissue infection (six), and breast abscess (one). (See Table 1 for details.) Pleuropulmonary infections. Five patients (no. 1-5, Table 1) were treated with mezlocillin for an average duration of 14 (7 to 27) days. They became afebrile within 3 to 7 days. Three had exclusively aerobic infections. One had pure anaerobic infection and the other had both aerobic and anaerobic bacteria. Three patients were cured. A patient with postoperative anaerobic empyema (no. 5) failed to respond to mezlocillin therapy. She had refractory P. aeruguwsa infection, although the associated anaerobe, Fusobacterium bullosum, was eradicated. One patient with B. fragilis lung abscess (no. 4) improved on therapy but had a recurrence 6 months after mezlocillin therapy was discontinued. Bronchoscopy revealed no explanation for the recurrence of the lung abscess. A repeat transtracheal aspiration also yielded B. fragilis on culture. Osteomyelitis. Five patients (no. 6-10) with osteomyelitis were treated for an average duration of 9 (6 to 13) days, of which four patients had post-traumatic osteomyelitis of the mandible and one had spontaneous osteomyelitis of the femur. Sequestrectomy was done before or during mezlocillin therapy in all patients. All four patients with mandibular osteomyelitis had anaerobic bacteria; they responded well to therapy, but one due to S. aureus (MIC of mezlocillin, 64 ug/ml) infection had recurrence 4 weeks after discontiuing therapy. The fifth patient, with femoral osteomyelitis, failed. She had relatively resistant organisms. No improvement was noted even after 14 days of therapy. Urinary tract infection. Four patients (no. 11-14) were treated for an average period of 9 (6 to 14) days. One of them hiad pyelonephritis; prostatic hypertrophy was noted in one patient, carcinoma of the prostate was found in one, and the other had carcinoma of the urinary bladder. Associated renal failure was noted in one patient (no. 13). He received a reduced dose of mezlocillm (2 g every 6 h). All patients had satisfactory clinical and bacteriological improvement, and no
ANTimICROB. AGENTS CHEMOTHER.
recurrences were noted during the 6- to 12-week follow-up. Abdominal and perineal abscess. Four patients (no. 15-18) were treated for an average duration of 10 days (5 to 20 days). One patient had liver abscess secondary to a gunshot injury and one had subdiaphragmatic abscess; two others had perirectal abscess. All of these patients underwent surgical drainage of the pus. Good clinical response was noted in all four patients, and there were no recurrences. Skin and soft-tissue infections. Six patients (no. 19-24) were treated for an average duration of 11 (5 to 25) days. One patient (no. 21) with a giant stasis ulcer failed earlier on several antibiotic regimens but showed remarkable improvement on mezlocillin therapy, followed by excellent "take" of skin grafts. One patient with Fournier's gangrene of the penis and scrotum complicated by renal failure was treated with 2 g of mezlocillin every 6 h. He showed bacteriological and clinical cure. One patient had B. fragilis septicemia associated with Pseudomonas urinary tract infection (no. 23). In this patient, B. fragilis septicemia was eradicated, but the overall response could not be evaluated due to his death during therapy. At autopsy, he was found to have had an acute myocardial infarction. One patient with S. aureus scalded skin syndrome (no. 20) initially responded well to mezlocillin therapy, but the infection recurred 4 to 6 weeks after the discontinuation of mezlocillin. Breast abscess. One patient (no. 25) with breast abscess was treated for 12 days after surgical drainage. She responded well to mezlocillin and had no recurrence. Microbiological results. Fourteen patients had pure aerobic infections, five had exclusive anaerobic infections, and six had mixed aerobic and anaerobic infections. In all, 58 isolates were recovered from these patients; included were 45 aerobic and 13 anaerobic bacteria. All but two isolates were susceptible to mezlocillin at 128 yg/ml or less. The exceptions were one strain of E. coli (MIC, 1024 ,g/ml) and one strain of K. pneumoniae (MIC, 256 yg/ml). In spite of resistant strains, these two patients responded to mezlocilHin therapy. In contrast, persistent infection occurred in two patients with mezlocillinsusceptible bacteria, P. aeruginosa (MIC of mezlocillin, 128 tig/ml) in one and E. coli (MIC, 128 ug/ml) in the other. The infections recurred in three patients with mezlocillin-susceptible bacteria; one had anaerobic lung abscess (no. 4) and the other two (no. 6 and 20) had S. aureus (MICs 64 and 128 IAg/ml) infections. Seruih specimens were studied m lb patuents
VOL. 16, 1979
CLINICAL EVALUATION OF MEZLOCILLIN
at different time intervals. The average serum levels were 370 (100 to 1,200 ,Lg/ml) at 1 h, 350 (110 to 600) ,ug/ml at 2 h, 300 (50 to 600) ug/ml at 3 h, 63 (55 to 72) ,ug/ml at 4 h and 14 (6 to 35) ,tg/ml at 6 h after infusing 5 g of i.v. mezlocillin over a period of 15 to 20 min. Two patients with renal failure on a dose of 2 g every 6 h had higher serum mezlocillin levels (see no. 13 and 24, Table 1). One patient with severe renal failure inadvertently received 5 g of i.v. mezlocillin, after which the serum levels were up to 1,200 ,ug/ml 1 h after the infusion. Adverse effects. Thrombophlebitis was noted in most of the patients receiving the therapy for 7 days or more. It was severe in three patients but it did not require change in therapy. No hematological, renal, or hepatic dysfunction related to mezlocillin was noted in any of these patients. DISCUSSION The in vivo efficacy of mezlocillin is not established. In our study of 25 patients, 14 had aerobic infections, of which 12 were cured without recurrence, 1 failed, and 1 recurred. Seven patients in our study were infected with K. pneumoniae, of which six patients responded to mezlocillin therapy and one patient associated with Pseudomonas and Fusobacterium failed. Four of these Klebsiella isolates were resistant to carbenicillin. Pseudomonas infection is another indication for broad-spectrum penicillin therapy. Mezlocillin, in our laboratory, was more effective than carbenicillin, ticarcillin, and piperacillin against P. aeruginosa (7). Nine patients in our study were infected with P. aeruginosa, of which one of these isolates was resistant to carbenicillin (MIC, 256 ,g/ml). In eight patients, the organism was eradicated, the infected site clinically improved, and the infection did not recur. In one patient, the infection persisted, although this strain was susceptible to mezlocillin at 128 ,g/ ml. Inclusion of nine patients with S. aureus infections in this study was purely serendipitous. We were unaware of the culture results on initiation of antibiotic therapy, and, interestingly, in all nine instances there was rapid clinical improvement; therefore, no change in therapy was made. The fact that two of these patients had recurrences of their infection suggests that alternate antibiotic therapy should be considered in cases of penicillin-resistant S. aureus infection. There was a reasonably good correlation between the MICs of the pathogens and the final clinical response. For example, patients 4, 5, 6, 10, and 20 (Table 1) harbored bacteria at MICs
607
close to 128 ,ug/ml, and they had either failed or recurred. The exceptions were patients 13 and 24, who had renal failure. They had bacteria resistant to mezlocillin, but these bacteria were eradicated from the site of infection. The discrepancy between in vitro and in vivo bacterial susceptibility to antibiotics is well known. The clinical efficacy of mezlocillin in the treatment of anaerobic infections is unknown. In our study, 11 patients with anaerobic infections were treated with mezlocillin, of which 7 were cured and had no recurrences. The infection recurred after eradication in two patients and persisted in one, and one patient expired due to myocardial infarction. Five patients had Bacteroides infections, of which three were due to B. fragilis. All three patients clinically improved and B. fragilis was eradicated on mezlocillin therapy. Six months later, the infection recurred in one patient due to B. fragilis associated with other anaerobic bacteria, and in one patient the B. fragilis septicemia was promptly eradicated within 2 days, but he died of an unrelated cause 1 week later. Mezlocillin therapy for anaerobic infections, though, appears satisfactory, but more patients with B. fragilis infections should be evaluated in future studies. Mezlocillin at 64 ,ug/ml was effective against 85% of the isolates of P. aeruginosa, Klebsiella, Proteus, E. coli, and B. fragilis (6, 7). In our study, the serum mezlocillin levels were at least 300 ,tg/ml at 3 h after an i.v. infusion of 5 g of mezlocillin. With similar doses, Bodey and Pan (3) observed serum levels of 426 ± 61.3 ILg/ml after 1 h. Therefore, satisfactory serum antibiotic levels against most of the common aerobic and anaerobic bacterial pathogens can be easily achieved with i.v. mezlocillin when given in a dose of 20 g/day. At this dosage, no major adverse effects were noted. In our experience, severe thrombophlebitis requiring frequent change in the infusing site was common with i.v. mezlocillin therapy, and it occurred in almost all
patients. Our study suggests that i.v. mezlocillin may be a satisfactory form of therapy for aerobic gram-negative infections such as Klebsiella and Pseudomonas and in infections associated with anaerobic bacteria. Further studies are needed to evaluate its efficacy in B. fragilis infections (6). Perhaps by further dilution and slow i.v. drip the incidence of thrombophlebitis could have been decreased. With the exception of thrombophlebitis, mezlocillin appears to be a safe and well-tolerated antibiotic. Our previous in vitro results and the present in vivo results suggest that mezlocillin can be used as a single antibiotic even in mixed aerobic and anaerobic
ANTIMICROB. AGENTS CHEMOTHER.
THADEPALLI AND RAO
608
0
CD
0~~00
0 0
0
d0
~ -~~ C 00
ade00
030
Od "0
~~~~
cq cq
00 ~~ c'~ ~ ~ bQ ~~~~~
0
o~~~~~~~~~~~~~0
0
cis~
"e
0d
~
'0
'0
0
0
~
' 0(' '0 ..
~ -6 c~~~ c~~~~Ci -
0.-0 0~~~~~~~~~~~~~~~~~4
0
U~~~~~~~~~~~~~~~~~~~~ N~~~~~~~
0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
A
U~~~~O U~~~~~~~~
0
z Z Z ~~~~~~~A4-o~ 0 ~~~~
Z4 Z
P
0
.0>
0 0 ~~ ~~~~0
0
0 0~
S'~~~~ ~ ~
~0
0.
cq m ~
~
~
o
0
0
t-
S0
~
~ 0
0
42
4
0
Z
Z
VOL. 16, 1979
CLINICAL EVALUATION OF MEZLOCILLIN
609
I
C)
00
'b
=C
10C
0
C)
0a
0
10
0
C)
C)
+a *1
la
0
0
10
C)
C)
C)
C)
-4~~~~.4
.4j
-62
C
0
0
*0
C)0S 0
Q
$14
14
C)
1.4
cw
ad
w
t
1
w
Y
-~~~~e
-
c11
CD
$i
CL
C)
U)
_ 0S 0
a
~
0 C.)
1..
)
co C) C)
1_
CU
0
0
0
0
q00
~
00~~~
CA _ _
0-^
_
oD
* :
w
'Ilr-E
S C4 C
0
C)
0s
"0
S3F3
I
Do
,
go
a
w'
0o
^p
F
A4
0
LO
X
wco 3
)
00 -4a
CD
r-
0
Om r-4
0
c'
Cq4
Cq
m e
c~1
10l
cq1
610
THADEPALLI AND RAO
infections caused by mezlocilhin-susceptible bacteria. LITERATURE CITED 1. Aranki, A., S. A. Syed, E. B. Kenny, and R. Freter. 1969. Isolation of anaerobic bacteria from gingiva and mouse cecum by means of a simplified glove box procedure. Appl. Microbiol. 17:568-572. 2. Bauer, A. W., W. M. M. Kirby, J. C. Sherris, and M. Turck. 1966. Antibiotic testing by a standardized single disc melthod. Am. J. Clin. Pathol. 45:493-496. 3. Bodey, G. P., and T. Pan. 1977. In vitro studies of a new broad-spectrum penicillin. Antimicrob. Agents Chemother. 11:74-79.
ANTIMICROB. AGENTS CHEMOTHER. 4. Holdeman, L. V., and W. E. C. Moore. 1977. Anaerobe laboratory manual. Virginia Polytechnic Institute Anaerobe Laboratory, Virginia Polytechnic Institute and State University, Blacksburg. 5. Steers, E., E. L. Foltz, and B. S. Graves. 1959. An inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother. 9:307-311. 6. Sutter, V. L., and S. M. Finegold. 1976. Susceptibility of anaerobic bacteria to 23 antimicrobial agents. Antimicrob. Agents Chemother. 10:736-752. 7. Thadepalli, H., L. Roy, V. T. Bach, and D. Webb. 1979. In vitro activity of mezlocillin and its related compounds against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 15:487-490.
