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The efficacy of mexlocillin-amikacin combination as empirical therapy for febrile neutropenic patients was studied in 30 children (21 males, 9 females) with various oncologic diseases aged 1-15 years (mean age 7.3 +/- 4.4) in the Istanbul Medical School, Oncologic Disease Research and Treatment Center, and Department of Pediatric Hematology-Oncology between January 1 and May 31, 1988. The response rate was 76.6%. Profound persistent granulocytopenia (fewer than 100 ml) was present in 70% of the patients. In 63.3% of patients, the infections were microbiologically documented (60%) Gram(+) and 40% Gram(-). The combination was well tolerated with hepatic and/or renal disturbances in 8 cases (26.6%). We conclude that mezlocillin-amikacin is an effective empirical combination in the initial treatment of infections in febrile neutropenic children with various oncologic diseases.

It is already known that physiological microflora of the digestive system plays an important role in local immunity. Studies on immunomodulating activity of some autoantibodies have shown that drugs affecting intestinal microflora possess potent immunosuppressive effect on systemic immunity. These observations inspired to recent investigation on the mechanisms of the influence of digestive tract bacteria on the immune system.

Charts were reviewed for 63 patients whose chronic pseudomonas osteomyelitis was treated with high doses of extended-spectrum penicillins for prolonged periods. The incidence of untoward drug reactions was significantly higher than expected. Carbenicillin evoked adverse reactions in 22.8% of patients. However, most of these reactions were mild, and a change of drug was required in only 5.7% of cases. No adverse drug reactions were observed with cumulative doses of less than 750 g. In contrast to carbenicillin, the ureidopenicillins were associated with adverse reactions in 67.7% of patients; most reactions were moderate to severe in intensity; a cumulative dose of greater than 250 g produced adverse reactions; and discontinuation or change of therapy was required in 51.6% of cases. The main adverse reactions to both carbenicillin and the ureidopenicillins included rash, drug fever, leukopenia, eosinophilia, thrombocytopenia, and hepatic damage.

In a prospective, randomized trial of 195 febrile episodes in granulocytopenic patients short course aminoglycoside treatment (initial tobramycin and cefoperazone followed by tobramycin discontinuation at day four of therapy) was compared with two regimens (tobramycin plus cefoperazone and tobramycin plus mezlocillin) in which both drugs were continued for up to 26 days. All regimens were successful as empirical therapy with comparable response rates of just over seventy per cent. Fifty-three per cent of the initial episodes of fever were related to documented infections which responded less well (P = 0.007) than unexplained fever. Patients with bacteraemia, pneumonia or Gram-positive aerobic or Pseudomonas aeruginosa infections responded poorly to all regimens. The recovery from granulocytopenia was the most important determinant of successful response. Aminoglycoside discontinuation followed by cefoperazone monotherapy after day four was statistically as effective as the combination regimens. Short course tobramycin therapy eliminated the nephrotoxicity seen in the combination limbs. The use of cefoperazone was not associated with an increased incidence of hypoprothrombinemia; however, the only three bleeding episodes occurred in patients given cefoperazone but not vitamin K. Short course aminoglycoside therapy will reduce cost and nephrotoxicity when compared with prolonged combination therapy and should be further explored in this setting, with use of different agents and comparison with monotherapy.

Increasing pressure to cut the length of hospital stay has resulted in a large number of patients receiving home parenteral antibiotic therapy. We present a case of an immediate allergic reaction in a penicillin-sensitive spouse of a patient receiving parenteral mezlocillin sodium therapy. A seminal level of 42 micrograms/mL of mezlocillin was documented by bioassay.

In 54 patients suffering from a variety of severe systemic infections the combination of mezlocillin (4 g iv 6-hourly) plus cefotaxime (2 g iv 8-hourly) was compared to that of gentamicin (1.5 mg/kg im or iv 8-hourly) plus cefoxitin (2 g iv 6-hourly). In the gentamicin/cefoxitin group metronidazole (500 mg iv 8-hourly) was added for anaerobic infections. Treatment assignment was randomized. The patients' diagnoses were: pyelonephritis (24), pneumonia (14), infected burns (9), osteomyelitis (2), and abdominal infections (5). Pathogens included: Escherichia coli (31), other Enterobacteriaceae (21), Pseudomonas aeruginosa (13), anaerobes (4), and others (2). Treatment with mezlocillin/cefotaxime cured 20 (74%) of 27 patients and caused improvement in 5, while in 19 (70%) patients the pathogens were eradicated. In the gentamicin/cefoxitin group 17 (63%) of 27 patients were cured and 6 improved, while in 15 (56%) pathogens were eradicated. One patient in the first group developed a rash, while in the second group two patients developed thrombophlebitis and another two transient nephrotoxicity. The combination of mezlocillin and cefotaxime can be recommended for the rational and empirical treatment of serious systemic infections.

This study was done to determine if a single drug, mezlocillin (Mezlo), is as safe and as effective as combined clindamycin (Clind) and gentamicin (Gent) in the treatment of penetrating abdominal wounds. One hundred seventy-three patients received either Mezlo or Clind/Gent combined therapy as assigned by computer-generated randomization. Of these, 147 patients were evaluable. Of 73 patients treated with Clind/Gent the mean duration of hospital stay was 8.9 +/- 4.0 days. Infectious complications developed in 18 patients of whom five failed to respond promptly, but only one required change in therapy. Of 74 patients treated with Mezlo, the mean duration of hospital stay was 9.1 +/- 5.0 days. Infectious complications occurred in 17, in whom four patients failed to eliminate their infections, and two needed changes in antibiotic therapy. None of the patients in either antibiotic group failed because of Enterococcus or Pseudomonas infections. There were no deaths. Twelve isolates of Bacteroides were found in peritoneal fluid cultures and all these patients had colon injuries. The overall therapeutic response was excellent to good in 94% on Clind/Gent and 93% on Mezlo. Azotemia developed in one patient on Clind/Genet and one on Mezlo but no other adverse reactions occurred. The differences shown between the two groups were not statistically significant. We conclude that a single drug mezlocillin is as safe and as effective in the treatment of abdominal trauma as combined clindamycin and gentamicin.

Two patients developed acute interstitial nephritis (AIN) following treatment with mezlocillin sodium. Diagnosis was made by renal biopsy. Gallium 67 citrate scanning was abnormal in both. All patients were receiving multiple-drug therapy, but AIN has either not been described with the other drugs, or the temporal relationship between the AIN and termination of other drug therapy makes a causative relationship unlikely. All were infected with Pseudomonas aeruginosa. A role for the infecting organism or drug synergism in contributing to the renal disease cannot be excluded.

The efficacy of mezlocillin versus cefoxitin versus clindamycin plus gentamicin was evaluated in 152 patients with postpartum endometritis. There were no statistically significant differences in rate of cure among the three groups (87% with mezlocillin, 82% with cefoxitin, and 92% with clindamycin-gentamicin). There were no severe adverse reactions observed in any of the three treatment regimens. Mezlocillin is as safe and effective as cefoxitin and clindamycin-gentamicin for treatment of postpartum endometritis.

Neutropenia associated with beta-lactam antibiotics has been widely reported since the first case was described in 1946. Cross-reactivity between beta-lactam antibiotics for this phenomenon rarely has been reported. This case describes the development of neutropenia after a course of mezlocillin, resolution upon discontinuation, and recurrence promptly after initiation of piperacillin, with resolution subsequent to discontinuation. Clinical practitioners should be aware that this adverse drug reaction has been associated with the newer beta-lactam antibiotics and that cross-reactivity may occur between these antibiotics.

Two dosing regimens of cefoperazone plus mezlocillin were compared in a prospective, randomized trial for therapy of febrile cancer patients. The two regimens were 5 g mezlocillin plus 2 g cefoperazone intravenously every four hours (higher dose) or 3 g mezlocillin plus 1 g cefoperazone intravenously every four hours (lower dose). Although the overall response rate was higher with the higher dose regimen (78 percent versus 66 percent, p = 0.04), the two regimens were comparable in patients with documented infections (72 percent versus 68 percent). Likewise, the two regimens were equally effective against those infections in which the pathogen could be determined (82 percent versus 82 percent). Serum bactericidal titers of at least 1:32 against a known pathogen were associated with a higher response rate than were titers of less than 1:32, but the higher dose regimen did not result in higher serum bactericidal titers. Hypoprothrombinemia was a side effect, especially with the higher dose regimen, before prophylactic vitamin K was routinely administered to patients. Since there were no major benefits with the use of the higher dose regimen of mezlocillin plus cefoperazone, the lower dose regimen is more appropriate for routine usage.

The double beta-lactam combination of cefoperazone plus piperacillin was compared with an aminoglycoside-containing regimen of mezlocillin plus tobramycin in a prospective, randomized trial of empiric therapy for febrile neutropenic patients (neutrophils no more than 1,000/mm3). Thirty febrile episodes were treated with cefoperazone plus piperacillin and mezlocillin plus tobramycin, respectively. There was no significant difference between the two groups with respect to age, sex, pretherapy neutrophil count, and mean duration of therapy. The majority of patients had neutrophil counts of no more than 200/mm3 at the initiation of therapy. Only microbiologically and clinically documented infections were evaluated for efficacy. The cefoperazone plus piperacillin regimen appeared to have a comparable response rate with the mezlocillin plus tobramycin regimen (20 of 24 patients [83 percent] versus 16 of 23 patients [70 percent]). Gram-positive micro-organisms were seen predominantly in this study, with the cefoperazone plus piperacillin regimen achieving a bacteriologic response in 84 percent, as opposed to 60 percent for those organisms treated with the mezlocillin plus tobramycin regimen. Neither regimen was totally effective against coagulase-negative staphylococci. Eight superinfections occurred in the cefoperazone plus piperacillin arm, whereas 11 superinfections occurred in the mezlocillin plus tobramycin arm. Although fungal superinfections were most common, the number of gram-positive superinfections in the mezlocillin plus tobramycin arm exceeded those seen in the cefoperazone plus piperacillin arm. The incidence of antibiotic-related side effects was similar in the two groups. Hypokalemia was most frequently seen. Both skin rashes and nephrotoxicity were more common with mezlocillin plus tobramycin. Cefoperazone plus piperacillin was found to be effective empiric therapy in febrile neutropenic patients. This double beta-lactam combination may be particularly useful for patients who have or are at high risk for the development of renal insufficiency.

Clinical and bacteriological efficacy of mezlocillin was evaluated in 41 neonates (including 12 premature babies) with clinical and laboratory evidence of bacterial infection, as shown by elevated C-reactive protein serum concentrations. They received intravenous mezlocillin (80 to 100 mg/kg/dose) every 8 h for 10.4 days. The mean serum concentration (+/- S.E.M.) of mezlocillin in full-term neonates was 214 +/- 19.8 mg/l 1 h after the infusion and 52.0 +/- 9.3 mg/l prior to the next infusion. In premature neonates these mean concentrations were respectively 167 +/- 23.4 mg/l and 40.7 +/- 6.7 mg/l. The efficacy of mezlocillin was documented by the decrease in C-reactive protein serum concentrations and by improvement in clinical condition. Therapy with mezlocillin alone proved to be safe and effective when used for non-nosocomial infections during the neonatal period.

The acylureidopenicillins azlocillin and mezlocillin cover a broad spectrum of bacteria, including gramnegative and grampositive species as well as anaerobes. Azlocillin is especially active against P. aeruginosa. Mezlocillin has a good activity against Klebsiella. Both antibiotics inhibit Hemophilus, N. meningitidis and D. pneumoniae in low concentrations. Clinical and kinetic studies were made in more than 300 pediatric patients. Elimination-constant halflife, distribution volume and area under the curve were determined to propose dosage recommendations. Concentrations of azlocillin (44) and mezlocillin (77) were measured in the bronchial secretions. Up to hour 5 after i.v. injection a wide range of concentration values were observed. Azlocillin was found in the meconium in different concentrations after a single injection into the newborn. Mezlocillin diffused into the CSF even in uninflamed meninges, 3 h after injection the mean concentrations were 5.5 mg/l. 39 patients, 35 of them infected by P. aeruginosa, were treated by azlocillin. Urinary tract infections, wound infections and dacryocystitis were cured with one exception. Less convincing were the results in complicated bronchopulmonary diseases. The clinical efficacy of mezlocillin was similar. In a group of 59 patients there were only 3 without effect and some with improvement again in complicated pulmonary diseases. Side effects worth to be mentioned were not seen. In 2 patients the azlocillin injection caused nausea. Mezlocillin led to some minor transitory elevations of the transaminases and dyspepsia in some patients.

Seventy-eight patients with cancer experienced 88 episodes of fever while neutropenic and were randomly assigned to receive empiric antibiotic therapy with cefoperazone 2 g intravenously every 12 hours and mezlocillin 4 g intravenously every six hours or imipenem/cilastatin 500 mg intravenously over 30 to 60 minutes every six hours. Within 96 hours of starting antibiotic treatment, 24 patients (57 percent) treated with cefoperazone and mezlocillin and 34 patients (74 percent) receiving imipenem/cilastatin became afebrile. One half of the patients in each arm required changes in the antibiotic regimen because of side effects, persistent fever with a site suspicious for infection, resistant organisms, or breakthrough bacteremias. Forty patients (95 percent) receiving cefoperazone and mezlocillin and 43 patients (93 percent) receiving imipenem/cilastatin recovered from the neutropenic episode. Two patients in each regimen group died of their underlying disease. One patient in the imipenem/cilastatin arm died of Pseudomonas aeruginosa sepsis. Although the two regimens are comparable in efficacy, the incidence of side effects favored the cefoperazone and mezlocillin group. No seizures or bleeding were seen in either arm; however, 19 patients (41 percent) receiving imipenem/cilastatin required pretreatment antiemetic drugs for nausea.

In a prospective, randomized, open trial, efficacy of one dose of sulbactam/ampicillin (1 g:2 g) was compared to three doses of mezlocillin/oxacillin (2 g:1 g), starting with induction of anesthesia in 80 breast surgery patients with an increased risk of postoperative infection. No infections at the site of operation were seen in either group. Fever due to postoperative pulmonary complications occurred in one patient in the sulbactam/ampicillin group. The only side effect was a moderate exanthema observed in one patient in the mezlocillin/oxacillin group. In this study of the prophylaxis of patients with an increased risk of postoperative infections having the potential to jeopardize the results of surgery, a single dose of sulbactam/ampicillin was as effective as a short term course of three doses of mezlocillin/oxacillin.

Carbenicillin and mezlocillin are widely used for treatment of Pseudomonas infections in patients with cancer. Carbenicillin has been reported to cause platelet dysfunction and bleeding diathesis in some individuals. We evaluated whether carbenicillin causes deterioration of platelet function in patients with cancer and whether mezlocillin causes similar effects on platelets from normal subjects or from patients with cancer. In these in vitro studies, carbenicillin and mezlocillin decreased ADP and epinephrine-induced platelet aggregation and thromboxane A2 generation similarly, but only in concentrations of 3.2 mg/ml or higher. In contrast, carbenicillin was more potent than mezlocillin in decreasing ristocetin-induced platelet aggregation. We also evaluated effects of these antibiotics on platelet function in 19 patients with cancer who developed fever and neutropenia. These patients received either mezlocillin (10 patients) or carbenicillin (nine patients) in combination with nafcillin and gentamycin. Neither carbenicillin nor mezlocillin had any significant effect on platelet aggregation or thromboxane A2 generation. Lack of effects in vivo was due to defective platelet function in these patients prior to any antibiotics. These defects were most probably related to underlying disease and/or prior chemotherapy. Thus, carbenicillin and mezlocillin can both safely be used in patients with cancer who develop fever and neutropenia, and neither seems to have advantage over the other in terms of platelet function.

The nephrotoxicity of the aminoglycoside amikacin sulfate was evaluated in an open, controlled study of newborns with presumed neonatal sepsis. One hundred twelve neonates were randomly allocated to receive either amikacin-ampicillin or mezlocillin, a semisynthetic penicillin. Neonates receiving amikacin, in contrast to those receiving mezlocillin, showed significant nephrotoxicity as evidenced by a delayed postnatal fall in mean serum creatinine level (82 to 80 mumol/L [0.93 to 0.90 mg/dL] vs 84 to 72 mumol/L [0.95 to 0.82 mg/dL]) and a delayed postnatal rise in mean creatinine clearance per kilogram of body weight (12% vs 38%). Furthermore, 40% of neonates receiving amikacin-ampicillin compared with 19% of neonates receiving mezlocillin had a decline in creatinine clearance (greater than 25%). There was no relationship between amikacin nephrotoxicity and either peak or trough amikacin levels. In summary, in a controlled study of the use of amikacin and mezlocillin in neonates, the combination of amikacin and ampicillin proved more nephrotoxic to the newborn kidney.

In a retrospective study we have compared the toxic side effects related to the use of two antibiotic regimens in the treatment of febrile episodes in neutropenic, leukaemic patients undergoing first remission-induction. Nephrotoxicity was more severe in the gentamicin-mezlocillin (G/M) group: four patients developed oliguric renal failure and two others showed rises in the serum creatinine of more than 0.03 mmol/l. One of the two patients in the gentamicin-ticarcillin (G/T) group who showed nephrotoxicity developed renal failure. Ototoxicity and skin rashes were more commonly observed with G/M than with G/T, and the differences were statistically significant for both ototoxicity (P = 0.0004) and drug rashes (P = 0.02). The cause of the observed differences in toxicity has not been identified.

Compared with previously available penicillins, piperacillin, azlocillin, and mezlocillin have increased activity in vitro against gram-negative bacilli. After intravenous administration of conventional doses (50 to 100 mg/kg) in children, peak concentrations of these drugs are approximately 70 to 350 micrograms/ml. For piperacillin, azlocillin, and mezlocillin, the half-lives during the beta elimination phase (t 1/2 beta) are approximately 0.5 to 0.75, 0.8 to 1.7, and 0.8 to 1.0 hours, respectively. In patients receiving the higher dosage, particularly of azlocillin, the t 1/2 beta may be prolonged by approximately 20%. A total daily dosage of 300 mg/kg or 9 gm/m2 given in four to six divided dosages should produce peak concentrations of approximately 150 micrograms/ml, and concentrations greater than 16 micrograms/ml for at least 2 hours after each administration. Lower daily dosages are needed in neonates, but precise dosage recommendations cannot be made at this time. Only approximately 60% of piperacillin and approximately 45% of azlocillin are eliminated unchanged in the urine; thus only modest dosage reductions are needed in patients with decreased renal function. In children, adverse effects have been infrequent.

Forty-six patients with cholangitis were randomized to receive therapy with mezlocillin sodium (24 patients) or a combination of ampicillin sodium--gentamicin sulfate (22 patients). The biliary concentration of mezlocillin was 112 times higher than that of ampicillin and 778 times higher than that of gentamicin. The ratio of the concentration in serum or bile over the minimum inhibitory concentration against aerobic gram-negative bacilli (therapeutic index) was higher for mezlocillin than for either ampicillin or gentamicin. Twenty (83%) of 24 patients were cured following mezlocillin therapy compared with 9 (41%) of 22 patients after ampicillin-gentamicin therapy. The 3 patients with superinfection were in the ampicillin-gentamicin arm of the study. Fewer toxic or adverse effects occurred in association with mezlocillin treatment than with ampicillin-gentamicin treatment. Mezlocillin therapy was more effective, less toxic, and less expensive than treatment with ampicillin and gentamicin for patients with cholangitis.

Forty-one patients with cancer who were receiving cefoperazone sodium plus mezlocillin sodium were prospectively followed up for the development of abnormal bleeding or hypoprothrombinemia. Ten of 41 patients developed an increased prothrombin time, three with a hemorrhagic episode. Serum transport proteins and serum carotene were measured in 18 patients, six of whom developed hypoprothrombinemia. Low serum prealbumin and low serum carotene levels were associated with the development of hypoprothrombinemia. Patients with cancer are especially predisposed to the development of antibiotic-associated hypoprothrombinemia. This is probably a result of protein-calorie malnutrition and low vitamin K stores.

The nephrotoxicity of the aminoglycoside gentamicin was evaluated in an open, controlled study of newborn infants randomly allocated to receive either combination drug therapy with gentamicin and ampicillin or single drug therapy with mezlocillin for treatment of presumed neonatal sepsis. There were no significant differences in initial clinical characteristics between the groups. Neonates receiving gentamicin, in contrast to those receiving mezlocillin, had significant nephrotoxicity manifested by a smaller postnatal fall in mean serum creatinine concentration (-9%, P NS vs -21%, P less than 0.005, respectively) and a diminished postnatal rise in mean creatinine clearance (+ 21%, P NS vs + 51%, P less than 0.01, respectively). In neonates with a fall in creatinine clearance, the mean decline was significantly greater in those receiving gentamicin (44% vs 20%, P less than 0.01). There was no relationship between the incidence of gentamicin nephrotoxicity and either peak or trough gentamicin levels. For treatment of presumed neonatal sepsis, gentamicin proved more nephrotoxic than mezlocillin.