Latamoxef-induced coagulation disorders: Incidence and risk factors.

WHAT IS KNOWN AND OBJECTIVE: To observe the effect of latamoxef on coagulation function and to analyse its risk factors. METHODS: A retrospective cohort study was performed to compare patients receiving latamoxef versus those treated with ceftazidime. Baseline characteristics and coagulation parameters were recorded and analysed to explore whether treatment with latamoxef increased the risks of coagulation disorders and bleeding. RESULTS AND DISCUSSION: A total number of 162 patients receiving latamoxef and 93 patients receiving ceftazidime were included. Haemorrhagic events were similar between groups, but patients receiving latamoxef had a higher risk of coagulation disorders compared to those receiving ceftazidime. Multivariate analysis revealed that the exposure of antibiotics, especially the cumulative defined daily doses (DDDs), and the nutrition risk may be the predictors of coagulation disorders. WHAT IS NEW AND CONCLUSION: Latamoxef might induce coagulation disorders. Cumulative DDDs and the nutrition risk were linked with coagulation disorders.

Latamoxef induced a severe coagulation disorder in older patients in China: Two case reports.

WHAT IS KNOWN AND OBJECTIVE: We present two cases of severe coagulation disorders induced by latamoxef, thereby revealing risk factors of coagulation disorder in latamoxef-treated patients. CASE SUMMARY: Two very elderly patients developed haemorrhage, and coagulation tests showed a longer prothrombin time (PT), activated partial thromboplastin time (APTT) and a high international normalized ratio (INR). Latamoxef was thought to be responsible for the coagulopathy in these patients, and coagulation disorder was relieved after vitamin-K intake. WHAT IS NEW AND CONCLUSION: We report on two cases of coagulopathy in patients given latamoxef. Advanced age, deficiency in vitamin-K intake, poor nutritional status, abnormal coagulation history, ongoing anti-coagulation/anti-aggregation therapy, renal dysfunction and polypharmacy are possible contributory factors, and should be looked out for when prescribing latamoxef.

Enhanced bleeding with cefoxitin or moxalactam. Statistical analysis within a defined population of 1493 patients.

Most cases of beta-lactam-associated coagulopathy occur in patients with other risk factors. This study analyzed temporally related clinical bleeding events in 1493 patients who received one antibiotic for at least three days. Univariate and multivariate analyses controlled for condition variables (nutritional status, renal, hepatic, or hematologic dysfunction, intensive care unit stay) and treatment variables (use of antiplatelet agents, anticoagulants, vitamin K, antitumor chemotherapy or antiulcer therapy, steroids) that could have been associated with bleeding independently. Rates of bleeding ranged from 0% (chloramphenicol sodium succinate, vancomycin hydrochloride, erythromycin lactobionate) to 8.2% (cefoxitin) to 22.2% (moxalactam disodium). Multiple logistic regression analyses revealed that only moxalactam (odds ratio, 9.9) and cefoxitin (odds ratio, 2.1) exhibited significantly higher likelihoods of bleeding than other agents. This study statistically confirms increased risk of bleeding with moxalactam, heretofore reported only anecdotally. Cefoxitin may carry risks greater than previously believed.

Moxalactam epimer disposition in patients undergoing continuous ambulatory peritoneal dialysis.

The kinetics of the epimers of moxalactam (R-MOX, S-MOX) were investigated in patients without infections who were receiving continuous ambulatory peritoneal dialysis after both intravenous and intraperitoneal injections of moxalactam. R-MOX and S-MOX were well absorbed from the peritoneal cavity, with mean systemic availability of 0.71 +/- 0.18 and 0.79 +/- 0.18, respectively. After intravenous MOX, serum clearance was 10.2 +/- 3.4 (R-MOX) and 10.9 +/- 3.2 (S-MOX) ml/hr/kg. Net time-averaged peritoneal dialysis clearance of both epimers was minimal, about 10% of serum clearance. Serum and dialysate MOX concentrations were above the minimum inhibitory concentrations for susceptible bacteria for 24 hours after a 2.0 or 1.0 gm intravenous or intraperitoneal dose. Gastrointestinal side effects occurred after a 2.0 gm dose (both intravenous and intraperitoneal) but not after a 1.0 gm dose. There were no significant differences in the kinetics of R-MOX and S-MOX. A single 1.0 gm ip dose leads to serum and dialysate MOX concentrations above the minimum inhibitory concentration for susceptible pathogens for 24 hours.

Controlled trials of double beta-lactam therapy with cefoperazone plus piperacillin in febrile granulocytopenic patients.

The efficacy and safety of double beta-lactam therapy with cefoperazone plus piperacillin in febrile granulocytopenic patients were compared with moxalactam plus piperacillin, ceftazidime plus piperacillin, and imipenem alone in two separate clinical trials. All patients also received prophylactic vitamin K. When National Committee for Clinical Laboratory Standards breakpoints for susceptibility were used, a greater proportion of pretherapy isolates of gram-negative aerobic bacilli and gram-positive organisms were found to be susceptible to cefoperazone (94 percent) and imipenem (91 percent) than to moxalactam (84 percent), ceftazidime (85 percent), or piperacillin (85 percent). In trial I, the overall response rates for documented or possible infections were 78 percent (76 of 97 patients) for cefoperazone/piperacillin and 80 percent (72 of 90 patients) for moxalactam/piperacillin. In trial II, the overall response rates were 86 percent (25 of 29 patients) for cefoperazone/piperacillin, 74 percent (20 of 27 patients) for ceftazidime/piperacillin, and 72 percent (21 of 29 patients) for imipenem alone. There was no nephrotoxicity or hemorrhage related to the study drugs. Diarrhea was more frequent with each of the double beta-lactam regimens, whereas nausea and seizures were more common with imipenem given at a dosage of 1.0 g intravenously every six hours. Seizures occurred in three of 29 imipenem-treated patients but in none of 243 patients treated with the double beta-lactam regimens (p less than 0.001). These results suggest that cefoperazone plus piperacillin provides adequate coverage for most common bacterial pathogens and is safe and effective therapy for febrile granulocytopenic patients.

Moxalactam plus piperacillin versus moxalactam plus amikacin in febrile granulocytopenic patients.

In a prospective randomized trial, febrile granulocytopenic patients received either moxalactam plus piperacillin or moxalactam plus amikacin as initial empiric antimicrobial therapy. Most patients were also given prophylactic vitamin K. The overall response rates for the two regimens were similar (105 of 136, or 77 percent, for moxalactam plus piperacillin versus 107 of 136, or 79 percent, for moxalactam plus amikacin). For Pseudomonas aeruginosa infections, the response rate was better in patients receiving moxalactam plus amikacin (seven of nine versus one of five, p = 0.06); two patients treated with moxalactam plus piperacillin experienced relapse of P. aeruginosa bacteremia in association with the emergence of beta-lactam-resistant P. aeruginosa isolates. On the other hand, bacteremic enterococcal superinfections occurred in seven patients receiving moxalactam plus amikacin but in none given moxalactam plus piperacillin (p = 0.02). Serious side-effects were minimal with both regimens, and nephrotoxicity was less common in patients receiving moxalactam plus piperacillin (two of 136 versus six of 136, p = 0.28). There was no antibiotic-related hemorrhage. These results suggest that the overall efficacy and toxicity of moxalactam plus piperacillin and moxalactam plus amikacin are similar. Moxalactam/piperacillin therapy may be limited in certain patients by the emergence of beta-lactam-resistant P. aeruginosa, whereas enterococcal superinfections may complicate moxalactam/amikacin therapy.

A double beta-lactam combination versus an aminoglycoside-containing regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.

The double beta-lactam combination of moxalactam plus piperacillin was compared with the aminoglycoside-containing regimen of moxalactam plus amikacin in a prospective, randomized trial of empiric therapy for 302 febrile episodes in granulocytopenic cancer patients. The moxalactam/piperacillin regimen was found to be as effective as the moxalactam/amikacin regimen (70 percent overall responses); responses with moxalactam/piperacillin and moxalactam/amikacin were similar for microbiologically documented infections (24 of 37, 65 percent, versus 20 of 35, 57 percent), for the subgroup with bacteremias (19 of 32 versus 14 of 28), and for clinically documented infections (41 of 58, 71 percent, versus 40 of 48, 83 percent). Responses were similar also for bacteremia in patients with persistent, profound (less than 100/microliter) granulocytopenia. Among profoundly (less than 100/microliter) granulocytopenic patients with gram-negative bacteremia, an increase in the granulocyte count to more than 100/microliter during therapy and a peak bactericidal activity of 1:16 or more (the latter noted in seven of nine moxalactam/piperacillin trials and six of nine moxalactam/amikacin trials) correlated with a favorable clinical response in 85 percent (p less than or equal to 0.00003) and 92 percent (p less than or equal to 0.044), respectively. Although serious side effects were minimal with either regimen, the double beta-lactam combination was associated with significantly less frequent nephrotoxicity (two of 145 versus 12 of 130; p less than or equal to 0.003) and ototoxicity (none of 34 versus seven of 34; p less than or equal to 0.006). The double beta-lactam combination of moxalactam plus piperacillin was found to be as effective as moxalactam plus amikacin but to have significantly less nephro- and ototoxicity.

Empiric therapy with moxalactam alone in patients with bacteremia.

Moxalactam was administered (20 mg/kg intravenously every 8 hours) as single-drug empiric antimicrobial therapy to 63 patients with bacteremia who were neither neutropenic nor immunosuppressed. Six patients (10%) had microorganisms that were susceptible to moxalactam and resistant to all other antimicrobial agents tested; two patients (3%) had microorganisms that were resistant to moxalactam and other agents tested. Of these 63 patients, 47 (75%) were cured with moxalactam therapy. Nine patients (14%) had breakthrough bacteremia while receiving other antimicrobial therapy and were cured subsequently with moxalactam therapy alone. The two major risk factors for failure of moxalactam therapy were polymicrobial bacteremia and an extrahepatic intra-abdominal source of infection; these two conditions frequently coexisted. Six of nine patients with polymicrobial bacteremia died. Superinfection (one pseudomonal, five enterococcal) was responsible for 6 of the 16 treatment failures. Enterococcal superinfection occurred exclusively among patients who had received relatively prolonged therapy with moxalactam for extrahepatic intra-abdominal infection, especially intraabdominal abscess. These five patients died, and postmortem examination showed that enterococcal superinfection was the major cause of death in all. Mild, reversible adverse reactions associated with use of moxalactam occurred in 14 of the 63 patients (22%). None had clinically overt bleeding. The use of moxalactam alone seems to be safe and effective and a cost-effective alternative empiric antimicrobial therapy for most patients with bacteremia who are not immunosuppressed or neutropenic and who are not at high risk of having Pseudomonas or polymicrobial bacteremia.

Moxalactam disodium-induced pulmonary hemorrhage.

Fatal pulmonary hemorrhage occurred on the eighth day of moxalactam therapy. No other pharmacologic agent or obvious cause could be attributed to the hemoptysis. Moxalactam-induced pulmonary hemorrhage should be included in the differential diagnosis of an infiltrate when moxalactam is being administered.

Moxalactam. Evaluation of clinical bleeding in patients with abdominal infection.

Previous clinical studies have emphasized that hypoprothrombinemia may occur during treatment with moxalactam disodium, a new broad-spectrum cephalosporin. Usually, this abnormality is corrected by administering vitamin K. Recent case reports have described bleeding complications associated with moxalactam therapy and suggested that platelet function is depressed by this drug. We studied eight patients with abdominal infection who were treated with moxalactam. Six of them had prolonged template bleeding times, and two had clinically significant hemorrhage (epistaxis, hematuria, and rectal bleeding) during treatment with moxalactam. These observations suggest that coagulation studies and template bleeding times should be monitored during moxalactam therapy, especially before major surgery.

Single-dose antibiotic prophylaxis for biliary surgery. Cefazolin vs moxalactam.

Cefazolin was compared with moxalactam for single-dose prophylaxis against infection in a double-blind, prospective, randomized trial of 90 patients undergoing cholecystectomy. Risk factors for infection were present in 65 (72%) of the 90 patients and were evenly distributed. Antibiotic levels in plasma, bile, and tissue measured when the cystic duct was divided were similar for both drugs. Age greater than 65 years but not recent cholecystitis or type of antibiotic was predictive of recovery of bacteria from bile cultures. Wound infections occurred in two patients receiving cefazolin and one patient receiving moxalactam for an overall infection rate of 3%. No toxic reactions to antibiotics, including bleeding disorders, were observed. In conclusion, no significant difference in prophylactic efficacy was detected in this comparison of a first-generation with a third-generation cephalosporin. Because of its lower cost and narrower antimicrobial spectrum, however, cefazolin should remain the agent of choice.

Single-antibiotic use for penetrating abdominal trauma.

A prospective randomized study compared the use of moxalactam disodium vs clindamycin phosphate and tobramycin sulfate for treatment of 190 patients with penetrating abdominal trauma. Twenty-seven patients were disqualified because of early death or failure to follow the protocol. The patients in each group were comparable regarding the cause and severity of injury. No significant difference was seen in the incidence of intra-abdominal infection between the moxalactam-treated group (13%) and the clindamycin- and tobramycin-treated group (9%). The intra-abdominal infection rate in patients with colon injuries (21%) was significantly increased when compared with the patients without colon injuries (6%), but the antibiotic regimen did not significantly change the infection rate. No evidence of bleeding problems from moxalactam were noted. Changes in prothrombin and partial thromboplastin times appeared to be related to shock rather than the use of moxalactam. The most severe coagulopathies occurred prior to moxalactam therapy and were seen only in those patients who had shock requiring 10 or more units of blood. Moxalactam is as effective as combination (clindamycin and tobramycin) antimicrobial therapy in patients with penetrating abdominal trauma.

Moxalactam vs tobramycin-clindamycin. A randomized trial in secondary peritonitis.

One hundred five patients with peritonitis were randomized to receive either tobramycin sulfate plus clindamycin phosphate or moxalactam alone before surgical intervention. Fifty-nine patients were evaluable. A mean of 3.1 (moxalactam) and 3.5 (tobramycin-clindamycin) pathogens per patient were identified. Overall success rate was 85% (tobramycin-clindamycin, 24/30; moxalactam, 26/29). When patients with appendicitis were excluded, there was an observed but not statistically significant advantage of moxalactam over tobramycin-clindamycin (85% vs 67%). There were five deaths (tobramycin-clindamycin, four; moxalactam, one). Other complications included hypoprothrombinemia (tobramycin-clindamycin, five; moxalactam, five), renal dysfunction (tobramycin-clindamycin, three; moxalactam, one), and superinfection (tobramycin-clindamycin, nine; moxalactam, six). More wound infections were noted in the group given tobramycin-clindamycin. These data suggest that moxalactam is as safe and efficacious as tobramycin plus clindamycin. The observed benefits of this agent warrant study in a larger sample to verify advantages of moxalactam over combination therapy.

Specificity of renal tubular damage criteria for aminoglycoside nephrotoxicity in critically ill patients.

Two populations of critical care patients were studied using indices of renal tubular damage (beta 2-microglobulin, enzymes, casts) and indices of glomerular filtration (creatinine, creatinine clearance). The purpose of these studies had been initially to elucidate the type of renal failure typical of the critically ill patient treated with aminoglycoside gentamicin or tobramycin, then to determine its frequency. The second study population included a control group of patients given the nonnephrotoxic cephalosporin moxalactam, in order to assess the specificity of the renal tubular damage criteria for aminoglycoside nephrotoxicity versus other types of renal injury in critical care patients. Creatinine rise occurred in approximately 30 per cent of each tobramycin-treated group and in only 12 per cent in the moxalactam control patients (P less than 0.05). Thus, the data indicate that aminoglycosides are associated with an approximate doubling of the renal damage in those older, critically ill patients. Renal tubular damage criteria appear specific for the aminoglycoside effect, but a substantial percentage of the renal damage in this population is not associated with detectable alterations in renal tubular status.

A comparative trial of moxalactam plus ticarcillin and clavulanic acid or piperacillin as empiric antibiotic therapy for febrile cancer patients.

Resistance of bacteria to beta-lactam antibiotics remains a difficult clinical problem that can be compounded in infected patients with serious underlying illness, especially those who are immunocompromised. In a prospective randomized safety and efficacy trial, febrile cancer patients received either ticarcillin disodium combined with the beta-lactamase inhibitor clavulante potassium (Timentin, Beecham Laboratories, Bristol, TN) plus moxalactam (T+M), or piperacillin plus moxalactam (P+M) as initial empiric antimicrobial therapy. Sixty-six febrile episodes in 53 patients were studied. In the T+M group, 14 (78%) of 18 clinically evaluable infections in patients with profound granulocytopenia improved as did all 14 (100%) such infections in the P+M group. In the T+M group 17 of 21 (81%) similarly evaluable infections improved irrespective of granulocyte count, as did 14 (88%) of 16 of such infections in the P+M group. These results are not statistically significantly different. Serious side effects were infrequent and comparable with both regimens. There was one antibiotic related hemorrhage in the P+M group and a serious episode of nephrotoxicity in a patient who died without recovering renal function in the T+M group. These results suggest that the overall safety and efficacy of Timentin plus moxalactam, and piperacillin plus moxalactam are comparable and similar to previous empiric antibiotic trials.

The effects of 1-methyl-5-thiotetrazole in a rat liver vitamin K-dependent carboxylase assay.

1-Methyl-5-thiotetrazole (NMTT), a metabolite of moxalactam (MoxamR), was studied for its potential inhibition of vitamin K-dependent carboxylation. The assay system utilized a detergent solubilized rat liver microsomal preparation. Vitamin K1H2 was artificially produced in situ by the NADH-dependent reduction of exogenous phylloquinone and the resultant carboxylation monitored by 14CO2 incorporation into a soluble peptide substrate. Warfarin, used as a reference inhibitor, gave results expected from the literature - 50% inhibition at a pharmacologically excessive level of 1.0 mM. Carboxylation was unaffected by 1.0 mM NMTT and was marginally (0-14%) diminished by 5.0 mM NMTT. Carboxylation was 25% diminished at 10.0 mM NMTT, a concentration far above that achieved in human testing of moxalactam. When NMTT was pre-incubated with the liver microsomal carboxylase enzyme preparation, 10.0 mM NMTT again caused merely a 25% diminution of carboxylation in the assay. These results do not support a role for NMTT as an inhibition of Vitamin K-dependent carboxylation which would produce pharmacological side effects during moxalactam therapy. During these studies it was found that dramatic consumption of NADH occurs in the presence of liver microsomal preparations (independent of vitamin K and of NMTT) and that NMTT effects on these processes may explain the small carboxylation diminution observed at 10.0 nM NMTT in the carboxylase assay.

A high incidence of bleeding is observed in a trial to determine whether addition of metronidazole is needed with latamoxef for prophylaxis in colorectal surgery.

A prospective randomized trial has compared the use of latamoxef sodium (two doses) with latamoxef and metronidazole for elective colorectal surgery. The incidence of wound infection in patients receiving latamoxef alone was 34 per cent compared with 32 per cent in patients receiving latamoxef and metronidazole. Only eight of the 36 wound infections in this study could be classified as major. Only two patients developed an intra-abdominal abscess postoperatively and there was only one episode of septicaemia. Postoperative haemorrhage was recorded in 17 patients (15 per cent). Twelve episodes of bleeding occurred in the first 97 patients who entered the trial and prolongation of the prothrombin time was recorded in eight of 16 patients. In view of these findings 10 mg vitamin K was given with each dose of latamoxef to the last group of patients. However, bleeding occurred in five of 13 patients receiving vitamin K and entry to the study was therefore discontinued.

Empirical treatment of febrile, neutropenic patients with tobramycin and latamoxef.

One hundred and two febrile episodes in neutropenic patients were treated with intravenous tobramycin and latamoxef. After 48 h latamoxef at 6 g day-1, patients were randomized to continue this regimen or latamoxef at 3 g day-1. Infections responded to these regimens in 67% and 71% of patients, respectively. Two-thirds of the infections which failed to respond were due to coagulase-negative staphylococci in Hickman catheters, a trend which may necessitate the inclusion of additional antibiotics in future empirical regimens. Prolonged prothrombin times due to antibiotic therapy were seen in nine patients but there was only one episode of bleeding and this responded quickly to treatment with vitamin K and fresh frozen plasma. In 35 patients, coagulopathy was present before antibiotics were started, and these cases also responded to vitamin K. The study shows that the response to tobramycin and latamoxef is comparable to other broad-spectrum antibiotic regimens and that a reduction in the dose of latamoxef after 48 h treatment may safely permit cost savings.

Determinants of antibiotic-associated hypoprothrombinemia.

Hypoprothrombinemia is a relatively uncommon event in the hospitalized patient. When it does occur, it often is associated with surgery, dietary vitamin K deficiency, renal dysfunction, malignancy, and broad-spectrum antibiotic therapy. Several mechanisms have been proposed to account for antibiotic-associated hypoprothrombinemia, including eradication of gastrointestinal bacteria, direct inhibition of vitamin K-dependent coagulation, and indirect inhibition of coagulation. The anecdotal reports and comparative studies of antibiotic-associated hypoprothrombinemia were reviewed; these usually implicated broad-spectrum or the use of several antibiotics. The increased frequency of hypoprothrombinemia associated with moxalactam and cefoperazone also raises questions about the role of their N-methylthiotetrazole (NMTT) side chains. The hypoprothrombinemia associated with NMTT antibiotics does not occur in healthy volunteers and is rare in patients without complicating conditions. Although NMTT inhibits vitamin K-dependent carboxylation in vitro, the parent cephalosporins do not. It is not clear whether NMTT-containing antibiotics liberate sufficient amounts of NMTT in vivo to antagonize clotting in patients. Thus, although moxalactam, and possibly cefoperazone, may in some cases be responsible for increases in prothrombin time, most important question for further study is whether the newer NMTT-containing antibiotics pose a risk of hypoprothrombinemia that is greater than that of antibiotics lacking this side chain.

Prolonged bleeding time associated with moxalactam administration.

A case of moxalactam-induced coagulopathy is reported. The authors think that this coagulopathy is caused by an effect on platelet aggregation and not by inhibition of vitamin K-dependent clotting factors. It is recommended that bleeding times be routinely checked preoperatively in patients being treated with moxalactam.