Pacferatam

Cefoperazone sodium and sulbactam sodium.

Each vial contains cefoperazone sodium + sulbactam sodium 1 g.

When sulbactam/cefoperazone (1:1) was given subcutaneously to neonatal rats, the reduced testicular weights and immature tubules were seen.
In a domestic study (2001), drug tolerance has been reported in 3% of Escherichia coli, 7% of Klebsiella pneumoniae, 9% of Enterobacter cloacae, 15% of Serratia marcescens, Pseudomonas aeruginosa, 18% of Acinetobacter.

Susceptible Strains: Staphylococcus spp, Escherichia coli, Citrobacter spp, Klebsiella spp, Enterobacter spp, Serratia spp, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Proteus rettgeri, Pseudomonas, Haemophilus influenzae, Acinetobacter spp, Bacteroides spp.
Acute and chronic bronchitis, bronchiectasia (when infected), secondary infection of chronic respiratory diseases, pneumonia, pulmonary pyopoiesis, empyema, laryngopharyngitis, tonsillitis; pyelonephritis, cystitis; cholecystitis, cholangitis, hepatopostema, peritonitis (pelvic peritonitis including pouch of Douglas and abscess); uterine appendages, intrauterine infection; pelvic, parametrium and Bartholin gland inflammation; sepsis, infectious endocarditis, superficial secondary infection including trauma, surgical wound.

Adults: The usual daily dose (as mixture of cefoperazone sodium and sulbactam sodium) is 2-4 g daily administered IV in divided doses every 12 hrs.
Children: The daily dose is 40-80 mg/kg administered IV in 2-4 divided doses.
In severe and incurable infections, the daily dose of adult is 8 g administered in 2 divided doses and the daily dose of children may be increased up to 160 mg/kg in 2-4 divided doses.
Administration: IV use only. Do not inject hypodermically or intramuscularly.

The fact that high cerebrospinal fluid (CSF) concentrations of β-lactam antibiotics may cause neurologic effects including seizures should be considered. Because cefoperazone and sulbactam are both removed from the circulation by hemodialysis, these procedures may enhance elimination of Pacferatam from the body if overdosage occurs in patients with impaired renal function.

Hypersensitivity to any of the components of Pacferatam.

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all antibacterial agents including Pacferatam and may range in severity from mild diarrhea to fatal colitis. Treatment with anti-infectives alters normal colon flora and may permit overgrowth of C. difficile. Clostridium difficile produces toxin A and B which process CDAD. Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required. Consider CDAD if diarrhea develops during or after therapy and manage accordingly.
Careful medical history is necessary because CDAD has been reported to occur >2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.

In principle, Pacferatam is not used in patients with a history of hypersensitivity to cephem class. However, if inevitable, careful administration is required.
Patients with a history of hypersensitivity to penicillins; familial aggregation of allergic reaction including bronchial asthma, rash, urticaria; severe hepatic and renal failure [since serum half-life (t_½) of Pacferatam might be prolonged, caution is required in dose determination and dose interval]; patients who have problem of oral administration; patients with parenteral care, the old; patients who are in generally poor condition. (It is required to observe patients because of vitamin K deficiency.)
In order to prevent occurrence of the resistant microorganisms, susceptibility should be determined and treatment should be continued only for the minimum period of time required.
Sufficient injury and previous skin test are recommended to predict reaction eg, shock. Emergency first aid for shock should be made. After administration, patients are maintained in resting states and carefully observed.
Cefoperazone is extensively excreted in bile. The serum t_½ of cefoperazone is usually prolonged and urinary excretion of Pacferatam increased in patients with hepatic diseases and/or biliary obstruction. Even with severe hepatic dysfunction, therapeutic concentrations of cefoperazone are obtained in bile and only 2- to 4-fold increase in t_½ is seen. Dose modification may be necessary in cases of severe biliary obstruction, hepatic disease or in cases of renal dysfunction co-existent with either of those conditions. In patients with hepatic dysfunction and concomitant renal impairment, cefoperazone serum concentrations should be monitored and dosage adjusted as necessary. In these cases, dosage should not exceed cefoperazone 2 g/day without close monitoring of serum concentrations.
As with other antibiotics, vitamin K deficiency has occurred in a few patients treated with cefoperazone. The mechanism is most probably related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with poor diet, malabsorption states (eg, cystic fibrosis) and patients on prolonged IV alimentation regimens. Prothrombin time should be monitored in these patients.
Use in pregnancy: Since the safety for pregnant women has not been established, Pacferatam is used in women who are pregnant or considering pregnancy only if the therapeutic benefits justify the potential risks.
Use in lactation: Since Pacferatam is excreted in human milk, caution should be exercised when sulbactam/cefoperazone is administered to a nursing mother.
Use in children: The safety has not been established in newborn and premature infants.
Use in elderly: Because elderly patients have decreased biological function, adverse reaction is more likely to occur. Urticaria, stomatitis, leukocytopenia, thrombocytosis, oligochromemia, hepatic dysfunction [elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT)], proteinuria, increased serum creatinine value and increase of serum sodium have been reported.
Bleeding tendency due to vitamin K deficiency might occur.

Use in pregnancy: Since the safety for pregnant women has not been established, Pacferatam is used in women who are pregnant or considering pregnancy only if the therapeutic benefits justify the potential risks.
Use in lactation: Since Pacferatam is excreted in human milk, caution should be exercised when sulbactam/cefoperazone is administered to a nursing mother.

Shock: Shock, anaphylactoid symptom (dyspnea) may rarely occur; cautious observation is required. If symptoms eg, discomfort, abnormal sense of oral cavity, stridor, incontinence, tinnitus and sweating occur, administration should be discontinued.
Hypersensitivity: Hypersensitive reaction eg, rash, urticaria, erythema, pruritus, fever may occur. In these cases, administration should be discontinued and appropriate measures are taken. Since Stevens-Johnson syndrome may occur, cautious observation is required. In the event of abnormal reaction, therapy is discontinued and appropriate measures are taken.
Kidney: Rarely, acute renal failure; occasionally, renal dysfunction including increase of blood, urea, nitrogen (BUN) and creatinine, oliguria and proteinuria might occur. Therefore, careful observation and regular examination are instituted. In the event of the symptom, administration are discontinued and appropriate measures are taken.
Blood: Occasionally, severe blood disease including hemolytic anemia, panhematopenia, granulocytopenia (including agranulocytosis), erythropenia, eosinophilia, thrombocytopenia may occur. Therefore, careful observation and regular examination are instituted. In the event of the symptom, administration are discontinued and appropriate measures are taken. In other cephem class administration (cephalothin sodium, cephaloridine), hemolytic anemia was reported.
Liver: Occasionally, elevation of AST, ALT, ALP and bilirubin may occur. There is the risk of occurrence of fulminant hepatitis. Therefore, tests including periodic hepatic function test are instituted enough. In the event of abnormal reaction, therapy is discontinued and appropriate measures are taken.
Gastrointestinal Tract System: Rarely, fever, abnormal pain, leukocytosis, pseudomembranous colitis including a formation of pseudomembranous stigma in endoscopy (severe colitis including primary symptom of severe diarrhea with mucus and hemafecia) might occur. When abdominal pain and frequent diarrhea occur, appropriate measures, including drug therapy, are taken. Occasionally, diarrhea, loose stools, vomiting and nausea might occur.
Respiratory System: Rarely, fever, cough, dyspnea, abnormality in thoracic X-ray, interstitial pneumonia with increase of eosinophil and pulmonary infiltration with eosinophilia (PIE) syndrome might occur. In these cases, therapy is discontinued and appropriate measures including corticosteroidal therapy are taken.
Superinfection: Rarely, stomatitis and candidiasis might occur.
Vitamin Deficiency: Rarely, vitamin K deficiency symptoms (hypoprothrombinemia and bleeding tendency) and vitamin B deficiency symptoms (stomatitis, glossitis, anorexia, neuritis) might occur.
Central Nervous System: Convulsion may occur.
Others: Rarely, hypotension, vasculitis, headache, pain at injection site, phlebitis and chill might occur.

Increase of renal disorder has been reported in the concomitant administration of Pacferatam with other cephem drugs or diuretics eg, furosemide. In case of co-administration, pay attention to renal function.
Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine (Benedict's or Fehling's solution or with Clinitest tablets) except Tes-Tape.
Positive direct Coombs' tests have been reported.
A reaction characterized by flushing, sweating, headache and tachycardia has been reported when alcohol was ingested during and as late as the 7th day after cefoperazone administration.
Tetrazol thiomethyl inhibits decomposition of alcohol in liver to induce the accumulation of acetaldehyde followed by flushing, nausea, frequent pulse, sweating and headache.

For IV administration, each vial should be reconstituted in water for injection, normal saline for injection or glucose for injection and administered slowly. For intermittent IV administration, each vial should be reconstituted as previously mentioned then diluted with the same solution. (In use if water for injection, the solution is not isotonic, thereby it is not used.)
Rarely, vessel pain, thrombophlebitis might occur in massive IV injection. To prevent these reactions, care are required in preparation of injection solution, injection site and method of injection. Injection is performed as slowly as possible.
Cautions Before Administration: In case of fasciculus circularis, caution of infection is exercised.
In cold season, warm the solution to body temperature before administration.

Store in a hermetic container at room temperature.
It should be used immediately after reconstitution. If reconstituted solutions should be  kept inevitably, it should be used within 6 hrs at room temperature or within 48 hrs at refrigerator.

Cephalosporins

J01DD62 - cefoperazone and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

POM

Powd for inj (white to gray crystalline powder in clear, colorless vial) 1 g x 1's.