CEPHALOSPORINS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) FIRST GENERATION

a) Cefadroxil (synonym)
b) Cephalexin (synonym)
c) Cephalothin (synonym)
d) Cephapirin (synonym)
e) Cephazolin (synonym)
f) Cephradine (synonym)

2) SECOND GENERATION

a) Cefaclor (synonym)
b) Cefamandole (synonym)
c) Cefmetazole (synonym)
d) Cefonicid (synonym)
e) Cefotetan (synonym)
f) Cefotiam (synonym)
g) Cefoxitin (synonym)
h) Cefprozil (synonym)
i) Cefuroxime (synonym)
j) Loracarbef (synonym)

3) THIRD GENERATION

a) Cefdinir (synonym)
b) Cefditoren (synonym)
c) Cefixime (synonym)
d) Cefoperazone (synonym)
e) Cefotaxime (synonym)
f) Cefpodoxime (synonym)
g) Ceftazidime (synonym)
h) Ceftibuten (synonym)
i) Ceftizoxime (synonym)
j) Ceftriaxone (synonym)

4) FOURTH GENERATION

a) Cefepime (synonym)

5) OXACEPHALOSPORINS

a) Flomoxef (synonym)
b) Latamoxef (synonym)

6) Cephalosporin
7) Ceftaroline (synonym)
8) Ceftolozane (synonym)

1.2.1) MOLECULAR FORMULA
1) CEFACLOR: C15H14ClN3O4S.H2O
2) CEFADROXIL MONOHYDRATE: C16H17N3O5S.H2O
3) CEFAZOLIN SODIUM: C14H13N8NaO4S3
4) CEFDINIR: C14H13N5O5S2
5) CEFDITOREN PIVOXIL: C25H28N6O7S3
6) CEFEPIME: C19H24N6O5S2
7) CEFEPIME HYDROCHLORIDE: C19H24N6O5S2.HCl
8) CEFIXIME TRIHYDRATE: C16H15N5O7S2.3H2O
9) CEFOPERAZONE SODIUM: C25H26N9NaO8S2
10) CEFOTAXIME SODIUM: C16H17N5NaO7S2
11) CEFOTETAN DISODIUM: C17H15N7Na2O8S4
12) CEFOXITIN SODIUM: C16H16N3NaO7S2
13) CEFPODOXIME PROXETIL: C21H27N5O9S2
14) CEFPROZIL: C18H19N3O5S.H2O
15) CEFTAROLINE FOSAMIL: C22H21N8O8PS4.C2H4O2.H2O
16) CEFTAZIDIME: C22H32N6O12S2
17) CEFTIBUTEN DIHYDRATE: C15H14N4O6S2.2H2O
18) CEFTIZOXIME SODIUM: C13H12N5NaO5S2
19) CEFTOLOZANE SULFATE: C23H31N12O8S2+.HSO4-
20) CEFTRIAXONE SODIUM: C18H16N8Na2O7S3.3.5H2O
21) CEFUROXIME AXETIL: C20H22N4O10S
22) CEFUROXIME SODIUM: C16H15N4NaO8S
23) CEPHALEXIN: C16H17N3O4S.H2O
24) CEPHRADINE: C16H19N3O4S
25) LORACARBEF: C16H16ClN3O4.H2O

Available Forms Sources

1) FIRST GENERATION

a) Cefadroxil: 1 g tablets; 500 mg capsules; 125 mg/5 mL, 250 mg/5 mL, and 500 mg/5 mL oral suspension
b) Cephalexin: 250 mg, 500 mg, and 1 g tablets; 250 mg and 500 mg capsules; 125 mg/5 mL and 250 mg/5 mL powder for oral suspension
c) Cephalothin: 1g and 2 g premixed injection; 1 g, 2 g, and 20 g powder for injection
d) Cephapirin: 500 mg, 1 g, 2 g, 4 g, and 20 g powder for injection
e) Cefazolin: 500 mg and 1 g premixed injections; 250 mg, 500 mg, 1 g, 5 g, 10 g, and 20 g powder for injection
f) Cephradine: 250 mg and 500 mg capsules; 125 mg/5 mL and 250 mg/5 mL oral suspension; 250 mg, 500 mg, 1 g, and 2 g powder for injection

2) SECOND GENERATION

a) Cefaclor: 250 mg and 500 mg capsules; 125 mg/5 mL, 187 mg/5 mL, 250 mg/5 mL, and 375 mg/5 mL powder for oral suspension
b) Cefamandole: 500 mg, 1 g, 2 g, and 10 g powder for injection
c) Cefmetazole: 1 g and 2 g powder for injection
d) Cefonicid: 500 mg, 1 g, and 10 g powder for injection
e) Cefotetan: 1 g, 2 g, and 10 g powder for injection
f) Cefoxitin: 1 g and 2 g premixed injections; 1 g, 2 g, and 10 g powder for injection
g) Cefprozil: 250 mg and 500 mg tablets; 125 mg/5 mL and 250 mg/5 mL powder for oral suspension
h) Cefuroxime: 125 mg, 250 mg, and 500 mg tablets; 125 mg/5 mL oral suspension; 750 mg, 1.5 g, and 7.5 g powder for injection; 750 mg and 1.5 g premixed injection
i) Loracarbef: 200 mg capsules; 100 mg/5 mL powder for oral suspension

3) THIRD GENERATION

a) Cefdinir: 300 mg capsules; 125 mg/5 mL powder for oral suspension
b) Cefditoren: 200 mg tablets
c) Cefixime: 200 mg and 400 mg tablets; 100 mg/5 mL powder for oral suspension
d) Cefoperazone: 1 g and 2 g premixed injection; 1 g and 2 g powder for injection
e) Cefotaxime: 1 g and 2 g premixed injection; 1 g, 2 g, and 10 g powder for injection
f) Cefpodoxime: 100 mg and 200 mg tablets; 50 mg/5 mL and 100 mg/5 mL granules for suspension
g) Ceftazadime: 500 mg, 1 g, 2 g, 6 g, and 10 g powder for injection; 1 g and 2 g premixed injection
h) Ceftibuten: 400 mg capsules; 90 mg/5 mL and 180 mg/5 mL powder for oral suspension
i) Ceftizoxime: 1 g and 2 g premixed injection; 500 mg, 1 g, 2 g, and 10 g powder for injection
j) Ceftriaxone: 1 g and 2 g premixed injection; 250 mg, 500 mg, 1 g, 2 g, and 10 g powder for injection

4) FOURTH GENERATION

a) Cefepime: 500 mg, 1 g, and 2 g injection
b) Oxacephalosporins differ structurally from the cephalosporins in that the sulfur atom of the 7-aminocephalosporanic acid nucleus is replaced by oxygen.

5) Ceftaroline: 400 mg or 600 mg anhydrous ceftaroline fosamil powder for injection (Prod Info TEFLARO(TM) IV injection, 2010).
6) Ceftolozane in combination with Tazobactam: 1g ceftolozane and 0.5 g tazobactam as a powder for reconstitution in single-dose vials for intravenous infusion (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).

Overview

Life Support

Clinical Effects

0.2.1)

A) WITH THERAPEUTIC USE

1) Seizures have been reported following therapeutic administration. Pseudocholelithiasis may follow intravenous administration of ceftriaxone.
2) A disulfiram-like reaction may develop following the use of either cefoperazone, moxalactam or cefamandole followed by ethanol ingestion.
3) Hypersensitivity reactions may follow any amount; may result in anaphylaxis. Oral exposures are less likely to cause severe allergic reactions than parenteral exposures.

B) WITH POISONING/EXPOSURE

1) Acute ingestion of large doses of cephalosporins may result in nausea, vomiting, diarrhea, and abdominal pain. Seizures have developed after parenteral overdose.

0.2.7)

A) Agitation and seizures have been reported following therapeutic cephalosporin administration. Neurologic side effects may be more common in patients with impaired renal function.

0.2.8)

A) WITH THERAPEUTIC USE

1) Vomiting, diarrhea, and pancreatitis may occur.
2) Hiccups have been reported following intravenous administration of cefotetan.

0.2.9)

A) WITH THERAPEUTIC USE

1) Elevated liver enzymes may occur with therapeutic use.
2) Choledocholithiasis and pseudocholelithiasis have been reported following administration of ceftriaxone.

0.2.10)

A) Rare effects reported with cephalosporin administration include renal failure, interstitial nephritis, nephrolithiasis, and crystalluria.

0.2.13)

A) Coagulopathies may occur following IV moxalactam, cefazolin, cefoperazone, cefmetazole, and cefamandole.
B) Leukopenia, thrombocytopenia, anemia, and agranulocytosis may occur following cephalosporin therapy.
C) Fatal hemolytic reactions occurred in children following ceftriaxone administration.

0.2.14)

A) WITH THERAPEUTIC USE

1) Skin rashes may occur with cephalosporin administration. Contact dermatitis has been reported following cefotiam exposure.
2) Stevens-Johnson syndrome has been reported with cephalexin ingestion, and toxic epidermal necrolysis occurred following cefazolin administration.
3) Pemphigus vulgaris occurred following cephalexin treatment, and pemphigus erythematosus was reported after beginning ceftazidime therapy.

0.2.19)

A) Hypersensitivity reactions, including cross-reactions and anaphylaxis, are common occurrences among the cephalosporins.
B) Pemphigus vulgaris and erythematosus occurred as a result of an auto-immune reaction with cephalexin and ceftazidime administration.
C) A serum sickness-like reaction has been reported with the therapeutic administration of cefaclor.
D) Fatal hemolytic reactions have occurred following cephalosporin administration.

0.2.20)

A) Cefadroxil, cefazolin, cefdinir, cefditoren, cefepime, cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftazidime/avibactam combination, ceftibuten, ceftizoxime, ceftolozane/tazobactam combination, ceftriaxone, cefuroxime, cephalexin, and cephradine are classified as FDA pregnancy category B. Cephalosporins may cross into the fetal circulation in small amounts, but teratogenicity has not been attributed to these agents. Cefepime and cefoperazone crossed the placental barrier in one human study.

0.2.22)

A) Patients receiving cefoperazone, moxalactam, cefotetan, or cefamandole followed by ingestion of ethanol, developed symptoms consistent with a disulfiram-ethanol reaction.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) GASTRIC DECONTAMINATION - Is generally not indicated in patients who do not have any underlying health problems. In patients with underlying renal insufficiency, gastric decontamination may be indicated when the amount ingested exceeds 15 times the usual single therapeutic dose.
B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
C) Following an ingestion exceeding the usual therapeutic dose, hold further doses until the overall situation is reassessed.
D) Evaluate patients for signs and symptoms of hypersensitivity. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
E) SEIZURES

1) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).

a) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
b) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

F) Monitor fluid and electrolyte status in patients with severe vomiting and/or diarrhea.
G) Monitor for renal and hematologic abnormalities.
H) COAGULOPATHIES - Vitamin K has been beneficial.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) Acute ingestion of large doses of cephalosporins may result in nausea, vomiting, diarrhea, and abdominal pain. Seizures have developed after parenteral overdose.

Vital Signs

3.3.3)

A) FEVER, which resolved upon drug discontinuation, was reported in three cases following intravenous cefuroxime (Mevorach et al, 1993).

Heent

3.4.3)

A) OCULAR EFFECTS: Blurred vision, deviation of the eyes, rapid eye movements, and bilateral mydriasis have been reported in patients who developed CNS toxicity (seizures, encephalopathy) following parenteral administration of cefazolin and ceftazidime (Manzella et al, 1988; Jackson & Berkovic, 1992) Martin III et al, 1992; (Lang et al, 1999).

Respiratory

3.6.2)

A) DYSPNEA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Three episodes of mild wheezing occurred in a 22-year-old woman following occupational exposure to ceftazidime. A challenge test was performed, confirming that the chest tightness and wheezing was due to ceftazidime exposure (Stenton et al, 1995).

Neurologic

3.7.1)

A) Agitation and seizures have been reported following therapeutic cephalosporin administration. Neurologic side effects may be more common in patients with impaired renal function.

3.7.2)

A) PSYCHOMOTOR AGITATION

1) WITH THERAPEUTIC USE

a) Cephalosporin administration may cause confusion, restlessness, and agitation (Geyer et al, 1988; Manzella et al, 1988; Jackson & Berkovic, 1992; Martin et al, 1992; Klion et al, 1994; Fishbain et al, 2000), particularly in patients with renal impairment.

B) SEIZURE

1) WITH THERAPEUTIC USE

a) CEFAZOLIN

1) Tremulousness, neuromuscular overexcitability, and seizures have been reported following intraventricular and intravenous administration of cefazolin (Geyer et al, 1988; Manzella et al, 1988; Martin et al, 1992). The neurological symptoms gradually subsided upon discontinuation of the cefazolin.

b) CEFEPIME

1) Seizures and neuromuscular excitability have been reported in several patients, with renal impairment, after receiving cefepime 2 grams/day for 3 to 7 days (Barbey et al, 2001) Prod Info Maxipime (R), 1996).
2) Non-convulsive status epilepticus was reported in two patients with renal failure, who received high-dose cefepime therapy. Both patients displayed subtle clonic movements of the upper extremities and the EEG's showed continuous, generalized spike and wave patterns. The status epilepticus resolved in both patients following administration of lorazepam and discontinuation of cefepime therapy (Dixit et al, 2000).
3) CASE REPORT: Confusion, unresponsiveness, and intermittent twitching of the neck and extremities were reported in a 74-year-old woman, with renal failure, four days after beginning cefepime therapy (2 grams/day). The patient recovered following dialysis and cessation of cefepime. The patient's cefepime level was 716.32 mg/mL while on therapy and 96.89 mg/mL the day after treatment cessation with dialysis (Fishbain et al, 2000).
4) CASE REPORT: A 15-year-old girl, with polycystic kidney disease and on hemodialysis, became confused and lethargic 4 days after initiating cefepime therapy, 1 g intravenously every 12 hours (100 mg/kg/day), for treatment of Pseudomonas aeruginosa. The patient's neurologic condition deteriorated (Glasgow Coma Scale of 8) with development of hyperreflexia in her lower extremities and bilateral ankle clonus. An EEG revealed continuous bursts of generalized spikes and sharp wave activity consistent with non-convulsive status epilepticus. Following supportive therapy including mechanical ventilation and discontinuation of cefepime, the patient recovered within 48 hours (Thabet et al, 2008).
5) CASE REPORT: An adult patient, with renal insufficiency, experienced obtundation and myoclonic jerks of his right arm approximately 4 weeks after beginning cefepime 6 grams/day in combination with amikacin 1.2 grams/day. An EEG revealed status epilepticus. He was treated with benzodiazepines and valproic acid. Over the next hour, the patient's mental status normalized; however, the next day the patient became lethargic and unresponsive. A repeat EEG showed no evidence of epileptic discharges. Suspecting cefepime-induced encephalopathy, cefepime therapy was discontinued. A serum cefepime concentration, obtained 3 hours after the last injection, was 284 mg/L (normal therapeutic range 2.5 to 5.1 mg/L). With supportive therapy, including high-volume continuous veno-venous hemofiltration, the patient completely recovered (Bresson et al, 2008).

c) CEFONICID: An ill-defined, unconfirmed seizure in one patient, with normal renal function, was associated with the administration of a therapeutic dose of cefonicid. The episode was subsequently described as a "syncopal episode" (Tse et al, 1986). However, cause and effect were not clearly established (Higbee et al, 1987).
d) CEFTAZIDIME: Myoclonic movements, a tonic-clonic seizure, and neuro- muscular overexcitability were reported after ceftazidime was administered intravenously (Geyer et al, 1988; Jackson & Berkovic, 1992; Klion et al, 1994).
e) MOXALACTAM - Seizures were described in a 91-year-old man with impaired renal function following a 1 gram dose of moxalactam. The moxalactam serum level 20 hours after the last dose was 85.9 mg/L (Hoffman, 1986).

2) WITH POISONING/EXPOSURE

a) CEFAZOLIN

1) CASE REPORT: A 53-year-old woman experienced generalized tonic-clonic seizures approximately 15 minutes after inadvertently receiving 1.5 grams cefazolin intrathecally. The patient's seizures were controlled with administration of phenobarbitone, diazepam, and cisatracurium (Lang et al, 1999).

b) CEFOTAXIME

1) A 34-year-old man experienced visual and auditory hallucinations associated with absence status epilepticus after receiving intravenous ceftazidime, 2 g every 12 hours for 3 days. The peak serum ceftazidime level was 402 mcg/mL two days after initiation of ceftazidime therapy (normal peak level 55 mcg/mL) (Jackson & Berkovic, 1992).

c) CEFTAZIDIME

1) A 70-year-old woman with chronic renal failure on chronic ambulatory peritoneal dialysis was inadvertently given 11 grams of ceftazidime in her dialysis fluid over 2 days. She presented with alteration of consciousness (GCS E4, V1, M5), mutism, asterixis, horizontal nystagmus, and an EEG consistent with non-convulsive status epilepticus. She was treated with hemodialysis, and phenytoin and recovered. Serum ceftazidime concentration before hemodialysis was 105.2 mcg/ml (normal peak is 55 mcg/mL) (Vannaprasaht et al, 2006).

C) PARAPLEGIA

1) WITH POISONING/EXPOSURE

a) CEFAZOLIN: A 53-year-old woman inadvertently received approximately 1.5 grams of cefazolin intrathecally and ten minutes later, experienced bilateral sciatica and a subsequent feeling of paraplegia. The patient gradually recovered with supportive care, which included cerebrospinal fluid drainage (Lang et al, 1999).

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Vomiting, diarrhea, and pancreatitis may occur.
2) Hiccups have been reported following intravenous administration of cefotetan.

3.8.2)

A) VOMITING

1) WITH THERAPEUTIC USE

a) CASE REPORT: Vomiting occurred in a 47-year-old woman 20 minutes after receiving intraventricular cefazolin, 50 mg in 2 mL of normal saline (Manzella et al, 1988).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea has been reported after treatment with cefaclor (Hyslop, 1988).

C) PANCREATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 71-year-old woman experienced increasing abdominal pain and jaundice three days after beginning ceftriaxone therapy, 2 g IV every 24 hours, to treat gram-negative sepsis. A CT scan revealed an enlarged pancreas, indicating acute pancreatitis. The ceftriaxone was discontinued and, 4 days later, a follow-up CT scan showed a decrease in the size of the pancreas (Zimmerman et al, 1993).

D) HICCOUGHS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 62-year-old man developed singultus (hiccups) within one hour of receiving an intravenous infusion of cefotetan, 1 gram twice daily, and lasting 4 to 5 hours. Complete resolution occurred when the antibiotic was stopped (Morris & McAllister, 1992).

1) The singultus recurred upon rechallenge and again lasted 4 to 5 hours (Morris & McAllister, 1992).

E) ANTIBIOTIC ENTEROCOLITIS

1) WITH POISONING/EXPOSURE

a) Clostridium dificile-related pseudomembranous colitis has been reported following chronic occupational inhalational exposure of several different third generation cephalosporins (Greenberg & Hendrickson, 2001).

Hepatic

3.9.1)

A) WITH THERAPEUTIC USE

1) Elevated liver enzymes may occur with therapeutic use.
2) Choledocholithiasis and pseudocholelithiasis have been reported following administration of ceftriaxone.

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Elevated hepatic enzymes have been reported after treatment with cefaclor (Hyslop, 1988).

B) BILIARY CALCULUS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 9-year-old boy developed epigastric abdominal pain and associated emesis five days after completing intravenous ceftriaxone therapy of 100 mg/kg per day, in two divided doses, for 7 days. Ultrasound showed cholelithiasis and a dilated common bile duct with a common bile duct stone. Common bile duct exploration was conducted and subsequent analysis of the stone revealed it to be 100% ceftriaxone (Robertson et al, 1996).
b) PSEUDOCHOLELITHIASIS has been reported, primarily in children, following intravenous administration of ceftriaxone (Kirejczyk et al, 1992; Anon, 1993; Blais & Duperval, 1994; Bonioli et al, 1994; Sahni et al, 1994; Stabile et al, 1995). The pseudocholelithiasis is reversible upon discontinuation of ceftriaxone therapy.

C) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 80-year-old man developed jaundice approximately 3 days after completing a 2-week course of oral ceftriaxone, 2 grams daily. Liver function tests revealed elevated liver enzyme levels and, 2 weeks later, the patient developed pruritus, pale stools, and darkened urine (Longo et al, 1998).
b) CASE REPORT: A 67-year-old man presented to the emergency department with anorexia, nausea, vomiting, fatigue, and abdominal pain 14 days after beginning cefonicid therapy. Laboratory analysis revealed elevated liver enzyme levels and eosinophil count, and an abdominal ultrasound showed an enlarged liver. Symptoms completely resolved four days after cessation of cefonicid therapy and serum liver enzyme levels and eosinophil count normalized seven weeks after discontinuation of cefonicid therapy (Famularo et al, 2001).

Genitourinary

3.10.1)

A) Rare effects reported with cephalosporin administration include renal failure, interstitial nephritis, nephrolithiasis, and crystalluria.

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 58-year-old woman experienced a gradual decline in renal function (the peak serum creatinine level was 3.3 mg/dL) 2 days after beginning cefuroxime therapy, 1.5 g intravenously every 8 hours. Cefuroxime was discontinued and the patient's renal function gradually normalized six days later.

1) The patient was then inadvertently placed on cefuroxime therapy again. Her serum creatinine level began to rise after administration of three doses of cefuroxime. After discontinuation of the antibiotic, the patient's serum creatinine level normalized (Goddard et al, 1994).

B) INTERSTITIAL NEPHRITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute interstitial nephritis occurred in a 20-year-old woman following ceftriaxone therapy to treat cystic problems. The nephritis gradually resolved (Grcevska & Polenakovic, 1996).

C) ABNORMAL URINE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Crystalluria and hematuria were reported in a 3-year-old boy who took 2500 mg (104 mg/kg) of cephalexin (Clark, 1992). The patient was encouraged to drink fluids for the next 24 hours and recovered without sequelae.

D) KIDNEY STONE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old man experienced dysuria, hematuria, and colicky left flank pain after completing eight days of ceftriaxone therapy. Abdominal ultrasound revealed two calculi in the left renal pelvis. The calculi spontaneously resolved six days later (Grasberger et al, 2000).

Hematologic

3.13.1)

3.13.2)

A) PROTHROMBIN TIME LOW

1) WITH THERAPEUTIC USE

a) Prolonged prothrombin times, thrombocytopenia, and coagulopathies associated with a qualitative platelet defect and aggregation abnormalities have been reported following IV therapy with moxalactam, cefonicid, cefoxitin, cefazolin, cefoperazone, cefamandole, and cefmetazole (Lee et al, 1983; Bailey, 1983; Pakter et al, 1982; D'elia et al, 1983; Neu, 1983; Weitekamp & Aber, 1983; Bruch, 1983; Kurz et al, 1986; Saura et al, 1994; Riancho et al, 1995; Breen & St Peter, 1997).

B) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Leukopenia, thrombocytopenia, and anemia have been reported after treatment with cefaclor (Hyslop, 1988).

C) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Severe neutropenia and agranulocytosis occurred following intravenous administration of ceftriaxone. The hematologic effects were reversible upon discontinuation of the antibiotic (Reichman et al, 1993; Tantawichien et al, 1994).
b) CASE REPORT: A 15-year-old boy developed agranulocytosis seven days after beginning intravenous ceftazidime therapy, 1 g twice daily. Treatment with granulocyte macrophage colony stimulating factor (GM-CSF) and discontinuation of the ceftazidime resolved the agranulocytosis (Hui & Chan, 1993).

D) HEMOLYSIS

1) WITH THERAPEUTIC USE

a) Several cases of fatal hemolytic reactions following intravenous ceftriaxone therapy have been reported in children with serious hematologic abnormalities (Bernini et al, 1995; Lascari & Amyot, 1995; Borgna-Pignatti et al, 1995; Scimeca et al, 1996; Moallem et al, 1998).

1) The patients were children with leukemia, sickle cell anemia, AIDS, and hypereosinophilic syndrome. The patient with sickle cell anemia received IV ceftriaxone and penicillin and experienced several unexplained episodes of hematuria. The leukemic patient had received other oral cephalosporins with no hematuria reported. All of the patients died within one hour of initiation of intravenous ceftriaxone.
2) Blood samples, drawn during crisis in the leukemic patient, demonstrated erythrocyte clumping and severe hemoglobin decrease (from 62 to 14 g/L). The sickle cell anemic patient's serologic evaluations indicated the presence of an IgM antibody against ceftriaxone, which agglutinated with and hemolyzed the patient's erythrocytes, indicating the presence of an immune-mediated hemolytic anemia.
3) The lab results of the patient reported by Moallem et al (1998) also demonstrated the presence of antibodies against ceftriaxone due to previous ceftriaxone exposures, indicating that the occurrence of fatal intravascular hemolysis was immune-mediated.

b) Immune-mediated hemolytic anemia was reported in five patients following intravenous cefotetan administration. Fatalities occurred in two of the cases, within one month of receiving the intravenous cefotetan (Chenoweth et al, 1992; Garratty et al, 1992; Wagner et al, 1992; Gallagher et al, 1992; Mohammed et al, 1994).
c) CASE REPORT: An 80-year-old man, previously hospitalized for ceftriaxone-induced hepatitis presented with lethargy and increasing jaundice. Lab tests showed an increase in serum bilirubin and a decrease in hemoglobin concentration. The direct Coombs IgG test was positive and a bone marrow biopsy showed an erythroblastocytopenia, consistent with autoimmune hemolytic anemia and erythroblastocytopenia. He recovered following administration of steroids, immunoglobulins, and a red cell transfusion (Longo et al, 1998).
d) CASE REPORT (CHILD): A 6-year-old boy with sickle cell anemia developed severe hemolysis approximately 30 minutes after the fourth infusion of ceftriaxone for treatment of a possible infection. The patient recovered following transfusion of fresh frozen plasma and packed red blood cells, discontinuation of ceftriaxone therapy, and administration of steroids (Viner et al, 2000).

Dermatologic

3.14.1)

A) WITH THERAPEUTIC USE

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 64-year-old woman developed a generalized skin rash following cefaclor and acetazolamide therapy to treat uveitis. Discontinuation of the medications gradually resolved the rash. Rechallenge with both agents produced the same rash (Ogoshi et al, 1992).
b) CASE REPORT: An erythematous maculopapular rash appeared on the upper trunk and upper extremities of a 77-year-old man 7 days after beginning ceftazidime therapy, 2 g IV every 8 hours. The rash gradually spread to the patient's lower extremities. Following discontinuation of ceftazidime, the rash subsided (Klion et al, 1994).
c) CASE REPORT: Intravenous ceftazidime caused a photosensitivity reaction in a 26-year-old cystic fibrosis patient. The reaction was characterized by a rash on the sun-exposed parts of her body after sunbathing for approximately 10 minutes. The rash reappeared a few times during sunlight exposure when the patient was continuing ceftazidime therapy (Vinks et al, 1993).

B) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 32-year-old woman developed a rash six days after beginning cephalexin therapy to treat bronchitis. The rash worsened, oral ulcers developed, and there was increased pain and stiffness in her knees and ankles twelve days after initiating cephalexin therapy. The symptoms gradually resolved after beginning treatment with methylprednisolone and erythromycin and discontinuing cephalexin therapy (Murray & Camp, 1992).

C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Toxic epidermal necrolysis occurred in a 37-year-old woman one week after beginning cefazolin therapy. Treatment with cyclophosphamide and discontinuation of the cefazolin caused the skin lesions to gradually disappear (Julsrud, 1994).

D) CONTACT DERMATITIS

1) WITH THERAPEUTIC USE

a) Nurses developed contact dermatitis due to occupational exposure to cefotiam. Open and closed patch tests showed wheal and flare reaction to cefotiam (Miyahara et al, 1993; Shimizu et al, 1996).

E) BULLOUS ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Pemphigus vulgaris was diagnosed in a healthy 68-year-old man after one month of treatment with 4 grams cephalexin daily. Signs included ulcerations of the mucosa, bullae, and encrusted lesions over the entire body.

1) Immunofluorescent microscopy showed intracellular deposition of IgG and C3. A mast cell degranulation test to cephalexin in this patient was positive; an MIF test was negative.
2) The patient recovered after cessation of antibiotic therapy and with fluocortolone and azathioprine treatment (Wolf et al, 1991).

b) CASE REPORT: A 37-year-old man began ceftazidime therapy, 1 g IM daily, to treat folliculitis of the beard. Eight days later, he developed flaccid bullae and encrusted lesions on the chest that gradually spread to the back and scalp.

1) Direct immunofluorescence showed deposits of IgG and C3 among the cells and along the dermo-epidermal junction. A diagnosis of pemphigus erythematosus was made and the ceftazidime was discontinued. The lesions completely disappeared after 40 days of cortisone treatment (Pellicano et al, 1993).

F) DRUG-INDUCED ERYTHRODERMA

1) WITH THERAPEUTIC USE

a) CASE REPORT/CEFEPIME: Red man syndrome, consisting of an erythematous maculopapular rash of the neck and upper torso accompanied by severe pruritus, was reported in a 25-year-old man approximately 30 minutes after receiving an intravenous cefepime infusion on the twelfth day of therapy. The dosage regimen of cefipime was 2 g three times daily, with each dose administered over a 30-minute period. There were no other symptoms present, including dyspnea, tachycardia, or hypotension. The rash resolved following intravenous antihistamine administration. Approximately 8 hours later, rechallenge with intravenous cefepime resulted in a recurrence of symptoms. Again, the rash resolved following intravenous antihistamine administration (Panos et al, 2012).

Immunologic

3.19.1)

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) Igea et al (1992) reported two cases of hypersensitivity reactions occurring following cefazolin administration, 1 g IV/IM for surgical prophylaxis (Igea et al, 1992).

1) In the first case, the cefazolin (IV) caused a generalized rash, hypotension, and tachycardia within a few seconds of administration. The symptoms disappeared twenty minutes later.
2) In the second case, a generalized urticarial rash was the only effect after cefazolin (IM) administration. The rash resolved with appropriate treatment.

b) Delayed hypersensitivity reactions were reported after administration of cefonicid and cefuroxime. Both patients developed a generalized rash which disappeared after discontinuation of the antibiotic (Romano et al, 1992; Martin et al, 1994).

B) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) CEFACLOR: Cefaclor was reported to cause anaphylactic reactions in 4 patients in Japan. The incidence of anaphylactic reactions (about 1 in 7000 patients) was more than 10 times that of ampicillin, cephalexin, amoxicillin, and injectable penicillins (Hama & Mori, 1988).
b) CEFAZOLIN: Anaphylactic reactions were reported following intravenous and intravitreal administration of cefazolin. The patients, who received cefazolin intravenously, submitted to skin testing. The testing demonstrated positive reactions to cefazolin only, indicating a side-chain specific immediate allergy to cefazolin (Kraushar et al, 1994; Warrington & McPhillips, 1996).
c) CEFOTETAN: Anaphylactic reactions were reported in 3 patients receiving intravenous cefotetan for surgical prophylaxis. These patients were 1.4% of those receiving the drug over a 4-month period (Bloomberg, 1988). Faro & Martens (1990) reported that in a prospective study of 2500 patients, who received cefotetan prophylactically, no anaphylactic reactions were seen (Faro & Martens, 1990).
d) CEFOTIAM: Occupational exposure to cefotiam was reported to have caused anaphylaxis in several nurses. In all cases, the nurses were handling the cefotiam, in preparation for intravenous administration, when the anaphylactic reactions occurred (Mizutani et al, 1994; Tadokoro et al, 1994).
e) CEFUROXIME: One case of an anaphylactic reaction to an IM injection of 750 mg cefuroxime has been reported in a 60-year-old man. The patient had previously tolerated cefuroxime. Subsequent oral challenge demonstrated sensitivity to cefuroxime but not to penicillin G, amoxicillin, or cefixime (Bravo et al, 1995).
f) CEPHALEXIN

1) CASE REPORT: A 25-year-old man was given cephalexin tablets to treat a minor infection. He developed a rash after ingesting the first tablet which he self-treated with diphenhydramine. One week later, the patient ingested another cephalexin tablet. Within minutes, he developed a fatal anaphylactic reaction (Hoffman et al, 1989).
2) An anaphylactic reaction (throat tightness, generalized urticaria) was reported following unintentional dermal exposure of cephalexin suspension (250 mg/5 mL). The patient recovered following epinephrine, diphenhydramine, and methylprednisolone administration in the emergency department. The patient had reported previous allergic reactions, that required hospital admission, following ingestions of penicillin and ampicillin (Nordt et al, 1999).

C) BULLOUS ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Pemphigus vulgaris, an autoimmune reaction was diagnosed in a healthy 68-year-old man after one month of treatment with 4 grams cephalexin daily. Signs included ulcerations of the mucosa, bullae, and encrusted lesions over the entire body.

b) CASE REPORT: A 37-year-old man began ceftazidime therapy, 1 gram IM daily, to treat folliculitis of the beard. Eight days later, he developed flaccid bullae and encrusted lesions on his chest that gradually spread to his back and scalp.

1) Direct immunofluorescence showed deposits of IgG and C3 among the cells and along the dermo-epidermal junction. A diagnosis of pemphigus erythematous was made and the ceftazidime was discontinued. The lesions completely disappeared after 40 days of cortisone treatment (Pellicano et al, 1993).

D) TRANSFUSION REACTION DUE TO SERUM PROTEIN REACTION

1) WITH THERAPEUTIC USE

a) A serum sickness-like reaction has been reported in children given cefaclor therapeutically.

1) The reaction is characterized by arthritis and/or arthralgias, pruritus, and urticarial eruptions.
2) Discontinuation of the drug produced improvement and recovery (Hebert et al, 1991; Parra et al, 1992; Stricker & Tijssen, 1992; Vial et al, 1992; Grammer, 1996; Boyd, 1998).
3) In a 10 year review of adverse drug reactions reported in Australia, of 860 adverse events associated with cefaclor, 259 were related to serum sickness, or specified a skin rash and joint involvement (Boyd, 1998). Onset was 5 to 21 days after the start of therapy as reported in 185 of the cases.

E) HEMOLYSIS

1) WITH THERAPEUTIC USE

a) Other hypersensitivity reactions include development of a positive Coombs test resulting in hemolytic anemia after intravenous administration of cefotetan (Chenoweth et al, 1992; Gallagher et al, 1992; Garratty et al, 1992; Wagner et al, 1992; Mohammed et al, 1994)and oral administration of ceftriaxone (Longo et al, 1998).
b) Several cases of fatal hemolytic reactions following intravenous ceftriaxone dosing, in children with serious underlying hematologic abnormalities, have been reported (Bernini et al, 1995; Lascari & Amyot, 1995; Scimeca et al, 1996; Moallem et al, 1998).

1) One patient with sickle cell anemia received IV ceftriaxone and penicillin and experienced several unexplained episodes of hematuria. patient with sickle cell anemia received oral ceftriaxone and penicillin and experienced several unexplained episodes of hematuria. Another patient with leukemia had received other oral cephalosporins with no hematuria reported. All of the patients died within one hour of initiation of intravenous ceftriaxone administration.
2) Blood samples, drawn during crisis in the leukemic patient, demonstrated erythrocyte clumping and severe hemoglobin decrease (from 62 to 14 g/L). The sickle cell anemic patient's serologic evaluations indicated the presence of an IgM antibody against ceftriaxone, which agglutinated with and hemolyzed the patient's erythrocytes, indicating the presence of an immune-mediated hemolytic anemia.
3) The lab results of the patient reported by Moallem et al (1998) also demonstrated the presence of antibodies against ceftriaxone due to previous ceftriaxone exposures, indicating that the occurrence of fatal intravascular hemolysis was immune-mediated.

c) CASE REPORT (CHILD): A 6-year-old boy with sickle cell anemia developed severe hemolysis approximately 30 minutes after the fourth infusion of ceftriaxone for treatment of a possible infection. The patient recovered following transfusion of fresh frozen plasma and packed red blood cells, discontinuation of ceftriaxone therapy, and administration of steroids (Viner et al, 2000).

Reproductive

3.20.1)

3.20.2)

A) ANIMAL STUDIES

1) CEFDINIR

a) RATS, RABBITS: No human studies of pregnancy outcomes after exposure to cefdinir have been published and there are no reports of outcomes after inadvertent exposure during pregnancy. No evidence of teratogenic effects was seen in pregnant rats given cefdinir doses up to 1000 mg/kg/day orally (70 times the recommended human dose based on weight) or in rabbits given up to 10 mg/kg/day orally (0.7 times the recommended human dose). At this dose, rabbits did experience maternal toxicity, manifested by decreased weight gain, without harm to the fetuses (Prod Info cefdinir oral suspension, 2009).

2) CEFEPIME

a) RATS, RABBITS: No teratogenic or embryocidal effects were observed in rats given cefepime at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose (MRHD) on a mg/m(2) basis) during organogenesis, mice given cefepime at doses up to 1200 mg/kg/day (approximately equal to the MRHD on a mg/m(2) basis), or rabbits given a dose of 100 mg/kg/day (0.3 times the MRHD on a mg/m(2) basis) (Prod Info MAXIPIME(R) IV, IM injection, 2009).

3) CEFTAROLINE FOSAMIL

a) The IV administration of ceftaroline fosamil to rats at doses up to approximately 4 times the human dose demonstrated no toxic fetal effects. No drug-induced malformations were noted in rabbits after the maternal administration of IV ceftaroline fosamil at doses up to 100 mg/kg. Neither postnatal development nor reproductive performance was affected in the offspring of pregnant rats administered IV ceftaroline fosamil at doses greater than or equal 4 times the human exposure of 600 mg every 12 hours (Prod Info TEFLARO(R) intravenous injection, 2016).

4) CEFTAZIDIME/AVIBACTAM

a) During animal studies, there was no evidence of fetal harm following administration of ceftazidime up to 40 times the human dose in mice and rats. Similarly, there were no reports of teratogenicity or embryofetal toxicity in rats following doses of avibactam 1000 mg/kg/day (approximately 9 times the human dose) and in rabbits after doses of avibactam 100 mg/kg (approximately twice the human dose). During pre- and post-natal studies in rats, administration of IV avibactam 825 mg/kg/day (approximately 11 times the human exposure) had no effects on pup growth or viability. A dose-related increase in the rate of renal pelvic and ureter dilatation was reported in female weaning pups. Renal pelvic dilatation persisted into adulthood (Prod Info AVYCAZ Intravenous injection powder, 2015).

5) CEFTOLOZANE/TAZOBACTAM

a) MICE, RATS: During embryofetal development studies, there was no evidence of fetal harm following administration of IV ceftolozane in mice and rats at doses up to 2000 (approximately 7 times the mean daily human exposure) and 1000 mg/kg/day (approximately 4 times the mean daily human exposure), respectively. During pre-postnatal studies, administration of IV ceftolozane doses greater than or equal to 300 mg/kg/day (approximately 0.4-fold the mean daily human exposure) during pregnancy and lactation in rats resulted in a decrease in auditory startle response (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).
b) RATS: Tazobactam has been shown to cross the placental barrier in rats, although the fetal concentrations were less than or equal to 10% of maternal plasma concentrations. During embryofetal studies, administration of IV tazobactam at doses up to 3000 mg/kg/day (approximately 19 times the recommended human dose) in rats resulted in maternal toxicities. There were no reports of fetal toxicity. In pre-postnatal studies, administration of intraperitoneal tazobactam twice daily at doses of 1280 mg/kg/day (approximately 8 times the recommended human dose) during gestation and lactation resulted in decreased maternal food consumption, body weight gain, and increased incidence of stillbirths. There were no reports of adverse effects on development, function, learning, or fertility. Decreased postnatal body weights were reported 21 days after delivery in F1 pups. The no-observed-adverse-effect-level (NOAEL) was determined to be 40 mg/kg/day (approximately 0.3 times the recommended human dose) (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).

6) CEFUROXIME

a) MICE, RABBITS: No evidence of teratogenic effects was seen in mice administered cefuroxime at doses up to 6,400 mg/kg/day (6.3 times the recommended maximum human dose based on mg/m(2)) or in rabbits at doses up to 400 mg/kg/day (2.1 times the recommended maximum human dose based on mg/m((2) (Prod Info ZINACEF(R) IV, IM injection, 2010).

3.20.3)

A) CEFTAROLINE FOSAMIL

1) There are no adequate and well controlled studies of the use of ceftaroline fosamil during pregnancy. In animal studies, there was no evidence of fetal teratogenicity, but maternal toxicity was reported at the highest doses (50 mg/kg and 100 mg/kg) (Prod Info TEFLARO(R) intravenous injection, 2016).

B) CEFTAZIDIME/AVIBACTAM

1) There are no adequate or well controlled studies of ceftazidime/avibactam use during human pregnancy. During animal studies, there was no evidence of fetal harm in mice, rats, and rabbits administered either ceftazidime or avibactam. Because animal studies are not always indicative of human response, the manufacturer recommends using ceftazidime/avibactam during pregnancy only if clearly needed (Prod Info AVYCAZ Intravenous injection powder, 2015).

C) CEFTOLOZANE/TAZOBACTAM

1) There are no adequate or well controlled studies of ceftolozane or tazobactam use during human pregnancy. During animal studies, there were no reports of fetal harm with use of either ceftolozane or tazobactam in mice and rats. Because animal studies are not always indicative of human response, the manufacturer recommends use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).

D) PLACENTAL TRANSFER

1) Antibiotic prophylaxis with quinolones in pregnant women resulted in significantly higher placental transfer rates compared with cephalosporins. Prior to Caesarean section, patients received one of four IV infusions: cefepime hydrochloride 1 g (n=9) or cefoperazone sodium 1 g (n=10), administered over 30 minutes; moxifloxacin 400 mg (n=10) or levofloxacin 500 mg (n=12) administered over 60 minutes. All infusions were completed 20 to 25 minutes prior to surgery and maternal and fetal blood samples were collected during delivery. The mean transplacental passage rates for moxifloxacin, levofloxacin, cefepime, and cefoperazone were 74.84%, 66.53%, 23.21%, and 12.68%, respectively, and the mean transfetal passage rates were 90.78%, 84.22%, 79.17%, and 79.78%, respectively (Ozyuncu et al, 2010).
2) CEFUROXIME

a) Although a number of studies have indicated that cefuroxime sufficiently crosses the placental barrier to result in therapeutic drug levels in amniotic fluid and umbilical cord blood, these studies were performed immediately prior to delivery or caesarean section (Coppi et al, 1982; Craft et al, 1981; Bousefield et al, 1981; Bergogne-Berezin et al, 1981; Bousefield, 1984). Plasma levels are significantly lower (20% to 50%) during pregnancy (11 to 35 weeks) than during or after delivery, following administration of the same dose (Philipson & Stiernstedt, 1982).

E) PREGNANCY CATEGORY

1) The following drugs have been classified as FDA pregnancy category B:

a) CEFADROXIL (Prod Info cefadroxil oral capsules, 2007)
b) CEFAZOLIN (Prod Info cefazolin injection, 2006)
c) CEFDINIR (Prod Info cefdinir oral suspension, 2009)
d) CEFDITOREN (Prod Info SPECTRACEF(R) oral tablets, 2008)
e) CEFEPIME (Prod Info MAXIPIME(R) IV, IM injection, 2009)
f) CEFOPERAZONE (Prod Info CEFOBID(R) intramuscular, intravenous injection, 2006)
g) CEFOTAXIME (Prod Info CLAFORAN(R) IM and IV injection, 2008)
h) CEFOTETAN (Prod Info cefotetan IV injection, 2009)
i) CEFOXITIN (Prod Info Cefoxitin IV injection, 2008)
j) CEFTAZIDIME (Prod Info FORTAZ(R) injection, 2007)
k) CEFTAZIDIME/AVIBACTAM (Prod Info AVYCAZ Intravenous injection powder, 2015)
l) CEFTIBUTEN (Prod Info CEDAX(R) oral capsules, suspension, 2008a)
m) CEFTIZOXIME (Prod Info CEFIZOX(R) injection, 2005)
n) CEFTOLOZANE/TAZOBACTAM (Prod Info ZERBAXA (TM) intravenous injection powder, 2014)
o) CEFTRIAXONE (Prod Info ceftriaxone sodium and dextrose IV injection, 2010)
p) CEFUROXIME (Prod Info ZINACEF(R) IV, IM injection, 2010)
q) CEPHALEXIN (Prod Info cephalexin oral capsules, 2008)
r) CEPHRADINE (Prod Info VELOSEF(R) 250 oral capsules, 2004)

2) CEFTAROLINE FOSAMIL

a) There are no adequate and well controlled studies of the use of ceftaroline fosamil during pregnancy (Prod Info TEFLARO(R) intravenous injection, 2016).

F) LACK OF EFFECT

1) CEFUROXIME

a) SUMMARY: There are no adequate and well-controlled studies of cefuroxime use in pregnant women (Prod Info ZINACEF(R) IV, IM injection, 2010). Congenital defects, major malformations, and minor malformations have been reported in infants of women who received cefuroxime during the second and third trimester of pregnancy. However, the overall incidence was low and did not differ significantly from a reference group administered an antibiotic with no teratogenic effects (Berkovitch et al, 2000; Manka et al, 2000).

1) A small prospective study of 106 women receiving cefuroxime during the first trimester of pregnancy suggests that cefuroxime is probably not associated with an increased risk of malformations or spontaneous abortions. The rate of major malformations among women who took cefuroxime was 3.2%, while that of a reference group treated with antibiotics known not to be teratogenic was 2% (p=0.61). Minor malformations were evident in 10.7% of the cefuroxime group and 6.2% of the reference group (p=0.25). There was no difference between groups in the occurrence of spontaneous abortions. The rate of induced abortions was higher with cefuroxime, presumably because of anxiety about having taken cefuroxime during early pregnancy (Berkovitch et al, 2000).
2) A small (n=78) retrospective study detected neither physical nor mental developmental abnormalities in children born to mothers treated with cefuroxime during pregnancy. Thirteen, 19, and 46 women were treated during the first, second, and third trimester, respectively. Three children had congenital defects at birth consisting of hip joint dysplasia (1), hypospadia (1), and imperforate anus (1). The mothers of these children were treated during the second or third trimester (Manka et al, 2000). This study does not provide definitive support for the use of cefuroxime during pregnancy; larger comparative trials are necessary.

G) ANIMAL STUDIES

1) CEFEPIME

2) CEFOPERAZONE

a) RATS, MICE, MONKEYS: Rats, mice, and monkeys administered cefoperazone during gestation at doses up to 10 times the maximum human dose did not show evidence of impaired fertility or fetal harm (Prod Info CEFOBID(R) intramuscular, intravenous injection, 2006).

3) CEFOTETAN

a) RATS, MONKEYS: Human studies of pregnancy outcomes after exposure to cefotetan have not been published and there are no reports of outcomes after inadvertent exposure during pregnancy. Reproduction studies in rats and monkeys administered cefotetan at doses up to 20 times the human dose showed no evidence of impaired fertility or harm to the fetus (Prod Info cefotetan IV injection, 2009).

4) CEFTOLOZANE/TAZOBACTAM

5) CEFTAROLINE FOSAMIL

a) No maternal toxicity was noted in rats after the administration of IV ceftaroline fosamil to pregnant rats at doses approximately 4 times the human exposure; however, an increase in spontaneous abortion, increased maternal morbidity and mortality, and an increased incidence of angulated hyoid alae were noted in rabbits after the administration of maternal doses of 50 and 100 mg/kg (Prod Info TEFLARO(R) intravenous injection, 2016).

3.20.4)

A) BREAST MILK

1) As a group, the cephalosporins do not pose a significant risk to the nursing infant because the drugs are highly protein-bound (Dillon et al, 1997).
2) Potential problems for the nursing infant whose mother is receiving these agents include sensitization, modification of bowel flora, and difficulty in the interpretation of culture results, although the clinical significance of any of these remains uncertain (Briggs et al, 1998).
3) CEFDINIR

a) Cefdinir has not been detected in human breast milk following administration of single 600-mg doses (Prod Info cefdinir oral suspension, 2009); however, the potential for adverse effects, if any, in the nursing infant from exposure to the drug is unknown. Exercise caution when cefdinir is administered to a nursing woman.

4) CEFEPIME

a) Cefepime is excreted in human breast milk in low concentrations (0.5 mcg/mL) (Prod Info MAXIPIME(R) IV, IM injection, 2009).

5) CEFOTETAN

a) Cefotetan is excreted in human milk in very low concentrations; however, reports concerning the use of cefotetan in breastfeeding mothers and the effect on the nursing infant are not available. Exercise caution when administering cefotetan to a woman who is breastfeeding (Prod Info cefotetan IV injection, 2009).

6) CEFTAROLINE FOSAMIL

a) It is unknown whether ceftaroline fosamil is excreted into human breast milk or affects milk production or the breastfed infant. Administer ceftaroline fosamil to a breastfeeding woman only after considering the developmental and health benefits of breastfeeding against the mother's clinical need for the drug and the potential risks to the breastfeeding infant (Prod Info TEFLARO(R) intravenous injection, 2016).

7) CEFTAZIDIME/AVIBACTAM

a) Lactation studies with the ceftazidime/avibactam combination product have not been conducted. It is unknown whether the ceftazidime/avibactam combination product is excreted into human milk. Ceftazidime is excreted into human milk in low concentrations. It is currently not known if avibactam is excreted into human milk, however, it has been shown to be excreted into the milk of lactating rats. Use caution when administering ceftazidime/avibactam to a lactating woman (Prod Info AVYCAZ Intravenous injection powder, 2015).

8) CEFTOLOZANE/TAZOBACTAM

a) No reports describing the use of ceftolozane/tazobactam during human lactation are available, and the effects on the nursing infant are unknown. It is unknown whether ceftolozane/tazobactam is excreted into human milk. Because many drugs are excreted in human milk and risk to the nursing infant cannot be excluded, caution is advised when administering ceftolozane/tazobactam to a lactating woman (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).

9) CEFUROXIME

a) Cefuroxime is excreted in human milk; however, the concentration is unknown. Reports concerning the use of cefuroxime in breastfeeding mothers are not available. Exercise caution when administering to a woman who is breastfeeding (Prod Info ZINACEF(R) IV, IM injection, 2010).

3.20.5)

A) ANIMAL STUDIES

1) CEFTAROLINE FOSAMIL

a) During animal studies, there was no evidence of fertility impairment at ceftaroline fosamil doses approximately 4 times the maximum recommended human dose (Prod Info TEFLARO(R) intravenous injection, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Urinalysis and electrolytes may be indicated in large ingestions.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Renal function and electrolytes should be monitored following very large doses of cephalosporins, or when such drugs are used in large doses for prolonged periods of time.
2) Plasma levels of these antibiotics are not clinically useful in overdose situations.

B) LABORATORY INTERFERENCE

1) False elevations in serum creatinine measured by Jaffe's method have been reported with cefoxitin and cephalothin (Piveral et al, 1986).

4.1.3)

A) URINALYSIS

1) Urinalysis should be monitored following very large doses of cephalosporins, or when such drugs are used in large doses for prolonged periods of time.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All patients with symptoms thought related to the exposure, and all patients with a history of hypersensitivity reactions to cephalosporins, should probably be evaluated at a health care facility.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) Activated charcoal may be indicated in patients, with underlying renal insufficiency, following an extremely large overdose (greater than 15 times the usual single therapeutic dose).

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) Gastric decontamination is generally not indicated in patients who do not have any underlying health problems. In patients with underlying renal insufficiency, gastric decontamination may be indicated when the amount ingested exceeds 15 times the usual single therapeutic dose.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) RECOMMENDATION TO STOP TREATMENT

1) Drug should be withheld for an appropriate period, and discontinued if so indicated.

B) HYPERSENSITIVITY REACTION

1) SUMMARY

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

2) BRONCHOSPASM

a) ALBUTEROL

1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

3) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

4) MILD CASES

a) DIPHENHYDRAMINE

1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).

5) MODERATE CASES

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

6) SEVERE CASES

a) EPINEPHRINE

1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).

7) AIRWAY MANAGEMENT

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

8) MONITORING

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

9) HYPOTENSION

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).

10) H1 and H2 ANTIHISTAMINES

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).

1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).

b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

11) DYSRHYTHMIAS

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

12) OTHER THERAPIES

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

C) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

D) BLOOD COAGULATION DISORDER

1) The coagulopathies associated with intravenous cephalosporin therapy have been corrected with the administration of exogenous vitamin K and fresh frozen plasma (Bailey, 1983; Pakter et al, 1982; Neu, 1983; Sattler et al, 1986).
2) The following protocol has been suggested (Sattler et al, 1986) -

a) Hypoprothrombinemia without apparent bleeding - 10 mg vitamin K subcutaneously.
b) Hypoprothrombinemia with bleeding - fresh frozen plasma.
c) Prolonged template bleeding time and bleeding present - platelet transfusions.
d) Prophylaxis - In patients with renal failure, malnutrition, intraabdominal infection, or recent gastrointestinal surgery, administer vitamin K 10 mg parenterally once or twice weekly.

Enhanced Elimination

1) In severe overdosage in patients with renal failure, dialysis may be considered.
2) CASE REPORT - A 70-year-old woman with chronic renal failure on chronic ambulatory peritoneal dialysis was inadvertently given 11 grams of ceftazidime in her dialysis fluid over 2 days. She presented with alteration of consciousness (GCS E4, V1, M5,) mutism, asterixis, horizontal nystagmus, and an EEG consistent with non-convulsive status epilepticus. She was treated with hemodialysis (two sessions one day apart), and phenytoin and recovered. Serum ceftazidime concentrations before and after hemodialysis were 105.2 and 39.4 mcg/mL for the first dialysis, and 36.2 and 5.2 mcg/mL for the second hemodialysis session (normal peak is 55 mcg/mL) (Vannaprasaht et al, 2006).

1) CASE REPORT - An adult patient, with renal insufficiency, experienced myoclonus and mental status changes approximately 4 weeks after beginning cefepime 6 grams/day. An EEG revealed status epilepticus and laboratory data indicated a serum cefepime concentration of 284 mg/L (normal therapeutic range 2.5 to 5.1 mg/L). High-volume continuous veno-venous hemofiltration was started. After 24 hours of therapy, the patient's cefepime concentration decreased to 5.6 mg/L. Therapy was discontinued after a total of 36 hours when the serum concentration was 3.2 mg/L, and the patient had completely recovered neurologically (Bresson et al, 2008).

Abstracts

Case Reports

1) Clara (1986) reported a case of inadvertent administration of 800 mg ceftriaxone intrathecally in a 74-year-old patient with persistent pneumococcal meningitis and pansinusitis. Upon completion of the intrathecal injection, the patient complained of severe burning lumbosacral pain. The pain was described as excruciating and did not subside after repeated doses of analgesics. The CSF concentration of ceftriaxone 12 hours after a previous 2 g IV dose and 2 hours after the intrathecal injection of 800 mg was 4387 +/- 6.5 mg/L. After the dosing error was realized, CSF exchange was performed in an attempt to dilute the antibiotic concentration. A total of 240 mL of CSF was exchanged with 240 mL of physiologic saline (twice the theoretical CSF volume) over a 1 hour period. At the end of the procedure, CSF ceftriaxone levels were only reduced to 3384 +/- 2.5 mg/L; however, the pain had completely subsided and did not recur. The patient recovered rapidly and was afebrile within 3 days (Clara, 1986).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) CEFACLOR

1) ORAL: The recommended total daily dosage is 750 to 1000 mg (Prod Info cefaclor extended-release oral tablets, 2005).

B) CEFADROXIL

1) ORAL: The recommended dosage is 1 to 2 g/day in a single daily dose or 2 divided doses (Prod Info cefadroxil oral capsules, 2007; Prod Info cefadroxil oral suspension, 2007).

C) CEFAZOLIN

1) INJECTION: The recommended total daily dosage is 750 mg to 6 g in divided doses. In rare cases, dosages up to 12 g/day may be warranted (Prod Info cefazolin injection, 2006).

D) CEFDINIR

1) ORAL: The recommended dosage is 600 mg/day in a single dose or 2 divided doses (Prod Info OMNICEF(R) oral capsules, suspension, 2007).

E) CEFDITOREN

1) ORAL: The recommended dosage is 400 to 800 mg/day (Prod Info SPECTRACEF(R) oral tablets, 2008).

F) CEFEPIME

1) INJECTION: The recommended dosage is 1 to 4 g/day in divided doses (Prod Info MAXIPIME(R) IV, IM injection, 2009).

G) CEFIXIME

1) ORAL: The recommended dosage is 400 mg/day in a single dose or 2 divided doses (Prod Info SUPRAX(R) oral tablets, suspension, 2008).

H) CEFOPERAZONE

1) INJECTION: The recommended dosage is 2 to 4 g/day divided every 12 hours. For severe or less susceptible infections, 6 to 12 g/day divided every 6 to 12 hours. MAXIMUM: 16 g/day (Prod Info CEFOBID(R) intramuscular, intravenous injection, 2006).

I) CEFOTAXIME

1) INJECTION: The recommended dosage is 0.5 to 12 g/day. MAXIMUM: 12 g/day (Prod Info CLAFORAN(R) IM and IV injection, 2008).

J) CEFOTETAN

1) INJECTION: The recommended dosage is 1 to 6 g/day. MAXIMUM: 6 g/day (Prod Info cefotetan IV, IM injection, 2008a).

K) CEFOXITIN

1) INJECTION: The recommended dosage is 3 to 12 g/day (Prod Info Cefoxitin IV injection, 2008).

L) CEFTAROLINE

1) INJECTION: The recommended dosage is 600 mg every 12 hours administered IV over 1 hour (Prod Info TEFLARO(TM) IV injection, 2010).

M) CEFTAZIDIME

1) INJECTION: The recommended dosage is 1 g every 8 to 12 hours. Depending on infection, 0.5 to 6 g/day may be given in divided doses (Prod Info FORTAZ(R) injection, 2007).

N) CEFTAZIDIME/AVIBACTAM

1) IV: The recommended dosage is 2.5 g administered every 8 hours infused over 2 hours (Prod Info AVYCAZ Intravenous injection powder, 2015).

O) CEFTIBUTEN

1) ORAL: The recommended dosage is 400 mg/day. MAXIMUM: 400 mg/day (Prod Info CEDAX(R) oral capsules, suspension, 2008).

P) CEFTOLOZANE/TAZOBACTAM

1) IV INJECTION: The recommended dosage is 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) every 8 hours infused over 1 hour. Duration of use is dependent on severity and site of infection (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).

Q) CEFTRIAXONE

1) INJECTION: The recommended dosage is 1 to 4 g/day in single or divided doses. MAXIMUM: 4 g/day. A single 250-mg IM dose is recommended for uncomplicated gonococcal infections (Prod Info ROCEPHIN(R) IV, IM injection, 2010).

R) CEFUROXIME

1) INJECTION: The recommended dosage is 750 mg to 1.5 g every 6 to 8 hours. MAXIMUM: 3 g every 8 hours. For uncomplicated gonococcal infection, the recommended dose is 1.5 g IM as a single dose (divided and given in 2 separate sites) (Prod Info ZINACEF(R) intravenous injection, 2007).
2) ORAL TABLET: The recommended dosage is 250 or 500 mg twice daily for 5 to 10 days. For uncomplicated gonorrhea, a single 1000-mg dose is recommended (Prod Info CEFTIN(R) oral tablets oral suspension, 2007).

S) CEPHALEXIN

1) ORAL: The recommended dosage is 250 mg every 6 hours for 7 to 14 days; alternatively, 500 mg every 12 hours may be given; MAX 4 g per day in 2 to 4 doses equally divided (Prod Info KEFLEX(R) oral capsules, 2015).

7.2.2)

A) CEFACLOR

1) 16 YEARS OF AGE AND OLDER

a) ORAL: The recommended total daily dosage is 750 to 1000 mg (Prod Info cefaclor extended-release oral tablets, 2005).

2) LESS THAN 16 YEARS OF AGE

a) Safety and efficacy have not been established (Prod Info cefaclor extended-release oral tablets, 2005).

B) CEFADROXIL

1) ORAL: The recommended dosage is 30 mg/kg/day in single or equally divided doses every 12 hours. Maximum dose is 1 g/day (Prod Info cefadroxil oral capsules, 2007; Prod Info cefadroxil oral suspension, 2007).
2) URINARY TRACT INFECTION

a) 30 mg/kg/day orally in 2 divided doses. Maximum 2 g/day (Prod Info cefadroxil oral suspension, 2007; Prod Info cefadroxil oral capsules, 2007).

C) CEFAZOLIN

1) PREMATURE INFANTS AND NEONATES

a) Safety and efficacy have not been established and use is not recommended (Prod Info cefazolin injection, 2006).
b) 1 MONTH OF AGE AND OLDER

1) INJECTION: 50 to 100 mg/kg/day IV or IM divided every 8 hours. Maximum 2 g/dose (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009; Prod Info cefazolin intramuscular injection, intravenous injection, 2006; Caloza et al, 1979; Pickering et al, 1974).

c) INFECTIVE ENDOCARDITIS, PROPHYLAXIS

1) 30 days of age and older: 50 mg/kg IV or IM 30 to 60 minutes prior to dental, respiratory, or infected skin/skin structure or musculoskeletal procedures. Maximum 1 g/dose (Wilson et al, 2007a).

2) SURGICAL PROPHYLAXIS

a) 30 days of age and older: 25 to 50 mg/kg IV within 60 minutes before incision. Repeat intraoperatively within 2 half-lives (2 to 5 hours) if the operation is still in progress. Maximum 2 g/dose (Milstone et al, 2008; Bratzler & Houck, 2004; Haessler et al, 2003; Maher et al, 2002; Dellinger et al, 1994).

D) CEFDINIR

1) 13 YEARS OF AGE AND OLDER

a) COMMUNITY-ACQUIRED PNEUMONIA: 300 mg orally every 12 hours for 10 days (Prod Info cefdinir oral capsules, 2009).
b) CHRONIC BRONCHITIS, ACUTE EXACERBATION: 600 mg orally once a day for 10 days or 300 mg orally every 12 hours for 5 to 10 days (Prod Info cefdinir oral capsules, 2009).
c) PHARYNGITIS/TONSILLITIS: 600 mg orally once a day for 10 days or 300 mg orally every 12 hours for 5 to 10 days (Prod Info cefdinir oral capsules, 2009).
d) SINUSITIS: 600 mg orally once a day or 300 mg orally every 12 hours for 10 days (Prod Info cefdinir oral capsules, 2009).
e) SKIN AND SKIN STRUCTURE INFECTIONS, UNCOMPLICATED: 300 mg orally every 12 hours for 10 days (Prod Info cefdinir oral capsules, 2009).

2) 6 MONTHS THROUGH 12 YEARS OF AGE

a) OTITIS MEDIA: 14 mg/kg orally once a day for 10 days or 7 mg/kg orally every 12 hours for 5 to 10 days. Maximum 600 mg/day (Prod Info cefdinir oral suspension, 2009).
b) PHARYNGITIS/TONSILLITIS: 14 mg/kg orally once a day for 10 days or 7 mg/kg orally every 12 hours for 5 to 10 days. Maximum 600 mg/day (Prod Info cefdinir oral suspension, 2009).
c) SINUSITIS: 14 mg/kg orally once a day or 7 mg/kg orally every 12 hours for 10 days. Maximum 600 mg/day (Prod Info cefdinir oral suspension, 2009; American Academy of Pediatrics Subcommittee on Management of Sinusitis and Committee on Quality Improvement, 2001).
d) SKIN AND SKIN STRUCTURE INFECTIONS, UNCOMPLICATED: 7 mg/kg orally every 12 hours for 10 days. Maximum 600 mg/day (Prod Info cefdinir oral suspension, 2009).

3) LESS THAN 6 MONTHS OF AGE

a) Safety and efficacy have not been established (Prod Info OMNICEF(R) oral capsules, suspension, 2007).

E) CEFDITOREN

1) 12 YEARS OF AGE AND OLDER

a) ORAL: The recommended dosage is 400 to 800 mg/day (Prod Info SPECTRACEF(R) oral tablets, 2008).

2) LESS THAN 12 YEARS OF AGE

a) Safety and efficacy have not been established. Use is not recommended (Prod Info SPECTRACEF(R) oral tablets, 2008).

F) CEFEPIME

1) 16 YEARS OF AGE AND OLDER

a) INJECTION: The recommended dosage is 1 to 4 g/day in divided doses (Prod Info MAXIPIME(R) IV, IM injection, 2009).

2) 2 MONTHS TO 16 YEARS OF AGE

a) FEBRILE NEUTROPENIA: 50 mg/kg IV every 8 hours. Maximum 2 g/dose (Prod Info MAXIPIME(R) IV, IM injection, 2009; Mustafa et al, 2001).
b) PNEUMONIA: 50 mg/kg IV every 8 to 12 hours. Maximum 2 g/dose (Prod Info MAXIPIME(R) IV, IM injection, 2009; Bradley & Arrieta, 2001).
c) SKIN/SKIN STRUCTURE INFECTIONS: 50 mg/kg IV every 12 hours. Maximum 2 g/dose (Prod Info MAXIPIME(R) IV, IM injection, 2009).
d) URINARY TRACT INFECTIONS: 50 mg/kg IV every 8 to 12 hours. Maximum 2 g/dose (Prod Info MAXIPIME(R) IV, IM injection, 2009; Arrieta & Bradley, 2001; Schaad et al, 1998).

3) 29 DAYS OF AGE AND OLDER

a) BACTERIAL MENINGITIS: 50 mg/kg IV every 8 hours. Maximum 2 g/dose (Tunkel et al, 2004a; Saez-Llorens & O'Ryan, 2001; Saez-Llorens et al, 1995).
b) INFECTIVE ENDOCARDITIS: 50 mg/kg IV every 8 hours in combination with appropriate antimicrobial therapy. Maximum 2 g/dose (Baddour et al, 2005).

4) LESS THAN 2 MONTHS OF AGE

a) Safety and efficacy have not been established (Prod Info MAXIPIME(R) IV, IM injection, 2009).

G) CEFIXIME

1) GREATER THAN 12 YEARS OF AGE (OR WEIGHING MORE THAN 50 KG)

a) ORAL TABLET: The recommended dosage is 400 mg/day in a single dose or 2 divided doses (Prod Info SUPRAX(R) oral tablets, suspension, 2008).
b) GONORRHEA, UNCOMPLICATED: 400 mg orally as a single dose plus azithromycin 1 gram orally as a single dose (Workowski et al, 2010; Prod Info SUPRAX(R) oral tablets, suspension, 2008).
c) STD PROPHYLAXIS - SEXUAL ASSAULT: 400 mg orally as a single dose plus metronidazole 2 g orally as a single dose plus azithromycin 1 g orally as a single dose (Workowski et al, 2010).

2) 2 MONTHS TO 12 YEARS OF AGE

a) ORAL SUSPENSION: The recommended dosage is 8 mg/kg/day in a single dose or 2 divided doses. Maximum 400 mg/day (Prod Info SUPRAX(R) oral tablets, suspension, 2008; Hoberman et al, 1999; Asmar et al, 1994).

3) LESS THAN 6 MONTHS OF AGE

a) Safety and efficacy have not been established (Prod Info SUPRAX(R) oral tablets, suspension, 2008).

H) CEFOPERAZONE

1) Safety and efficacy have not been established (Prod Info CEFOBID(R) intramuscular, intravenous injection, 2006).

I) CEFOTAXIME

1) 1 MONTH TO 12 YEARS OF AGE

a) LESS THAN 50 KG: The recommended dosage is 50 to 180 mg/kg IM/IV divided into 4 to 6 equal doses (Prod Info CLAFORAN(R) IM and IV injection, 2008).
b) 50 KG OR GREATER: The recommended dosage is 0.5 to 12 g/day IM/IV. MAXIMUM: 12 g/day (Prod Info CLAFORAN(R) IM and IV injection, 2008).
c) BACTERIAL MENINGITIS: 30 days of age and older, 200 mg/kg/day IV divided every 6 hours (Odio et al, 1999; Scholz et al, 1998; Kaplan & Patrick, 1990), or 225 to 300 mg/kg/day IV divided every 6 to 8 hours for suspected or documented S. pneumoniae infection, with the addition of vancomycin for suspected or documented decreased susceptibility to penicillin or cefotaxime (Tunkel et al, 2004; None Listed, 1997; Doit et al, 1997; Friedland & Klugman, 1997; Bradley et al, 1995). Maximum 12 g/day.

2) UP TO 1 MONTH OF AGE

a) 1 TO 4 WEEKS OF AGE: The recommended dosage is 50 mg/kg IV every 8 hours (Prod Info CLAFORAN(R) IM and IV injection, 2008).
b) LESS THAN 1 WEEK OF AGE: The recommended dosage is 50 mg/kg IV every 12 hours (Prod Info CLAFORAN(R) IM and IV injection, 2008).

3) 29 DAYS OF AGE AND OLDER

a) Usual dose: 100 to 200 mg/kg/day IV or IM divided every 6 to 8 hours. Maximum 2 g/dose (Prod Info CLAFORAN(R) IV, IM injection, 2009; Hoberman et al, 1999; None Listed, 1997).

4) DISSEMINATED GONOCOCCAL INFECTIONS

a) Children greater than 45 kg, 1 g IV every 8 hours. Continue for 24 to 48 hours after improvement begins followed by oral therapy (cefixime 400 mg orally twice daily) to complete at least 1 week of antibiotic therapy (Workowski et al, 2010).

5) LYME DISEASE

a) 150 to 200 mg/kg/day IV divided every 6 to 8 hours for 14 days (range, 10 to 28 days). Maximum 6 g/day (Wormser et al, 2006).

J) CEFOTETAN

1) According to the manufacturer, safety and efficacy have not been established (Prod Info cefotetan IV, IM injection, 2008a).
2) Usual Dose: 20 to 40 mg/kg/dose IV every 12 hours. Maximum 2 g/dose (Solomkin et al, 2010).
3) Surgical Prophylaxis: 20 to 40 mg/kg IV within 60 minutes before incision. Repeat intraoperatively within 3 to 6 hours (1 to 2 half-lives) if the operation is still in progress. Maximum 2 g/dose (Bratzler & Houck, 2004; None Listed, 1999; Dellinger et al, 1994).

K) CEFOXITIN

1) 3 MONTHS OF AGE AND OLDER

a) INJECTION: The recommended dosage is 80 to 160 mg/kg per day divided every 6 to 8 hours. MAXIMUM: 2 g/dose or 12 g/day (Prod Info Cefoxitin IV injection, 2008); (Gutierrez et al, 1987);(Rosaschino et al, 1985);(Feldman et al, 1980);(Jacobson et al, 1979).
b) SURGICAL PROPHYLAXIS: 20 to 40 mg/kg IV within 60 minutes before incision. Repeat intraoperatively within 2 half-lives (2 to 3 hours) if the operation is still in progress (Prod Info Cefoxitin IV injection, 2008);(Bratzler & Houck, 2004);(Dellinger et al, 1994). Maximum 2 g/dose (Prod Info Cefoxitin IV injection, 2008). Postoperatively, repeat dose every 6 hours after the initial dose (Prod Info Cefoxitin IV injection, 2008).

2) LESS THAN 3 MONTHS OF AGE

a) Safety and efficacy have not been established (Prod Info Cefoxitin IV injection, 2008).

L) CEFPODOXIME

1) 12 YEARS AND OLDER

a) CHRONIC BRONCHITIS, ACUTE EXACERBATION: 200 mg orally every 12 hours for 10 days (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
b) COMMUNITY-ACQUIRED PNEUMONIA: 200 mg orally every 12 hours for 14 days (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
c) GONORRHEA, UNCOMPLICATED: 200 mg orally as a single dose (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
d) SINUSITIS: 200 mg orally every 12 hours for 10 days (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
e) SKIN AND SKIN STRUCTURE INFECTION, UNCOMPLICATED: 400 mg orally every 12 hours for 7 to 14 days (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
f) STREPTOCOCCAL PHARYNGITIS: 100 mg orally every 12 hours for 5 to 10 days (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
g) URINARY TRACT INFECTION, UNCOMPLICATED: 100 mg orally every 12 hours for 7 days (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).

2) 2 MONTHS TO 11 YEARS

a) OTITIS MEDIA: 5 mg/kg orally every 12 hours for 5 days. Maximum 200 mg/dose (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008; MacLoughlin et al, 1996; Mendelman et al, 1992).
b) SINUSITIS: 5 mg/kg orally every 12 hours for 10 days. Maximum 200 mg/dose (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008).
c) STREPTOCOCCAL PHARYNGITIS: 5 mg/kg orally every 12 hours for 5 to 10 days. Maximum 100 mg/dose (Prod Info cefpodoxime proxetil oral suspension, 2008; Prod Info cefpodoxime proxetil oral tablets, 2008; Pichichero et al, 1994; Dajani et al, 1993). Guidelines recommend 10 days of therapy (Gerber et al, 2009).

M) CEFPROZIL

1) 13 YEARS AND OLDER

a) ACUTE OR CHRONIC BRONCHITIS: 500 mg orally every 12 hours for 10 days (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007).
b) SINUSITIS: 250 mg orally every 12 hours or 500 mg orally every 12 hours for 10 days (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007).
c) SKIN AND SKIN STRUCTURE INFECTION, UNCOMPLICATED: 250 mg orally every 12 hours, 500 mg orally every 24 hours, or 500 mg orally every 12 hours for 10 days (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007).
d) STREPTOCOCCAL PHARYNGITIS: 500 mg orally every 24 hours for 10 days (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007).

2) 2 YEARS THROUGH 12 YEARS

a) SKIN AND SKIN STRUCTURE INFECTION, UNCOMPLICATED: 20 mg/kg orally every 24 hours for 10 days. Maximum 500 mg/dose (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007).
b) STREPTOCOCCAL PHARYNGITIS: 7.5 mg/kg orally every 12 hours for 10 days. Maximum 250 mg/dose (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007; Milatovic et al, 1993).

3) 6 MONTHS THROUGH 12 YEARS

a) OTITIS MEDIA: 15 mg/kg orally every 12 hours for 10 days. Maximum 500 mg/dose (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007; Block et al, 2000; Hedrick et al, 2001).
b) SINUSITIS: 7.5 mg/kg orally every 12 hours or 15 mg/kg orally every 12 hours for 10 days. Maximum 500 mg/dose (Prod Info cefprozil oral suspension, 2007; Prod Info cefprozil oral tablets, 2007; Simon, 1997).

N) CEFTAROLINE

1) Safety and efficacy have not been established (Prod Info TEFLARO(TM) IV injection, 2010).

O) CEFTAZIDIME

1) 29 DAYS OF AGE AND OLDER

a) USUAL DOSE: 100 to 150 mg/kg/day IV or IM divided every 8 hours. Maximum 2 g/dose (Prod Info FORTAZ(R) injection, 2007a; Mustafa et al, 2001a; Fleischhack et al, 2001; Schaad et al, 1998; Richard et al, 1997).

2) 1 MONTH TO 12 YEARS OF AGE

a) INTRAVENOUS: The recommended dosage is 30 to 50 mg/kg every 8 hours. MAXIMUM: 6 g/day (Prod Info FORTAZ(R) injection, 2007).

3) LESS THAN 4 WEEKS OF AGE

a) INTRAVENOUS: The recommended dosage is 30 mg/kg every 12 hours (Prod Info FORTAZ(R) injection, 2007).

P) CEFTAZIDIME/AVIBACTAM

1) Safety and effectiveness have not been established in pediatric patients (Prod Info AVYCAZ Intravenous injection powder, 2015).

Q) CEFTIBUTEN

1) 12 YEARS OF AGE AND OLDER

a) ORAL: The recommended dosage is 400 mg/day for 10 days. MAXIMUM: 400 mg/day (Prod Info CEDAX(R) oral capsules, suspension, 2011).

2) 6 MONTHS TO 12 YEARS OF AGE

a) ORAL: The recommended dosage is 9 mg/kg/day for 10 days. MAXIMUM: 400 mg/day (Prod Info CEDAX(R) oral capsules, suspension, 2011).

3) LESS THAN 6 MONTHS OF AGE

a) Safety and efficacy have not been established (Prod Info CEDAX(R) oral capsules, suspension, 2008).

R) CEFTOLOZANE/TAZOBACTAM

1) Safety and effectiveness have not been established in pediatric patients (Prod Info ZERBAXA (TM) intravenous injection powder, 2014).

S) CEFTRIAXONE

1) Usual Dose: 50 to 75 mg/kg IV or IM once daily (or in equally divided doses twice daily). Maximum dose 2 g/day (Prod Info ROCEPHIN(R) IV, IM injection, 2009).
2) OTITIS MEDIA, ACUTE

a) Severe illness, unable to tolerate oral antibiotics - 50 mg/kg IM as a single dose. Maximum 1 g/dose (American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media, 2004; Cohen et al, 1999; Barnett et al, 1997; Green & Rothrock, 1993; Prod Info ROCEPHIN(R) IV, IM injection, 2009).
b) Severe illness, treatment failure - 50 mg/kg IV or IM once daily for 3 days. Maximum dose 1 g/day (American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media, 2004; Leibovitz et al, 2000).

3) BACTERIAL MENINGITIS: 29 days of age and older - 80 to 100 mg/kg/day IV divided every 12 to 24 hours. Maximum dose 4 g/day (Tunkel et al, 2004; Am Acad Pediatr (Committee on Infectious Diseases), 1997; Lebel et al, 1989; Peltola et al, 1989; Prod Info ROCEPHIN(R) IV, IM injection, 2009).
4) CHEMOPROPHYLAXIS AGAINST MENINGOCOCCAL DISEASE FOR CLOSE CONTACTS

a) Less than 15 years of age - 125 mg IM as a single dose (CDC, 2005).
b) 15 years of age and older - 250 mg IM as a single dose (CDC, 2005).

5) GONOCOCCAL INFECTIONS

a) CHILDREN AND ADOLESCENTS 45 KG OR LESS

1) Uncomplicated - 125 mg IM as a single dose (Workowski et al, 2010).
2) Concomitant bacteremia or arthritis - 50 mg/kg IM or IV once daily for 7 days. Maximum dose 1 g/day (Workowski et al, 2010).

b) CHILDREN AND ADOLESCENTS GREATER THAN 45 KG

1) Uncomplicated - 250 mg IM as a single dose plus azithromycin 1 gram orally as a single dose (Workowski et al, 2010).

c) GONOCOCCAL CONJUNCTIVITIS: 1 g IM as a single dose (Workowski et al, 2010).
d) CONCOMITANT BACTEREMIA OR ARTHRITIS: 1 g IM or IV once daily for 7 days (Workowski et al, 2010).
e) GONOCOCCAL MENINGITIS AND ENDOCARDITIS: 1 to 2 g IV every 12 hours. For meningitis, therapy should be continued for 10 to 14 days. For endocarditis, therapy should be continued for at least 4 weeks (Workowski et al, 2010).

6) INFECTIVE ENDOCARDITIS: 100 mg/kg IV or IM every 24 hours alone or in combination with appropriate antimicrobial therapy depending on microorganism. Maximum dose 2 g/day (Baddour et al, 2005).
7) INFECTIVE ENDOCARDITIS, PROPHYLAXIS: 50 mg/kg IV or IM 30 to 60 minutes prior to dental, respiratory, or infected skin/skin structure or musculoskeletal tissue procedures. Maximum 1 g/dose (Wilson et al, 2007).
8) LYME DISEASE: 50 to 75 mg/kg IV once daily for 14 days (range, 10 to 28 days). Maximum dose 2 g/day (Wormser et al, 2006).

T) CEFUROXIME

1) INTRAVENOUS/INTRAMUSCULAR

a) Usual dose, 2 months of age and older: 25 to 50 mg/kg/dose IV or IM every 8 hours. Maximum dose 1500 mg/dose (Prod Info ZINACEF(R) IV, IM injection, 2010; Korppi, 2003; Palacios et al, 2002; Peltola et al, 2001; Azimi et al, 1999; Barson et al, 1985; Nelson et al, 1982).

2) ORAL SUSPENSION

a) 3 months to 12 years

1) Early Lyme Disease: 30 mg/kg/day in 2 divided doses for 14 to 21 days (Wormser et al, 2006; Eppes & Childs, 2002).
2) Impetigo: 30 mg/kg/day orally in 2 divided doses for 10 days. Maximum dose 1000 mg/day (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
3) Otitis Media: 30 mg/kg/day orally in 2 divided doses for 10 days. Maximum dose 1000 mg/day (Prod Info CEFTIN(R) oral tablets, suspension, 2010). For pediatric patients who can swallow whole tablets, the dose of cefuroxime tablets for otitis media is 250 mg orally twice daily for 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
4) Pharyngitis/Tonsillitis: 20 mg/kg/day orally in 2 divided doses for 10 days. Maximum dose 500 mg/day (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
5) Sinusitis: 30 mg/kg/day orally in 2 divided doses for 10 days. Maximum dose 1000 mg/day (Prod Info CEFTIN(R) oral tablets, suspension, 2010). Antibiotic treatment until symptom-free then for an additional 7 days has also been suggested (American Academy of Pediatrics.Subcommittee on Management of Sinusitis and Committee on Quality Improvement, 2001). For pediatric patients who can swallow whole tablets, the dose of cefuroxime tablets for sinusitis is 250 mg orally twice daily for 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).

3) ORAL TABLETS

a) 13 years and older

1) Acute Bronchitis: 250 or 500 mg orally twice a day for 5 to 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
2) Chronic Bronchitis, Bacterial Exacerbation: 250 or 500 mg orally twice a day for 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
3) Early Lyme Disease: 500 mg orally twice a day for 20 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010; Luger et al, 1995).
4) Pharyngitis/Tonsillitis: 250 mg orally twice a day for 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
5) Sinusitis: 250 mg orally twice a day for 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010). Antibiotic treatment until symptom-free then for an additional 7 days has also been suggested (American Academy of Pediatrics.Subcommittee on Management of Sinusitis and Committee on Quality Improvement, 2001).
6) Skin and Skin Structure Infection, Uncomplicated: 250 or 500 mg orally twice a day for 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).
7) Urinary Tract Infection, Uncomplicated: 250 mg orally twice a day for 7 to 10 days (Prod Info CEFTIN(R) oral tablets, suspension, 2010).

U) CEFUROXIME AXETIL

1) 13 YEARS OF AGE AND OLDER

a) ORAL TABLET: The recommended dosage is 250 or 500 mg twice daily for 5 to 10 days. For uncomplicated gonorrhea, a single 1000-mg dose is recommended (Prod Info CEFTIN(R) oral tablets oral suspension, 2007).

2) 3 MONTHS TO 12 YEARS OF AGE

a) ORAL SUSPENSION: 20 mg/kg/day divided every 12 hours (MAXIMUM: 500 mg/day) or 30 mg/kg/day divided every 12 hours (MAXIMUM: 1000 mg/day) for 10 days (Prod Info CEFTIN(R) oral tablets oral suspension, 2007).

V) CEFUROXIME SODIUM

1) 13 YEARS OF AGE AND OLDER

a) INJECTION: The recommended dosage is 50 to 240 mg/kg/day in equally divided doses every 6 to 8 hours. MAXIMUM: 3 g every 8 hours (Prod Info ZINACEF(R) intravenous injection, 2007).

2) 3 MONTHS TO 12 YEARS OF AGE

a) INJECTION: The recommended dosage is 50 to 240 mg/kg/day in equally divided doses every 6 to 8 hours. MAXIMUM: 3 g every 8 hours (Prod Info ZINACEF(R) intravenous injection, 2007).

3) LESS THAN 3 MONTHS OF AGE

a) Safety and effectiveness have not been established (Prod Info ZINACEF(R) intravenous injection, 2007).

W) CEPHALEXIN

1) ORAL

a) The usual recommended dosage is 25 to 50 mg/kg/day in 3 to 4 divided doses (Chen et al, 2011; Prod Info cephalexin oral capsules, 2010; Prod Info cephalexin oral suspension, 2010; Huang et al, 2009; Prod Info KEFLEX(R) oral capsules, 2015). Maximum 2 g/day (Chen et al, 2011; Prod Info cephalexin oral capsules, 2010; Prod Info cephalexin oral suspension, 2010; Huang et al, 2009), or up to 100 mg/kg/day in equally divided doses for severe infections or otitis media (Prod Info KEFLEX(R) oral capsules, 2015).
b) 15 YEARS OF AGE AND OLDER: The recommended dosage is 250 mg every 6 hours for 7 to 14 days; alternatively, 500 mg every 12 hours may be given; MAX 4 g per day in 2 to 4 equally divided doses (Prod Info KEFLEX(R) oral capsules, 2015).
c) BONE AND JOINT INFECTIONS, UNCOMPLICATED: 100 mg/kg/day orally in 4 divided doses. Maximum 4 g/day. Oral therapy started after initial therapy with an appropriate intravenous antibiotic (Bachur & Pagon, 2007; Kocher et al, 2003; Jackson & Nelson, 1982; Tetzlaff et al, 1978).
d) INFECTIVE ENDOCARDITIS, PROPHYLAXIS; PENICILLIN-ALLERGIC: 50 mg/kg orally 30 to 60 minutes prior to procedure. Maximum 2 g/dose (Wilson et al, 2007).
e) STREPTOCOCCAL PHARYNGITIS, PENICILLIN-ALLERGIC: 25 to 50 mg/kg/day orally in 3 to 4 divided doses for 10 days. Maximum 2 g/day (Prod Info cephalexin oral capsules, 2010; Prod Info cephalexin oral suspension, 2010; Gerber et al, 2009; Disney et al, 1992).

Maximum Tolerated Exposure

1) 1 of 2 patients ingesting CEPHALEXIN experienced vomiting and a facial rash at less than 250 milligrams/kilogram.

a) Of 8 patients ingesting less than 250 milligrams/kilogram of CEFACLOR, none had symptoms.
b) However, the individual means, medians, and dose distributions for each of these agents were not available (Swanson-Biearman et al, 1988; Personal Communication, 1988).

2) CEPHALEXIN - Saker et al (1973) reported a patient with severe renal disease who developed a grand mal seizure after administration of CEPHALEXIN in a dose of 2 grams daily, which produced cephalexin serum levels of 120 micrograms/milliliter (Saker et al, 1973).
3) CEPHALEXIN/CASE REPORT (CHILD) - Crystalluria and hematuria were reported in a 3-year-old male who took 2500 mg (104 mg/kg) of cephalexin (Clark, 1992). The patient was encouraged to drink fluids for the next 24 hours and recovered without sequelae.

1) Murdoch et al (1964) reported two patients who developed hallucinations and nystagmus following a 100 milligram dose of cephaloridine intrathecally.

1) A 70-year-old woman with chronic renal failure developed non-convulsive status epilepticus after receiving 11 grams of ceftazidime in her peritoneal dialysis fluid over 2 days. She recovered with supportive care including hemodialysis(Vannaprasaht et al, 2006).

1) HUMAN: Seizures were described in 91-year-old man with impaired renal function following a 1 gram dose of MOXALACTAM. The moxalactam serum level 20 hours after the last dose was 85.9 milligrams/liter (Hoffman, 1986).
2) ANIMAL: Animals given 5.5 to 6 grams/kilogram of MOXALACTAM developed seizures and respiratory arrest (Harada et al, 1982).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CEFTAZIDIME

a) Jackson and Berkovic (1992) reported a patient who experienced seizures and hallucinations after administration of intravenous ceftazidime, 2 grams every 12 hours. One and two days later, the serum ceftazidime levels were 402 mcg/mL and 253 mcg/ml, respectively. The normal peak level is 55 mcg/mL (Jackson & Berkovic, 1992).

2) CEFEPIME

a) The cefepime level of a renal failure patient, who experienced disorientation and twitching four days after beginning therapy with 2 g/day of cefepime, was 716.32 mg/mL. The cefepime level, one day after performance of dialysis and treatment cessation of cefepime, was 96.89 mg/mL (Fishbain et al, 2000).
b) CASE REPORT: An adult patient with renal insufficiency was receiving cefepime, 6 grams/day, for 4 weeks when he began experiencing mental status changes and myoclonic jerks of his right arm. An EEG revealed status epilepticus. A serum cefepime concentration was 284 mg/L (normal therapeutic range 2.5 to 5.1 mg/L) and a cerebrospinal fluid (CSF) cefepime concentration was 18 mg/L. Following high-volume continuous veno-venous hemofiltration for 36 hours, the patient completely recovered with normalization of his serum cefepime concentration (3.2 mg/L) (Bresson et al, 2008).

Toxicity Information

7.7.1)

A) CEFACLOR -

1) LD50- (ORAL)MOUSE:

a) >20 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >20 g/kg (RTECS, 2000)

B) CEFADROXIL -

1) LD50- (ORAL)MOUSE:

a) >10 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

C) CEFIXIME -

1) LD50- (ORAL)MOUSE:

a) >10 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

D) CEFOTETAN -

1) LD50- (ORAL)MOUSE:

a) >10 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

E) CEFOXITIN -

1) LD50- (ORAL)MOUSE:

a) >10 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

F) CEFTAZIDIME -

1) LD50- (ORAL)MOUSE:

a) >20 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >20 g/kg (RTECS, 2000)

G) CEFTIBUTEN -

1) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

H) CEFUROXIME -

1) LD50- (ORAL)MOUSE:

a) >10 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

I) CEPHALEXIN -

1) LD50- (ORAL)MOUSE:

a) 1495 mg/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >20 g/kg (RTECS, 2000)

J) CEPHALOTHIN -
K) CEPHAPIRIN -

1) LD50- (ORAL)MOUSE:

a) 26088 mg/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) 16356 mg/kg (RTECS, 2000)

L) CEPHRADINE -

1) LD50- (ORAL)MOUSE:

a) 3549 mg/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >12 g/kg (RTECS, 2000)

M) FLOMOXEF -

1) LD50- (ORAL)MOUSE:

a) >15 g/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) >10 g/kg (RTECS, 2000)

Pharmacology Toxicology

Toxicologic Mechanism

1) Changes in renal histology and physiology, similar to those expected with renal ischemia, have been demonstrated in rats and rabbits following injection of some cephalosporins. Changes have included necrosis of the proximal tubular epithelium, inhibition of the respiration of mitochondria, increased membrane permeability of the mitochondria, and damage to intra- renal arterial walls (Kato et al, 1992) .
2) Biochemical changes in isolated preparations of rabbit proximal tubules included: cephaloridine-induced glutathione and ATP depletion, lipid peroxidation, and inhibition of tubule respiration. Tubular injury in this preparation occurred only in the absence of amino acids to support glutathione synthesis (Rush & Ponsler, 1991).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.5)

A) CEFTIOFUR SODIUM - Mahrt (1992) evaluated the safety of ceftiofur usage in horses. Fifty-two horses were dosed intramuscularly with either saline controls, or 2.2, 6.6, or 11 mg of aqueous ceftiofur sodium solution per kilogram body weight per day for 30 days. The recommended therapeutic dosage is 2.2 mg/kg/day.

1) Decreased feed consumption occurred in 13 of 19 horses given 6.6 mg/kg/day and in all horses given 11 mg/kg/day. All horses dosed with 11 mg/kg/day demonstrated elevated fibrinogen and aspartate transaminase levels and levels of circulating neutrophils. In addition, 4 of 6 horses showed a significant increase in creatine kinase levels. Diarrhea may also occur in horses given 10 to 25 times the therapeutic dose.
2) On necropsy, gross pathologic findings included muscle lesions at the site of injection in 15 of 28 female horses dosed with 2.2 mg/kg/day and 26 of 28 female horses dosed with 11 mg/kg/day 30 days prior to examination. Tissue examined at 30 days post-injection showed pallor due to fibrosis of muscle at injection sites. Lesions were more severe in horses dosed with more concentrated solutions.

11.1.13)

A) OTHER

1) Reports of hypersensitivity in animals to cephalosporins or other antibiotics are not common.

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian.
6) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
7) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) Discontinue administration of the cephalosporin.
b) OCULAR - Rinse eyes with copious amounts of tepid water for 15 minutes. If irritation, pain or photophobia persist, see your veterinarian.
c) INHALATION - Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed.

1) If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.

d) DERMAL - In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure. Clip hair as necessary to facilitate removal.
e) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

f) ACTIVATED CHARCOAL - Administer activated charcoal 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
g) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

11.2.5)

A) DOGS/CATS

1) MAINTAIN VITAL FUNCTIONS - as necessary.
2) ANAPHYLAXIS -

a) AIRWAY - Maintain a patent airway via endotracheal tube or tracheostomy.
b) EPINEPHRINE - For severe reactions.

1) DOGS - 0.5 to 1 milliliter of 1:10,000 (DILUTE) solution intravenously or subcutaneously.
2) CATS - 0.5 mL of 1:10,000 (DILUTE) solution intravenously or intramuscularly.
3) Be sure to dilute epinephrine from the bottle (1:1000) one part to 9 parts saline to obtain the correct concentration (1:10,000). If indicated, dose may be repeated in 20 minutes.

c) FLUID THERAPY - If necessary, begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour).

1) Monitor for urine production and pulmonary edema.

d) ANTIHISTAMINES/STEROIDS - Administer doxylamine succinate (1 to 2.2 milligrams/kilogram subcutaneously or intramuscularly every 8 to 12 hours), dexamethasone sodium phosphate (1 to 5 milligrams/kilogram intravenously every 12 to 24 hours), or prednisolone (1 to 5 milligrams/kilogram intravenously every 1 to 6 hours).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

1) If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.

Kinetics

11.5.1)

A) SPECIFIC TOXIN

1) FLOMOXEF SODIUM - Mochizuki et al (1993) dosed rabbits with 100 mg/kg flomoxef sodium intravenously. One hour later, serum concentration was 18.4 +/- 7.29 mcg/mL and aqueous humor concentration was 4.28 +/- 2.49 mcg/mL.

a) Peak flomoxef concentration in aqueous humor was 0.87 mcg/mL 3 hours post-injection, and declined until reaching undetectable levels 24 hours post-injection.

11.5.4)

A) SPECIFIC TOXIN

1) FLOMOXEF SODIUM - Intravitreal injection of 200 mcg flomoxef in rabbits demonstrated a half-life of 4.4 hours. Concentration remained high, 6.01 +/- 2.90 mcg/mL, after 24 hours. Flomoxef is probably eliminated via the retinal posterior route (Mochizuki et al, 1993).

References

General Bibliography

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CEPHALOSPORINS

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