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Pneumonia rocephin zithromax

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Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 gm dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 gm dose in healthy subjects are presented in Table 1.

Table 1 : Ceftriaxone Plasma Concentrations After Single Dose Administration

Dose/Route Average Plasma Concentrations (μg/mL)
0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 16 hr 24 hr
0.5 gm IV 0.5 gm IM 82 59 48 37 29 23 15 10 5
250 mg/mL 0.5 gm IM 22 33 38 35 30 26 16 ND 5
350 mg/mL 20 32 38 34 31 24 16 ND 5
1 gm IV 151 111 88 67 53 43 28 18 9
1 gm IM 40 68 76 68 56 44 29 ND ND
2 gm IV 257 192 154 117 89 74 46 31 15
IV doses were infused at a constant rate over 30 minutes.
ND = Not determined.

Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple IV or IM doses ranging from 0.5 to 2 gm at 12- to 24-hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values.

Ceftriaxone concentrations in urine are shown in Table 2.

Table 2 : Urinary Concentrations of Ceftriaxone After Single Dose Administration

Dose/Route Average Urinary Concentrations (μg/mL)
0-2 hr 2-4 hr 4-8 hr 8-12 hr 12-24 hr 24-48 hr
0.5 gm IV 526 366 142 87 70 15
0.5 gm IM 115 425 308 127 96 28
1 gm IV 995 855 293 147 132 32
1 gm IM 504 628 418 237 ND ND
2 gm IV 2692 1976 757 274 198 40
ND = Not determined.

Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 gm IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 μg/mL in the gallbladder bile, 788 μg/mL in the common duct bile, 898 μg/mL in the cystic duct bile, 78.2 μg/gm in the gallbladder wall and 62.1 μg/mL in the concurrent plasma.

Over a 0.15 to 3 gm dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of < 25 μg/mL to a value of 85% bound at 300 μg/mL. Ceftriaxone crosses the blood placenta barrier.

The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after a 50 mg/kg IV dose and after a 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Ceftriaxone penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV dose are also shown in Table 3.

Table 3 : Average Pharmacokinetic Parameters of Ceftriaxone in Pediatric Patients With Meningitis

  50 mg/kg IV 75 mg/kg IV
Maximum Plasma Concentrations (Mg/mL) 216 275
Elimination Half-life (hr) 4.6 4.3
Plasma Clearance (mL/hr/kg) 49 60
Volume of Distribution (mL/kg) 338 373
CSF Concentration - inflamed meninges (μg/mL) 5.6 6.4
  Range (μg/mL) 1.3-18.5 1.3-44
  Time after dose (hr) 3.7 (± 1.6) 3.3 (± 1.4)

Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone dosages up to 2 gm per day. Ceftriaxone was not removed to any significant extent from the plasma by hemodialysis; in six of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced.

Table 4 : Average Pharmacokinetic Parameters of Ceftriaxone in Humans

Subject Group Elimination Half-Life (hr) Plasma Clearance (L/hr) Volume of Distribution (L)
Healthy Subjects 5.8-8.7 0.58-1.45 5.8-13.5
Elderly Subjects (mean age, 70.5 yr) 8.9 0.83 10.7
Patients With Renal Impairment
  Hemodialysis Patients (0-5 mL/min) 14.7 0.65 13.7
  Severe (5-15 mL/min) 15.7 0.56 12.5
  Moderate (16-30 mL/min) 11.4 0.72 11.8
  Mild (31-60 mL/min) 12.4 0.70 13.3
Patients With Liver Disease 8.8 1.1 13.6
Creatinine clearance.

The elimination of ceftriaxone is not altered when Rocephin is co-administered with probenecid.

Pharmacokinetics in the Middle Ear Fluid

In one study, total ceftriaxone concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from 1 to 50 hours after a single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (± SD) ceftriaxone levels in the middle ear reached a peak of 35 (± 12) μg/mL at 24 hours, and remained at 19 (± 7) μg/mL at 48 hours. Based on middle ear fluid ceftriaxone concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, a half-life of 25 hours was calculated. Ceftriaxone is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown.

Interaction with Calcium

Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation.


Mechanism of Action

Ceftriaxone is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Mechanism of Resistance

Resistance to ceftriaxone is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Interaction with Other Antimicrobials

In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.

Ceftriaxone has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Gram-negative Bacteria

Acinetobacter calcoaceticus
Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Neisseria meningitidis

Proteus mirabilis

Proteus vulgaris

Pseudomonas aeruginosa

Serratia marcescens

Gram-positive bacteria

Staphylococcus aureus
Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci

Anaerobic bacteria

Bacteroides fragilis
Clostridium species

Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftriaxone. However, the efficacy of ceftriaxone in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-negative Bacteria

Citrobacter diversus
Citrobacter freundii

species (including Providencia rettgeri)
species (including Salmonella typhi)

Gram-positive Bacteria

Streptococcus agalactiae

Anaerobic Bacteria

Porphyromonas (Bacteroides) melaninogenicus
Prevotella (Bacteroides) bivius

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,3. The MIC values should be interpreted according to criteria provided in Table 5.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 30 mcg ceftriaxone to test the susceptibility of microorganisms to ceftriaxone. The disk diffusion interpretive criteria are provided in Table 5.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by a standardized agar test method3.4. The MIC values obtained should be interpreted according to the criteria provided in Table 5.

Table 5 : Susceptibility Test Interpretive Criteria for Ceftriaxone

Pathogen Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion Zone Diameters (mm)
(S) Susceptible (I) Intermediate (R) Resistant (S) Susceptible (I) Intermediate (R) Resistant
Enterobacteriaceaea ≤ 1 2 ≥ 4 ≥ 23 20-22 ≤ 19
Haemophilus influenzaeb,c ≤ 2 - - ≥ 26 - -
Neisseria gonorrhoeaea ≤ 0.25 - - ≥ 35 - -
Neisseria meningitidisc ≤ 0.12 - - ≥ 34 - -
Streptococcus pneumoniae d meningitis isolates ≤ 0.5 1 ≥ 2 - - -
Streptococcus pneumoniae d non-meningitis isolates ≤ 1 2 ≥ 4 - - -
Streptococcus species beta-hemolytic groupc ≤ 0.5 - - ≥ 24 - -
Viridans group streptococci ≤ 1 2 ≥ 4 ≥ 27 25-26 ≤ 24
Anaerobic bacteria (agar method) ≤ 1 2 ≥ 4 - - -
a Susceptibility interpretive criteria for Enterobacteriaceae are based on a dose of 1 gram IV q 24h. For isolates with intermediate susceptibility, use a dose of 2 grams IV q 24h in patients with normal renal function.
b For Haemophilus influenzae, susceptibility interpretive criteria are based on a dose of 2 grams IV every 24 hours in patients with normal renal function.
c The current absence of data on resistant isolates precludes defining any category other than 'Susceptible'. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.
d Disc diffusion interpretive criteria for ceftriaxone discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of > 20 mm are susceptible (MIC ≤ 0.06 mcg/mL) to penicillin and can be considered susceptible to ceftriaxone. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of ≤ 19 mm. The ceftriaxone MIC should be determined for those isolates with oxacillin zone diameters ≤ 19 mm.

Susceptibility of staphylococci to ceftriaxone may be deduced from testing only penicillin and either cefoxitin or oxacillin.

A report of Susceptible indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug d reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test1,2,3,4.

Standard ceftriaxone powder should provide the following range of MIC values noted in Table 6. For the diffusion technique using the 30 mcg disk, the criteria in Table 6 should be achieved.

Table 6 : Acceptable Quality Control Ranges for Ceftriaxone

QC Strain Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone diameters (mm)
Escherichia coli ATCC 25922 0.03 - 0.12 29 - 35
Staphylococcus aureus ATCC 25923 - 22 - 28
Staphylococcus aureus ATCC 29213 1 - 8 -
Haemophilus influenzae ATCC 49247 0.06 - 0.25 31 - 39
Neisseria gonorrhoeae ATCC 49226 0.004 - 0.015 39 - 51
Pseudomonas aeruginosa ATCC 27853 8-64 17-23
Streptococcus pneumoniae ATCC 49619 0.03 - 0.12 30 - 35
Bacteroides fragilis ATCC 25285 (agar method) 32 - 128 -
Bacteroides thetaiotaomicron ATCC 29741 (agar method) 64 - 256 -

Animal Pharmacology

Concretions consisting of the precipitated calcium salt of ceftriaxone have been found in the gallbladder bile of dogs and baboons treated with ceftriaxone.

These appeared as a gritty sediment in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon has been observed in baboons but only after a protracted dosing period (6 months) at higher dose levels (335 mg/kg/day or more). The likelihood of this occurrence in humans is considered to be low, since ceftriaxone has a greater plasma half-life in humans, the calcium salt of ceftriaxone is more soluble in human gallbladder bile and the calcium content of human gallbladder bile is relatively low.

Clinical Studies

Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media

In two adequate and well-controlled US clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below:

Table 7 : Clinical Efficacy in Pediatric Patients with Acute Bacterial Otitis Media

Clinical Efficacy in Evaluable Population
Study Day Ceftriaxone Single Dose Comparator -10 Days of Oral Therapy 95% Confidence Interval Statistical Outcome
Study 1 - US   amoxicillin/ clavulanate    
14 74% (220/296) 82% (247/302) (-14.4%, -0.5%) Ceftriaxone is lower than control at study day 14 and 28.
28 58% (167/288) 67% (200/297) (-17.5%, -1.2%)
Study 2 - US5   TMP-SMZ    
14 54% (113/210) 60% (124/206) (-16.4%, 3.6%) Ceftriaxone is equivalent to control at study day 14 and 28.
28 35% (73/206) 45% (93/205) (-19.9%, 0.0%)

An open-label bacteriologic study of ceftriaxone without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows:

Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen:

Table 8 : Bacteriologic Eradication Rates by Pathogen

Organism Study Day 13-15 Study Day 30+2
No. Analyzed No. Erad. (%) No. Analyzed No. Erad. (%)
Streptococcus pneumoniae 38 32 (84) 35 25 (71)
Haemophilus influenzae 33 28 (85) 31 22 (71)
Moraxella catarrhalis 15 12 (80) 15 9 (60)


1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eight Edition. CLSI document M11-A8, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012


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