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Cipro IV

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Cipro I.V.

CLINICAL PHARMACOLOGY

Absorption

Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 g/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2 g/mL, respectively.

Steady-state Ciprofloxacin Serum Concentrations (g/mL) After 60-minute I.V. Infusions q 12 h.

  Time after starting the infusion
Dose 30 min. 1 hr 3 hr 6 hr 8 hr 12 hr
200 mg 1.7 2.1 0.6 0.3 0.2 0.1
400 mg 3.7 4.6 1.3 0.7 0.5 0.2

The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation.

The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.

Steady-state Pharmacokinetic Parameter Following Multiple Oral and I.V. Doses

Parameters 500 mg
q12h, P.O
400 mg
q12h, I.V.
750 mg
q12h, P.O.
400 mg
q8h, I.V.
AUC (g•hr/mL) 13.7a 12.7a 31.6b 32.9c
Cmax (g/mL) 2.97 4.56 3.59 4.07
a AUC0-12h
b AUC 24h=AUC0-12h x 2
c AUC 24h=AUC0-8h x 3

Distribution

After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in serum.

Metabolism

After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: DRUG INTERACTIONS).

Excretion

The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 g/mL 0–2 hours after dosing and are generally greater than 15 g/mL 8–12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 g/mL 0–2 hours after dosing and are usually greater than 30 g/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.

Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after intravenous dosing, only a small amount of the administered dose ( < 1%) is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after dosing.

Special Populations

Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects ( > 65 years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.)

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been fully elucidated.

Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean Cmax was 2.4 g/mL (range: 1.5 – 3.4 g/mL) and the mean AUC was 9.2 g*h/mL (range: 5.8 – 14.9 g*h/mL). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 g/mL (range: 4.6 – 8.3 g/mL) in 10 children less than 1 year of age; and 7.2 g/mL (range: 4.7 – 11.8 g/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 g*h/mL (range: 11.8 – 32.0 g*h/mL) and 16.5 g*h/mL (range: 11.0 – 23.8 g*h/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.

Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS: PRECAUTIONS: DRUG INTERACTIONS.)

Microbiology

Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations.

Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.

Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS section of the package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).

Aerobic gram-positive microorganisms

Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus
(methicillin-susceptible strains only)
Staphylococcus epidermidis
(methicillin-susceptible strains only)
Staphylococcus saprophyticus

Streptococcus pneumoniae
(penicillin-susceptible strains)
Streptococcus pyogenes

Aerobic gram-negative microorganisms

Citrobacter diversus Morganella morganii
Citrobacter freundii Proteus mirabilis
Enterobacter cloacae Proteus vulgaris
Escherichia coli Providencia rettgeri
Haemophilus influenzae Providencia stuartii
Haemophilus parainfluenzae Pseudomonas aeruginosa
Klebsiella pneumoniae Serratia marcescens
Moraxella catarrhalis  

Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker (see INDICATIONS and INHALATIONAL ANTHRAX ADDITIONAL INFORMATION).

The following in vitro data are available, but their clinical significance is unknown.

Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 g/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Staphylococcus haemolyticus
Staphylococcus hominis

Streptococcus pneumoniae
(penicillin-resistant strains)

Aerobic gram-negative microorganisms

Acinetobacter Iwoffi Salmonella typhi
Aeromonas hydrophila Shigella boydii
Campylobacter jejuni Shigella dysenteriae
Edwardsiella tarda Shigella flexneri
Enterobacter aerogenes Shigella sonnei
Klebsiella oxytoca Vibrio cholerae
Legionella pneumophila Vibrio parahaemolyticus
Neisseria gonorrhoeae Vibrio vulnificus
Pasteurella multocida Yersinia enterocolitica
Salmonella enteritidis  

Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosaa:

MIC (g/mL) Interpretation
≤ 1 Susceptible(S)
2 Intermediate(I)
≥ 4 Resistant(R)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood. For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (g/mL) Interpretation
≤ 1 Susceptible (S)
b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.

The current absence of data on resistant strains precludes defining any results other than "Susceptible". Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC values:

Organism   MIC (g/mL)
E. faecalis ATCC 29212 0.25 – 2.0
E. coli ATCC 25922 0.004 – 0.015
H. influenzaea ATCC 49247 0.004 – 0.03
P. aeruginosa ATCC 27853 0.25 – 1.0
S. aureus ATCC 29213 0.12 – 0.5
a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-g ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-g ciprofloxacin disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosaa:

Zone Diameter (mm) Interpretation
≥ 21 Susceptible (S)
16 - 20 Intermediate (I)
≤ 15 Resistant (R)
a These zone diameter standards are applicable only to tests performed for streptococci using Mueller- Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

For testing Haemophilus influenzae and Haemophilus parainfluenzae b:

Zone Diameter (mm) Interpretation
≥ 21 Susceptible (S)
b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.

The current absence of data on resistant strains precludes defining any results other than "Susceptible". Strains yielding zone diameter results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-g ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

Organism   Zone Diameter (mm)
E. coli ATCC 25922 30-40
H. influenzaea ATCC 49247 34-42
P. aeruginosa ATCC 27853 25-33
S. aureus ATCC 25923 22-30
a These quality control limits are applicableto only H. influenzae ATCC 49247 testing using Haemophilus Test Medium (HTM)2.

Animal Pharmacology

Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent them. Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).

In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release because they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension, but the effect in this species is inconsistent and less pronounced. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.

Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.

Inhalational Anthrax - Additional Information

The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 g/mL, and 4.56 g/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 g/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 g/mL and trough concentrations range from 0.09 to 0.26 g/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 g/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 g/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 g/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 g/mL5. Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.6

More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were also given anthrax vaccine or were switched to alternative antibiotics. No one who received ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax. The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis regimen is unknown.

Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more frequent than had been previously reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of these factors and limitations in the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.

Clinical Studies

Empircal Therapy In Adult Febrile Neutropenic Patients

The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.

Clinical response rates observed in this study were as follows:

Outcomes Ciprofloxacin / Piperacillin
N= 233
Success (%)
Tobramycin / Piperacillin
N= 237
Success (%)
Clinical Resolution of Initial Febrile Episode with No Modifications of Empirical Regimen* 63 (27.0%) 52 (21.9%)
Clinical Resolution of Initial Febrile Episode Including Patients with Modifications of Empirical Regimen 187 (80.3%) 185 (78.1%)
Overall Survival 224 (96.1%) 223 (94.1%)
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological eradication of infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.

Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients

NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.

Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.

Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).

The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below.

Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)

  CIPRO Comparator
Randomized Patients 337 352
Per Protocol Patients 211 231
Clinical Response at 5 to 9 Days Post-Treatment 95.7% (202/211) 92.6% (214/231)
  95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment* 84.4% (178/211) 78.3% (181/231)
  95% CI [-1.3%, 13.1%]
Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment  
Escherichia coli 156/178 (88%) 161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.

REFERENCES

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.

2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests- Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.

4. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).

5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.

6. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42.

Last reviewed on RxList: 12/30/2008
This monograph has been modified to include the generic and brand name in many instances.

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