Mechanism Of Action
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology].
Following 60-minute intravenous infusions of 200 mg and 400 mg CIPRO IV to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively (Table 9).
Table 9: Steady-state Ciprofloxacin Serum Concentrations (mcg/mL) After 60-minute INTRAVENOUS Infusions every 12 hours.
|Time after starting the infusion|
|Dose||30 minutes||1 hour||3 hour||6 hour||8 hour||12 hour|
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th intravenous dose on an every 12 hour 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 intravenous dose results in a C max similar to that observed with a 750-mg oral dose. An infusion of 200 mg CIPRO given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours (Table 10).
Table 10: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous Doses
|Parameters||500 mg||400 mg||750 mg||400 mg|
|every 12 hours Orally.||every 12 hours, intravenously||every 12 hours, orally||every 8 hours,|
| 1AUC 0-12h |
2AUC 24h = AUC 0-12h x 2
3AUC 24h = AUC 0-8h x 3
After intravenous administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected renault ci cipro 856 in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
After intravenous administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The metabolites have antimicrobial activity, but are less active than unchanged. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration 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 co-administered drug [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
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 intravenous dose, concentrations in the urine usually exceed 200 mcg/mL 0–2 hours after dosing and are generally greater than 15 mcg/mL 8–12 hours after dosing. Following a 400 mg intravenous dose, urine concentrations generally exceed 400 mcg/mL 0–2 hours after dosing and are usually greater than 30 mcg/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 ( < less than1%) is recovered from the bile as unchanged drug. Approximately 15% of an intravenous dose is recovered from the feces within 5 days after dosing.
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 (older than 65 years) as compared to young adults. Although the Cmax is increased 16% to40%, 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 Use In Specific Populations]
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations, DOSAGE AND ADMINISTRATION].
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been fully studied.
Following a single oral dose of 10 mg/kg CIPRO suspension to 16 children ranging in age from 4 months to 7 years, the mean C max was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2 mcghr/mL (range: 5.8 mcghr/mL to 14.9 mcghr/mL). There was no apparent age-dependence, and no notable increase in C max or AUC upon multiple dosing (10 mg/kg three times a day). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean C max was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The AUC values were 17.4 mcghr/mL (range: 11.8 mcghr/mL to 32.0 mcghr/mL) and 16.5 mcghr/mL (range: 11 mcghr/mL to 23.8 mcghr/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 hours–5 hours, and the bioavailability of the oral suspension is approximately 60%.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C max 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500 mg twice a day for 3 days). Concomitant administration of tizanidine and CIPRO IV is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see CONTRAINDICATIONS].
In a study conducted in 12 patients with Parkinson's disease who were administered 6 mg ropinirole once daily with 500 mg CIPRO twice-daily, the mean C max and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see WARNINGS AND PRECAUTIONS].
Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO IV are advised.
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to healthy subjects, the mean C max and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in the exposure of sildenafil upon co-administration of CIPRO IV.
In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean C max of duloxetine.
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily resulted in an increase of lidocaine C max and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with CIPRO IV and an increase in adverse reactions related to lidocaine may occur upon concomitant administration.
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of Resistance
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. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, cipro or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6.
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE].
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin ( ≤ 1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
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.
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 test method (broth and/or agar).5,6,7 The MIC values should be interpreted according to criteria provided in Table 10.
Quantitative methods that require measurement of zone diameters can 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.6,7,8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 11.
Table 11: Susceptibility Test Interpretive Criteria for Ciprofloxacin
|Bacteria||MIC||(mcg/mL)||Zone Diameter (mm)|
|Enterobacteriaceae||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Enterococcus faecalis||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Staphylococcus aureus||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Staphylococcus epidermidis||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Staphylococcus saprophyticus||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Pseudomonas aeruginosa||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Haemophilus influenzae1||≤ 1||-||-||≥ 21||-||-|
|Haemophilus parainfluenzae1||≤ 1||-||-||≥ 21||-||-|
|Streptococcus pneumoniae||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Streptococcus pyogenes||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Bacillus anthracis1||≤ 0.25||-||-||-||-||-|
|Yersinia pestis1||≤ 0.25||-||-||-||-||-|
| S=Susceptible, I=Intermediate, and R=Resistant. |
1The current absence of data on resistant isolates precludes defining any results other than “Susceptible”. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.5,6,7,8 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 12. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 12 should be achieved.
Table 12: Acceptable Quality Control Ranges for Ciprofloxacin
|Bacteria||MIC range (mcg/mL)||Zone Diameter (mm)|
|Enterococcus faecalis ATCC 29212||0.25-2||-|
|Escherichia coli ATCC 25922||0.004-0.015||30-40|
|Haemophilus influenzae ATCC 49247||0.004-0.03||34-42|
|Pseudomonas aeruginosa ATCC 27853||0.25-1||25-33|
|Staphylococcus aureus ATCC 29213||0.12-0.5||-|
|Staphylococcus aureus ATCC 25923||-||22-30|
Animal Toxicology And/Or Pharmacology
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see WARNINGS AND PRECAUTIONS].
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-times 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 body surface area). 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 body surface area).
In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since 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
Empirical Therapy In Adult Febrile Neutropenic Patients
The safety and efficacy of CIPRO IV, 400 mg intravenously every 8 hours, in combination with piperacillin sodium, 50 mg/kg intravenously every 4 hours, 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 intravenously every 8 hours, in combination with piperacillin sodium, 50 mg/kg intravenously every 4 hours.
Clinical response rates observed in this study were as follows:
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown in Table 13.
Table 13: Clinical Response Rates
|Outcomes|| CIPRO IV/Piperacillin |
N = 233 Success (%)
| Tobramycin/ Piperacillin |
N = 237 Success (%)
|Clinical Resolution of Initial Febrile Episode with No||63 (27%)||52 (21.9%)|
|Modifications of Empirical Regimen1|
|Clinical Resolution of Initial Febrile Episode Including Patients with Modifications of Empirical Regimen||187 (80.3%)||185 (78.1%)|
|Overall Survival||224 (96.1%)||185 (78.1%)|
|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
Ciprofloxacin, administered IV 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 in Table 14.
Table 14: Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
|Per Protocol Patients||211||231|
|Clinical Response at 5 to 9 Days PostTreatment||95.7% (202/211)||92.6% (214/231)|
95% CI [-1.3%, 7.3%]
|Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment1||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 PostTreatment|
|Escherichia coli||156/178 (88%)||161/179 (90%)|
|1 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.|
Inhalational Anthrax In Adults And Pediatrics
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. 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 mcg/mL, and 4.56 mcg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 mcg/mL to 0.26 mcg/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 mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.11
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 LD 50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected T max (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 mcg/mL to 0.19 mcg/mL.10 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.11
More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial 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 antibacterial drugs. 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.
A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110 LD50 (range 92 to 127 LD50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL. Mean peak serum concentrations of ciprofloxacin achieved at the end of a single 60 minute infusion were 3.49 mcg/mL ± 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day 6 and Day 10 of treatment in African green monkeys, respectively All trough concentrations (Day 2, Day 6 and Day 10) were < 0.5 mcg/mL. Animals were randomized to receive either a 10-day regimen of intravenous ciprofloxacin 15 mg/kg, or placebo beginning when animals were found to be febrile (a body temperature greater than 1.5oC over baseline for two hours), or at 76 hours post-challenge, whichever occurred sooner. Mortality in the ciprofloxacin group was significantly lower (1/10) compared to the placebo group (2/2) [difference: -90.0%, 95% exact confidence interval: -99.8% to -5.8%]. The one ciprofloxacin-treated animal that died did not receive the proposed dose of ciprofloxacin due to a failure of the administration catheter. Circulating ciprofloxacin concentration was below 0.5 mcg/mL at all timepoints tested in this animal. It became culture negative on Day 2 of treatment, but had a resurgence of low grade bacteremia on Day 6 after treatment initiation. Terminal blood culture in this animal was negative.12
5. Clinical and Laboratory Standards Institute (CLSI), Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–9th Edition. CLSI Document M7-A9 . Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087-1898.
6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; 24th Informational Supplement. CLSI Document M100 S24 . Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
7. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–2nd Edition. CLSI Document M45-A2 . Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
8. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard–11th Edition. CLSI Document M2-A11. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
9. CReport presented at the FDA's Anti-Infective Drug and Dermatological Drug Product's Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
10. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
11. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167:1239-42.
12. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 -The efficacy of Ciprofloxacin for treatment of Pneumonic Plague.
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