Pharmacokinetic Prediction of Levofloxacin Accumulation in Tissue and Its Association to Tendinopathy


Objectives: We investigated pharmacokinetic tissue distributions of Levofloxacin to explain adverse tendon incidents. Methods: The pharmacokinetic profiles of single and multiple dosing of 500 mg Levofloxacin following oral and IV infusion administration were simulated. Monte Carlo simulation was used to simulate the drug concentration profiles in plasma and tissue after seven dosing regimens while varying the drug’s elimination and distribution rates to analyze the effects of changing those rates on Levofloxacin accumulation in tissue. Results: Simulated data following oral and IV administration reflect well the reported data (mean simulated plasma Cmax = 6.59 μg/mL and 5.19 μg/mL for IV and oral versus 6.4 μg/mL and 5.2 μg/mL for observed clinical IV and oral route, respectively). Simulations of seven repetitive doses are also in agreement with reported values. Low elimination rates affect the drug concentration in plasma and tissue significantly with the concentration in plasma rising to 35 μg/mL at day 7. Normal elimination rates together with escalation of distribution rates from plasma to tissue increase tissue concentration after 7 doses to 9.5 μg/mL, a value is more than twice that of normal. Conclusions: Simulation can be used to evaluate drug concentration in different tissues. The unexpectedly high concentrations in some cases may explain the reason for tendinopathy in clinical settings.

Share and Cite:

L. Pham, J. Christensen and R. Rodriguez-Proteau, "Pharmacokinetic Prediction of Levofloxacin Accumulation in Tissue and Its Association to Tendinopathy," Pharmacology & Pharmacy, Vol. 4 No. 1, 2013, pp. 121-131. doi: 10.4236/pp.2013.41018.

1. Introduction

Tendinitis and tendon rupture have emerged with the popular use ofLevofloxacin [1-5]. Tendinopathy accounted for 4.1% of the cases and the compound could cause Achilles tendon rupture in 1% of subjects, a rate higher than previously thought [6,7]. The risk factors of Fluoroquinolones-induced tendinopathy include older age, concomitant corticosteroid therapy and renal dysfunction. Caution has been raised when prescribing a combination therapy of steroids and Levofloxacin to patients, particularly to those with known risk factors [8].

It has been shown that Levofloxacin levels were achievable in all tissue samples after a single intravenous dose despite high variability in its pharmacokinetics (PK) [9]. In bone and cartilage, Levofloxacin penetrated well into cortical and spongiosa tissue of femoral head and distal femur, with mean penetration ratios between 0.34 and 1.51. The penetration of Levofloxacin into bone was rapid, taking approximately 2 hours to reach the maximum concentration. By 5 hours, apparent equilibrium of Levofloxacin concentrations occurred between the bone tissues and plasma [9]. The Levofloxacin concentration observed in plasma and in the interstitial space fluid (ISF) of lung tissue, and that of muscle and subcutaneous adipose tissue were significantly different after receiving a single intravenous dose of 500 mg producing a 2-fold and 1.5-fold higher AUC from 0 to infinity (AUC0-inf) for the ISF of muscle and adipose tissue as compared to lung, respectively. The difference in AUC0-inf was postulated to be by higher clearance of Levofloxacin from lung tissue as compared to muscle and adipose tissue [10]. No difference in peak concentration between fat, skeletal muscle and lung was documented. Time to reach Cmax (Tmax) values in adipose (60 min) and muscle tissue (80 min) were shorter than that in lung tissue (90 min) yielding a shorter elimination half-life of Levofloxacin in the lung compared to muscle and adipose tissue [10]. The possible reason is that the capillary blood flow is higher in lung and much lower in peripheral soft tissue and possibly substantial differences in redistribution processes from tissue to the blood [11]. These results are of importance and should be taken into account when evaluating the distribution and clearance of Levofloxacin in different tissues regarding the relationship of capillary blood flow to the tissue and the concentration seen in peripheral blood and/or distribution and toxicity of the drug to a specific tissue and organ. It indicates that the distribution and peak concentration of Levofloxacin can be obtained in various tissues regardless of some limitation in blood perfusion and differences in Tmax of the drug. In addition, stromatous tissue such as adipose tissue, articular capsule, trachea cartilage and tendon achieved similar concentrations of quinolones when subjected to a single dose of Fluoroquinolones intravenously in an experimental canine model albeit fat and the three latter kinds of tissues have significant discrepancy in structural constitution and distributive vasculatures [12]. Relatively, human Achilles tendon has little to no vasculature for itself [13] and is nurtured ultimately by permeation from the peripheral tissues suggesting that once a Fluoroquinolone has reached its peak concentration, it is likely to reside semi-permanently in tendon tissue and be harmful due to its prolonged residency. This may explain the higher prevalence of Achilles tendon incidents in diabetic and aged patients, who also suffer from a decreased circulatory network in Achilles tendon [13-17].

The accumulation of Levofloxacin/Fluoroquinolones in tendon may be the reason for tendon incidents, however there is no confirmed mechanism or relationship between plasma concentrations to tendonitis and Achilles tendon rupture or whether additional unknown reasons cause increased drug accumulation in tendon tissue leading to complications. Therefore, a simple process useful to determine drug distribution rate to tendon tissue and to predict the biological outcomes in order to provide early warning for Levofloxacin toxicity in daily practice is warranted. Monte Carlo simulation was used in this study to assess the usefulness of pharmacokinetic prediction in relation to Levofloxacin tissue accumulation and tendinopathy. The objective was to elucidate possible factors that will delineate the potential relationships between Levofloxacin accumulation in tendon tissue (such as Levofloxacin tissue concentration, and distribution processes) and tendinopathy incidents that will lead to further studies that will refine the understanding of the Mechanism that cause tendinopathy so that prevention of the events can be better predicted.

2. Methods

2.1. Pharmacokinetics of Levofloxacin

A two-compartment open model with first-order absorption and elimination process was used to describe Levo-

floxacin plasma concentration time profile. The model is described by the following system of ordinary differential equations. Equation 1:. Equation (2):. Equation (3):. With Xa, X1, X2 are the milligram amounts of drug in the gut, the central (plasma) and the peripheral compartments, respectively. Ka (hr−1) and K0 (mg/h) are the absorption rate constant and the intravenous (IV) infusion rate of Levofloxacin, respectively. Kel (h−1) is the elimination rate constant from the central compartment. K12, K21 are the between-compartment transfer rate constants (all in hr−1).

The other pharmacokinetic parameters are the volume of distribution (V). Equation (4):. Equation (5):. With C1, C2 are Levofloxacin concentration in μg/mL in the central compartment and the peripheral compartments, respectively. V1, V2 represent volume of distribution in the central and peripheral compartments in mL, respectively. F is the fraction of dose absorbed. In extravascular models, the fraction of dose absorbed cannot be estimated separately. Therefore, V1/F was estimated together in PK modeling. Dpo is the administered dose orally. Pharmacokinetic parameter values (Table 1), obtained from literature [18], were used in Monte Carlo simulation of drug concentration versus time profiles for Levofloxacin after single or multiple oral and IV infusion dosing administration.

2.2. Derivations of Drug Concentration in Plasma and Tissue Compartments after IV Infusion Single and Multiple Doses Using Laplace Transforms

Recall the ordinary differential Equations (2) and (3) above:

where: is the unit function

and T is the duration time of infusion.

Using the Laplace transform, we have the following

Table 1. Summary Levofloxacin pharmacokinetics used in Monte Carlo Simulation Derivations of drug concentration in plasma and tissue compartments after IV infusion single and multiple doses using Laplace transforms.

equation in the s domain:

where: are the initial conditions of.

At t = 0:

Linear equation and solution are as follows:


and α, β are defined by:

, then:



Now, by the inverse Laplace transform, we have the solution for in the time domain:




2.3. Derivations of Drug Concentration in Compartment after and Administration of IV Infusion Multiple Dose Using Laplace Transforms

For a simulation of a 7 days treatment duration and 1 dose was administered a day, was replaced by in the above differential equations (Equations (6) and (7)). And as a result, was replaced by

in its representation in the s domain. Therefore, we had a similar solution for as follows:

And, see Equations (8) and (9).

2.4. Data Analysis

Descriptive statistics of all levofloxacin PK parameters in healthy subjects and patients (mean, standard deviation, coefficient of variation) were obtained from literature. Pharmacokinetic simulation was then used to reveal the effect of input variables. A direct comparison of the experimental data (mean ± sd) obtained from simulation was involved. Comparison between the experimental and observed data from various studies reported in literature was conducted using a student t-test. Mean and standard deviations of PK parameters were determined to assess how well the model described the clinical data. The best PK model and log-normal distribution (mean and variance) of all the transfer rates were then used as input in the Monte Carlo simulation process to generate plasma and tissue concentrations.

2.5. Matlab/Simulink Monte Carlo Simulations

A 2-compartment open model without a lag time was used to generate each concentration-time profile, where drug distribution rates (K12, K21) or drug elimination rate (Kel) were random variables associated with their distribution information. Their distributions were considered lognormal distributions. The mean concentration-time profile was generated by using mean values of PK parameters.

2.6. Study the Effect of Elimination and Distribution Rate on Drug Level in Plasma and Tissue

Investigation of varying the effect of elimination and distribution rates was performed using various values of those parameters. Monte Carlo simulation of 5000 drug concentration profiles was performed by importing elimination/distribution rates randomly into pharmacokinetic model and according gain blocks as in Figure 1. Random values were chosen from their associated log-normal distributions (mean and standard deviation) of reference values.

2.7. Simulink for Single and Multiple Dose IV Infusion Administration

Random function (rand) was used to randomly select pharmacokinetic parameter values which were associated to their distribution. The bounds for each PK parameter were set in accordance with the pharmacokinetic parameter values obtained. Simulink (Matlab, Natick, Massachusetts, USA) was used to simulate signals and determine how these concentrations vary over time using a system of 2 differential equations to describe plasma concentrations in compartment 1 and tendon concentration were in compartment 2.

The block Plasma (X1) and Tissue(X2) were two integrators. They took the integration of the inputs dX1/dt, dX2/dt and returned the outputs X1 and X2. The block Pulse Generator 1 was to reset the integrator plasma compartment each 24 time steps (corresponding to 24 hours per day). The block Pulse Generator was to describe multiple doses: One dose oral or infusion calculated as amount over the time of infusion or duration of absorption (1 time step) dose per 24 hours (24 time steps). Other blocks including gain blocks (K12, K21, Kel, 1/V1, 1/V2) and sum blocks were to implement the left hand side of each of two differential equations. Concentration time profiles in two compartments were obtained in two scope blocks by running this simulation.

3. Results

3.1. Simulated Levofloxacin Concentration Time Profiles Following a 1 h-Infusion and Oral 500 mg Single Dose Administration

Plasma and well-perfused organs such as lung, skin, and



Figure 1. Simulink for intravenous infusion 1 hour q24 for 7 days.

spongiosa etc. were grouped in compartment 1. Tissues characterized by poor blood flow such as tendon tissue (including Achilles tendon) along with adipose and cartilage were grouped in compartment 2. Tendon was anticipated to have very low redistribution rate compared to other sites, and was grouped in compartment 2 where the distribution rate is comparable to those of cortical bone and adipose tissue [9,11,13].

Figure 2 shows that generated drug concentration time curves were approximately super-imposable in plasma and in tissue after oral administration and IV infusion. This is in agreement with clinical data when approximately 100% drug absorption occurs in the oral route. The drug peak concentration produced with IV infusion was higher than that of oral administration. This initial simulation of the average drug concentration ratio between plasma and tissue showed no obvious change with time 4 hr post dosing onward, and that equilibrium between plasma and tissue drug concentrations were actually achieved 4 hr after dosing and the tissue concentrations declined proportionally to the plasma concentrations.

In addition, simulated data also show that after a single dose, drug concentration values in tissue achieved at Cmax of 3.08 μg/mL and 3.28 μg/mL, and Tmax of 3.25 hrs and 3.11 hr, and AUC0-24 of 42.05 μg∙hr/mL and 42.91 μg∙hr/mL for 500 mg oral dose and IV infusion, respectively.

Figure 2. Simulated mean plasma and tissue levofloxacin concentration-time profiles following the oral and IV infusion administrations of a single 500 mg dose. Key […□]: drug concentrations in plasma; […+]: drug concentrations in tissue after a single intravenous infusion; [−∆]: drug concentrations in plasma, [−o]: drug concentrations in tissue after a single oral dosing.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Durey, et al., “Levofloxacin-Induced Achilles Tendinitis in a Young Adult in the Absence of Predisposing Conditions,” Yonsei Medical Journal, Vol. 51, No. 3, 2010, pp. 454-456. doi:10.3349/ymj.2010.51.3.454
[2] J. B. Kahn, “Latest Industry Information on the Safety Profile of Levofloxacin in the US,” Chemotherapy, Vol. 47, Suppl. 3, 2001, pp. 32-37. doi:10.1159/000057842
[3] A. S. Mathis, et al., “Levoflox-acin-Associated Achilles Tendon Rupture,” Annals of Pharmacotherapy, Vol. 37, No. 7-8, 2003, pp. 1014-1017. doi:10.1345/aph.1C505
[4] A. Melhus, et al., “Levoflox-acin-Associated Achilles Tendon Rupture and Tendinopathy,” Scandinavian Journal of Infectious Diseases, Vol. 35, No. 10, 2003, pp. 768-770. doi:10.1080/00365540310015863
[5] J. R. Lewis, J. G. Gums and D. L. Dickensheets, “Levoflox-acin-Induced Bilateral Achilles Tendonitis,” Annals of Pharmacotherapy, Vol. 33, No. 7-8, 1999, pp. 792-795. doi:10.1345/aph.18298
[6] F. Fleisch, K. Hartmann and M. Kuhn, “Fluoroquinolone-Induced Tendinopathy: Also Occurring with Levofloxacin,” Infection, Vol. 28, No. 4, 2000, pp. 256-257. doi:10.1007/s150100070050
[7] L. J. Haddow, et al., “Spontaneous Achilles Tendon Rupture in Patients Treated with Levofloxacin,” Journal of Antimicrobial Chemotherapy, Vol. 51, No. 3, 2003, pp. 747-748. doi:10.1093/jac/dkg081
[8] C. Parmar and K. P. Meda, “Achilles Tendon Rupture Associated with Combination Therapy of Levofloxacin and Steroid in Four Patients and a Review of the Literature,” Foot & Ankle International, Vol. 28, No. 12, 2007, pp. 1287-1289. doi:10.3113/FAI.2007.1287
[9] H. von Baum, et al., “Tissue and Serum Concentrations of Levofloxacin in Orthopaedic Patients,” International Journal of Antimicrobial Agents, Vol. 18, No. 4, 2001, pp. 335-340. doi:10.1016/S0924-8579(01)00423-X
[10] M. A. Zeitlinger, et al., “A Pilot Study Testing Whether Concentrations of Levof-loxacin in Interstitial Space Fluid of Soft Tissues May Serve as a Surrogate for Predicting Its Pharmacokinetics in Lung,” International Journal of Antimicrobial Agents, Vol. 29, No. 1, 2007, pp. 44-50. doi:10.1016/j.ijantimicag.2006.08.045
[11] K. De Angelis, et al., “Blood Flow Measurements in Rats Using Four Color Mi-crospheres during Blockade of Different Vasopressor Systems,” Brazilian Journal of Medical and Biological Research, Vol. 38, No. 1, 2005, pp. 119-125. doi:10.1590/S0100-879X2005000100018
[12] D. M. Boothe, et al., “Tissue Concentrations of Enrofloxacin and Ciprofloxacin in Anesthetized Dogs Following Single Intravenous Administration,” Veterinary Therapeutics, Vol. 2, No. 2, 2001, pp. 120-128.
[13] M. N. Doral, et al., “Functional Anatomy of the Achilles Tendon,” Knee Surgery, Sports Traumatology, Arthroscopy, Vol. 18, No. 5, 2010, pp. 638-643. doi:10.1007/s00167-010-1083-7
[14] J. M. Casparian, et al., “Quinolones and Tendon Ruptures,” Southern Medical Journal, Vol. 93, No. 5, 2000, pp. 488-491.
[15] M. M. Hall, J. T. Finnoff and J. Smith, “Musculoskeletal Complications of Fluoro-quinolones: Guidelines and Precautions for Usage in the Athletic Population,” PM & R, Vol. 3, No. 2, 2011, pp. 132-142. doi:10.1016/j.pmrj.2010.10.003
[16] Y. Kashida and M. Kato, “Characterization of Fluoroquinolone-Induced Achilles Tendon Toxicity in Rats: Comparison of Toxicities of 10 Fluoroquinolones and Effects of Anti-Inflammatory Compounds,” Antimi-crobial Agents and Chemotherapy, Vol. 41, No. 11, 1997, pp. 2389-2393.
[17] P. D. van der Linden, et al., “Increased Risk of Achilles Tendon Rupture with Quinolone Antibacterial Use, Especially in Elderly Patients Taking Oral Corticosteroids,” Archives of Internal Medicine, Vol. 163, No. 15, 2003, pp. 1801-1807. doi:10.1001/archinte.163.15.1801
[18] Levaquin NDA 020634 Approval Package Study #K09-077 and LOF-BIV-MULT-001, 2012.
[19] R. Bellmann, et al., “Tissue Pharma-cokinetics of Levofloxacin in Human Soft Tissue Infections,” British Journal of Clinical Pharmacology, Vol. 57, No. 5, 2004, pp. 563-568. doi:10.1111/j.1365-2125.2004.02059.x
[20] T. Rimmele, et al., “Diffusion of Levofloxacin into Bone and Synovial Tissues,” Journal of Antimicrobial Chemotherapy, Vol. 53, No. 3, 2004, pp. 533-535. doi:10.1093/jac/dkh110
[21] C. B. Landersdorfer, et al., “Penetration of Antibacterials Into Bone: Pharmacokinetic, Phar-macodynamic and Bioanalytical Considerations,” Clinical Pharmacokinetics, Vol. 48, No. 2, 2009, pp. 89-124. doi:10.2165/00003088-200948020-00002
[22] F. Pea, “Penetration of Antibacterials Into Bone: What Do We Really Need to Know for Optimal Prophylaxis and Treatment of Bone and Joint Infections?” Clinical Pharmacokinetics, Vol. 48, No. 2, 2009, pp. 125-127. doi:10.2165/00003088-200948020-00003
[23] S. C. Chien, et al., “Pharmacokinetic Profile of Levofloxacin Following Once-Daily 500-Milligram Oral or Intravenous Doses,” Anti-microbial Agents and Chemotherapy, Vol. 41, No. 10, 1997, pp. 2256-2260.
[24] J. E. Mazuski, et al., “The Surgical Infection Society Guidelines on Antimicrobial Therapy for Intra-Abdominal Infections: Evidence for the Recommendations,” Surgical Infections, Vol. 3, No. 3, 2002, pp. 175-233. doi:10.1089/109629602761624180
[25] New Drug Application 20-634, 2012.
[26] Levaquin NDA 020634 Label, 2012.
[27] F. Pouzaud, et al., “In Vitro Discrimination of Fluoroquinolones Toxicity on Tendon Cells: Involvement of Oxidative Stress,” Journal of Pharmacology and Experimental Therapeutics, Vol. 308, No. 1, 2004, pp. 94-402.
[28] K. Yabe, et al., “A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Oflox-acin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs,” Journal of Veterinary Medical Science, Vol. 63, No. 8, 2001, pp. 867-872. doi:10.1292/jvms.63.867
[29] A. Meissner, K. Borner and P. Koeppe, “Concentrations of Ofloxacin in Human Bone and in Cartilage,” Journal of Antimicrobial Chemotherapy, Vol. 26, Suppl. D, 1990, pp. 69-74.
[30] P. D. van der Linden, et al., “Tendon Disorders Attributed to Fluoroquinolones: A Study on 42 Spontaneous Reports in the Period 1988 to 1998,” Arthritis & Rheumatism, Vol. 45, No. 3, 2001, pp. 235-239. doi:10.1002/1529-0131(200106)45:3<235::AID-ART254>3.0.CO;2-7
[31] J. M. Michot, et al., “Influence of Efflux Transporters on the Accumulation and Efflux of Four Quinolones (Ciprofloxacin, Levofloxacin, Garenoxacin, and Moxifloxacin) in J774 Macrophages,” Antimicrobial Agents and Chemotherapy, Vol. 49, No. 6, 2005, pp. 2429-2437. doi:10.1128/AAC.49.6.2429-2437.2005
[32] J. T. Jagose, et al., “Achilles Tendon Rupture Due to Ciprofloxacin,” New Zealand Medical Journal, Vol. 109, No. 1035, 1996, pp. 471-472.
[33] Y. Khaliq and G. G. Zhanel, “Fluoroquino-lone-Associated Tendinopathy: A Critical Review of the Literature,” Clinical Infectious Diseases, Vol. 36, No. 11, 2003, pp. 1404-1410. doi:10.1086/375078
[34] M. H. Gotfried, L. H. Danziger and K. A. Rodvold, “Steady-State Plasma and Intra-pulmonary Concentrations of Levofloxacin and Ciprofloxacin in Healthy Adult Subjects,” Chest, Vol. 119, No. 4, 2001, pp. 1114-1122. doi:10.1378/chest.119.4.1114
[35] S. Swoboda, et al., “Tissue and Serum Concentrations of Levofloxacin 500 mg Administered Intravenously or Orally for Antibiotic Prophylaxis in Biliary Surgery,” Journal of Antimicrobial Chemotherapy, Vol. 51, No. 2, 2003, pp. 459-462. doi:10.1093/jac/dgk056
[36] A. Boeckh, et al., “Time Course of Enrofloxacin and Its Active Metabolite in Peripheral Leukocytes of Dogs,” Veterinary Therapeutics, Vol. 2, No. 4, 2001, pp. 334-344.
[37] M. B. Carlier, et al., “Cellular Uptake, Localization and Activity of Fluoroquinolones in Uninfected and Infected Macrophages,” Journal of Antimicrobial Chemotherapy, Vol. 26, Suppl. B, 1990, pp. 7-39.
[38] P. Schuler, et al., “Penetration of Sparfloxacin and Ciprofloxacin into Alveolar Macrophages, Epithelial Lining Fluid, and Polymorphonuclear Leucocytes,” European Respiratory Journal, Vol. 10, No. 5, 1997, pp. 1130-1136. doi:10.1183/09031936.97.10051130
[39] K. Taira, H. Koga and S. Kohno, “Accumulation of a Newly Developed Fluoro-quinolone, OPC-17116, by Human Polymorphonuclear Leuko-cytes,” Antimicrobial Agents and Chemotherapy, Vol. 37, No. 9, 1993, pp. 1877-1881. doi:10.1128/AAC.37.9.1877
[40] P. M. Tulkens, “Accumulation and Subcellular Distribution of Antibiotics in Macrophages in Relation to Activity against Intracellular Bacteria,” Ciprofloxacinn in Pulmonology, San Francisco, 1990.
[41] R. P. Smith, et al., “Levofloxacin Penetrates Human Monocytes and Enhances Intracellular Killing of Staphylococcus aureus and Pseudomonas aeruginosa,” Journal of Antimicrobial Chemotherapy, Vol. 45, No. 4, 2000, pp. 483-488. doi:10.1093/jac/45.4.483
[42] M. Egerbacher, B. Wolfesberger and C. Gabler, “In Vitro Evidence for Effects of Magnesium Supplementation on Quinolone-Treated Horse and Dog Chondrocytes,” Veterinary Pathology, Vol. 38, No. 2, 2001, pp. 143-148. doi:10.1354/vp.38-2-143
[43] D. Vazifeh, A. Bryskier and M. T. Labro, “Mechanism underlying levofloxacin Uptake By human polymorphonuclear neutrophils,” Antimicrobial Agents and Chemotherapy, Vol. 43, No. 2, 1999, pp. 246-252.
[44] M. Kato, et al., “Histological Examination on Achilles Tendon Lesions Induced by Quinolone Antibacterial Agents in Juvenile Rats,” Toxicologic Pathology, Vol. 23, No. 3, 1995, pp. 85-392. doi:10.1177/019262339502300315
[45] R. J. Williams III, et al., “The Effect of Ciprofloxacin on Tendon, Paratenon, and Capsular Fibroblast Metabolism,” American Journal of Sports Medicine, Vol. 28, No. 3, 2000, pp. 364-369.
[46] G. K. Kim, “The Risk of Fluoroquinolone-Induced Tendinopathy and Tendon Rupture: What Does the Clinician Need to Know?” Journal of Clinical and Aesthetic Dermatology, Vol. 3, No. 4, 2010, pp. 49-54.
[47] P. Szaro, et al., “Fascicles of the Adult Human Achilles Tendon—An Anatomical Study,” Annals of Anatomy, Vol. 191, No. 6, 2009, pp. 586-593. doi:10.1016/j.aanat.2009.07.006
[48] H. Vyas and G. Krish-naswamy, “Images in Clinical Medicine. Quinolone-Associated Rupture of the Achilles’ Tendon,” New England Journal of Medicine, Vol. 357, No. 20, 2007, p. 2067. doi:10.1056/NEJMicm061227
[49] T. Movin, et al., “Pathology of the Achilles Tendon in Association with Ciprofloxacin Treatment,” Foot & Ankle International, Vol. 18, No. 5, 1997, pp. 297-299.
[50] C. B. Landersdorfer, et al., “Penetration of Moxifloxacin into Bone Evaluated by Monte Carlo Simulation,” Antimicrobial Agents and Chemotherapy, Vol. 53, No. 5, 2009, pp. 2074-2081. doi:10.1128/AAC.01056-08

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.