AU2015364677A1

AU2015364677A1 - Triphasic dosing regimens for the administration of time-dependent antibiotics and devices for the same

Info

Publication number: AU2015364677A1
Application number: AU2015364677A
Authority: AU
Inventors: Pieter Muntendam
Original assignee: ScPharmaceuticals Inc
Current assignee: ScPharmaceuticals Inc
Priority date: 2014-12-18
Filing date: 2015-12-16
Publication date: 2017-07-27
Also published as: WO2016100523A3; EP3233063A4; EP3233063A2; WO2016100523A2

Abstract

Methods for the treatment of infections and other diseases or conditions with a biphasic or triphasic dosing regimen of a time-dependent antibiotic are provided, where the total time of administration can occur over a period of less than 24 hours. The present teachings also provide a micropump or patch pump device which permits controlled, subcutaneous infusion of a time-dependent antibiotic according to the dosing regimens of the present teachings.

Description

PCT/US2015/066112 WO 2016/100523 TRIPHASIC DOSING REGIMENS FOR THE ADMINISTRATION OF TIME-DEPENDENT ANTIBIOTICS AND DEVICES FOR THE SAME-

FIELD

The present teachings reiate to the administration of antibiotics. More 5 specifically, the present teachings relate to biphasic and triphasic dosing regimens for administration of time-dependent antibiotics and devices for administering the same.

BACKGROUND

Unlike antibiotics whose biological action (e.g., bactericidal activity) is 10 concentration dependent, for many antibiotics whose biological action is time dependent, in particular beta-lactam antibiotics, the fraction or amount of time above the minimum inhibitory concentration (“MIC”) for an organism is an important indicator of the likelihood of successful treatment. It has been suggested that a time above MIC of 70% or greater results in maximum bactericidal effect. See Craig, 15 “interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad spectrum cephalosporins,” Diagn. Microbiol, Infect. Dis. 22(1-2):89-96 (1995).

While it can be relatively easy to achieve peak plasma concentrations of an antibiotic above the MIC of an organism with a traditional rapid intravenous or 20 intramuscular administration, maintaining a concentration above the MIC for moderately to highly resistant organisms for an extended time typically requires multiple infusions or administrations per day, or inpatient treatment to enable for continuous intravenous infusion. These factors can add cost to the treatment and/or pose challenges for patient compliance, 25 Therefore, there is a need to improve the amount of time in a patient a time-dependent antibiotic is above the MIC of an organism to be treated without requiring inpatient treatment and/or multiple infusions or administrations per day. Such a therapy has the potential benefits of maximizing the effectiveness of the antibiotic treatment, reducing the cost of drug administration, and increasing the 30 likelihood of patient compliance. PCT/U S2015/066112 WO 2016/100523

SUMMARY in light of the foregoing, the present teachings provide methods for the treatment of infections and other diseases or conditions with dosing regimens of a time-dependent antibiotic that can address various deficiencies and short comings of 5 the state-of-the-art including those mentioned above. The dosing regimens can be biphasic or triphasic in administration of the time-dependent antibiotic, The dosing regimens can occur over about 6 to about 12 hours and can be administered by a mieropump or a patch pump device, which can permit controlled subcutaneous infusion of the time-dependent antibiotic with ambulatory or at-home treatment. 10 More specifically, the triphasic dosing regimens of the present teachings generally include a loading phase (a first dosing period), a maintenance or continuous phase (a second dosing period), and a pre-removal or end bolus phase (a third dosing period). The triphasic dosing regimen can be administered over about 6 hours to about 16 hours. The loading phase can deliver a sufficient dose of the time-15 dependent antibiotic over about 15 minutes to about an hour, to achieve a plasma serum level of the time-dependent antibiotic above a minimum inhibitory concentration (“MIC”) for an organism to be treated. The maintenance or continuous phase typically is the longest in time and can deliver a steady or continuous amount of the time-dependent antibiotic to maintain a plasma serum 20 level of the time-dependent antibiotic above the MIC, for example, for at least a majority of this time period, The maintenance or continuous phase can be from about 5 hours to about 14 hours. Finally, the pre-removal or end bolus phase can deliver at least about 25% and up to about 70% of the daily dose of the time-dependent antibiotic over about 15 minutes to about an hour. 25 The triphasic dosing regimen can improve and/or maximize the time a patient's plasma concentration or level of the time-dependent antibiotic is above the MIC, In various applications, the triphasic dosing regimen of the present teachings can be administered subcutaneously, for example, using a micropump device or a pump patch device, in such cases, a patient can wear the device for about 6 hours to 30 receive ait effective daily dose of the time-dependent antibiotic and have 18 hours device-free without being attached to a constant intravenous (“IV”) drip or receiving -2- PCT/U S2015/066112 WO 2016/100523 IV infusions every 6 to 8 hours. Being device-free also reduces interference with a patient’s daily activities such as bathing and sleeping. Consequently, for at least these reasons, patient compliance should certainly improve with such a treatment regimen, 5 Accordingly, in one aspect, the present teachings provide methods of administering a time-dependent antibiotic to a patient. In various embodiments, the methods generally include the steps of: (a) administering to a patient between about 15% to about 35% of a daily dose of a time-dependent during a first dosing period, w'here the first dosing period is between about 3% to about 17% of a total time of 10 administration; (b) administering to the patient between about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is between about 66% to about 94% of the total time of administration; and (c) administering to the patient between about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, 15 where the third dosing period is between about 3% to about 17% of the total time of administration. 30

In some embodiments, the methods generally include (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, where 20 administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; (b) administering to the patient a second dose of the antibiotic sufficien t to maintain the plasma concentration of the time-dependent antibiotic above the minimum Inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), where administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration. The sum of the first, second, and third doses can equal a daily dose of the time-dependent antibiotic. PCT/US2015/066112 WO 2016/100523

In certain embodiments, the methods generally include the steps of: (a) administering to a patient between about 15% to about 35% of a daily dose of a time-dependent antibiotic for a first dosing period, where the first dosing period is between about 15 minutes to about 60 minutes; (b) administering to the patient 5 between about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is between about 4 hours to about 15.5 hours; and (c) administering to the patient between about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, where the third dosing period is between about 15 minutes to about 60 minutes. 10 In particular embodiments, the methods generally include the steps of: (a) administering to a patient a first dose of time-dependent antibiotic sufficient to provide a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; (b) administering to the 15 patient a second dose of the time-dependent antibiotic sufficient to maintain a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 4 hours to about 15.5 hours; and (¢) administering to the patient a third dose of the time-dependent 20 antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), where administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes. The sum of the first, second and third doses can equal a daiiv dose of the time-dependent antibiotic. 25 in various embodiments, the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient about 15% to about 35% of a daily dose of a time-30 dependent, antibiotic during a first dosing period, wherein the first dosing period is about 3% to about 17% of a total time of administration; (b) administering to the patient about ! 5% to about 40% of the daily dose of the time-dependent antibiotic , 4 . PCT/U S2015/066112 WO 2016/100523 for a second dosing period, wherein the second dosing period is about 66% to about 94% of the total time of administration; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 3% to about 17% of the total 5 time of administration.

In some embodiments, the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) 10 administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the 15 plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-20 dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), wherein administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration; wherein the sum of the first, second and third doses equals a daily dose of the time-dependent antibiotic. 25 in certain embodiments, the methods generally include a time-dependent antibiotic for use in a method for the treatment of an Infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient about 15% to about 35% of a daily dose of a time-30 dependent antibiotic for a first dosing period, wherein the first dosing period is about 15 minutes to about 60 minutes; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, PCT/US2015/066112 WO 2016/100523 wherein the second dosing period is about 4 hours to about IS.5 hours; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 15 minutes to about 60 minutes. 5 in some embodiments, the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to 10 provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at i 5 least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 4 hours to about 15.5 hours; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), 20 wherein administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes; wherein the sum of the first, second and third doses equals a daily dose of the time-dependent antibiotic.

In various embodiments, the methods can include a two phase or biphasic dosing regimen. Such methods generally can include the steps of: (a) administering 25 to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic during a first dosing period, where the first dosing period is about 83% to about 96% of a total time of administration; and (b) administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 4% to about 17% of the total time of 30 administration. - 6 PCT/US2015/066112 WO 2016/100523

The preseni teachings also include a rnicropump device or a patch pump device for practicing the methods of the present teachings. The micropump or patch pump device can include a reservoir containing an antibiotic composition, where the antibiotic composition includes at least one time-dependent antibiotic and a 5 pharmaceuticaliy acceptable carrier. The micropump or patch pump device can include a subcutaneous injection needle configured for removable insertion into the skin of a patient; and a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the subcutaneous injection needle. The micropump or patch pump device can include a control system 10 configured to control the rnicropump to deliver the antibiotic composition from the reservoir through the subcutaneous injection needle to a patient. The rnicropump or patch pump can include a housing for supporting the reservoir, the subcutaneous injection needle, the rnicropump, and the control system. The control system can be configured to deliver the antibiotic composition in accordance with the methods 15 (dosing regimens) of the preseni teachings.

The foregoing as well as other features and advantages of the present teachings will be more fully understood from the following figures, description, tables, and claims,

BRIEF DESCRIPTION OF THE DRAWINGS 20 It should be understood that the drawings described below are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings in any way. FIGS, 1A-1C are histograms of MIC values for three test organisms: S. aureaus, P. aeruginosa and B. fragilis, respectively, 25 FIG. 2 is a schematic of the ceftriaxone pharmacokinetic model. FIGS, 3-12 are the results of the pharmacokinetic simulations for each of the 10 dosing regimens analyzed including embodiments of diphasic and triphasic dosing regimens of the preseni teachings. FIG. 13 is a graph depicting the results in Table 4 for 5. aureaus for each of 30 the 10 dosing regimens (x-axis), where the y-axis represents the median time in .7. PCT/US2015/066112 WO 2016/100523 hours that simulated patients have a plasma concentration of ceftriaxone above the MIC for S. aureaus during the 72 hour treatment period, FIG. 14 is a graph depicting the results in Table 4 for P. aeruginosa for each of the 10 dosing regimens (x-axis), where the y-axis represents the median time in 5 hours that simulated patients have a plasma concentration of ceftriaxone above the MIC for P. aeruginosa during the 72 hour treatment period. FIG. 15 is a graph depicting the results in Table 4 for B.fragiiis for each of the 10 dosing regimens (x-axis), where the y-axis represents the median time in hours that simulated patients have a plasma concentration of ceftriaxone above the 10 MIC tor B. fragilis during the 72 hour treatment period. FIG. 16 is a graph depicting the results in Table 5 for S, aureaus for each of the 10 dosing regimens (x-axis), where the y-axis represents the fraction of simulated patients having a plasma concentration of ceftriaxone above the MIC for S, aureaus for greater than 70% of the 72 hour treatment period. 15 FIG. 17 is a graph depicting the results in Table 5 for P. aeruginosa for each of the 10 dosing regimens (x-axis), where the y-axis represents the fraction of simulated patients having a plasma concentration of ceftriaxone above the MIC for P, aeruginosa for greater than 70% of the 72 hour treatment period. FIG. IB is a graph depicting the results in Table 5 tor B. fragiiis for each of 20 the 10 dosing regimens (x-axis), where the y-axis represents the fraction of simulated patients having a plasma concentration of ceftriaxone above the MIC for B.fragiiis for greater than 70% of the 72 hour treatment period.

DETAILED DESCRIPTION it has now been discovered that a triphasic dosing regimen of a time-25 dependent antibiotic, for example, a beta-Jaetam such as ceftriaxone, can improve the time above the MIC of an organism without requiring multiple daily infusions and/or inpatient treatment. A daily triphasic dosing regimen can achieve a prolonged plasma concentration of the time-dependent antibiotic above the MIC in a patient. Unlike known and conventional dosing regimens, the total time of 30 administration can occur over about 6 hours to about 12 hours. Consequently, the -8- PCT/US2015/066112 WO 2016/100523 triphasic dosing regimen can he subcutaneously administered conveniently via a micropurnp or patch pump device, which can be worn during administration and then removed for dally device-free time for the patient.

Although the description herein is focused on subcutaneously administration 5 or delivery of a time-dependent antibiotic, the triphasic (and biphasic) dosing regimen concept can apply equally to administering intravenously a time-dependent antibiotic, although the need to be connected to a source of IV fluid containing the time-dependent antibiotic would be a limitation not present when a wearable micropurnp or patch pump device is used. Nevertheless, the use of the triphasic 10 dosing regimen administered via an IV can afford a patient about 8 to about 18 hours of needle-free time for attending to daily activities.

In addition, although the triphasic dosing regimens tend to be superior to the biphasic or two phase dosing regimens described herein, the biphasic dosing regimens can be considered distinct from the triphasic dosing regimens and can be 15 used effectively in the appropriate circumstances depending on the time-dependent antibiotic, organism to be treated, patient characteristics, and other factors. For example, a biphasic dosing regimen of the present teachings can include administering to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic tor a first dosing period, where the first dosing period is 20 about 5 hours to about 12 hours; and administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 15 minutes to about one hour, That is, a biphasic closing regimen typically includes a maintenance or continuous phase, and a pre-removal or end bolus phase, 25 Throughout the application, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that, the processes of the present teachings also consist 30 essentially of, or consist of, the recited process steps. -9- PCT/U S2015/066112 WO 2016/100523

In the application, where an element or component is said to be included in and/or selected from a list of recited dements or components, it should be understood that the dement or component can be any one of the recited dements or components, or the element or component can be selected from a group consisting of 5 two or more of the recited elements or components.

Further, it should be understood that elements and/or features of a composition, an apparatus, or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present teachings, whether explicit or implicit herein. For example, where reference is made to a 10 particular structure, that structure can be used in various embodiments of apparatus of the present teachings and/or in methods of the present teachings, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that 15 embodiments may be variously combined or separated without parting from the present teachings and irwention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

It should be understood that the expression “at least one of includes 20 individually each of the recited objects aider the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context. as 30

The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

The use of the singular herein, for example, “a,” “an,” or “the,” includes the plural (and vice versa) unless specifically stated otherwise. - 10- PCT/U S2015/066112 WO 2016/100523

Where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. 5 Where a percentage is provided with respect to an amount of a component or material in a structure or a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context.

Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an 10 average molecule weight, unless otherwise stated or understood from the context.

At various places in the present specification, values are disclosed in groups or in ranges. It is specifically intended that the description include each and every Individual subcombination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges. For example, an

Integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, 20 The use of any and all examples, or exemplary language herein, for example, “such as,” “Including,” or “for example,” is intended merely to illustrate better the present teachings and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present teachings. 25 As used herein, “patient” refers to a mammal, such as a human.

As used herein, a “compound” refers to the compound itself and its pharmaceutically acceptable salts, hydrates and esters, and biological derivatives, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a 30 pharmaceutically acceptable salt, hydrate or ester thereof. A compound of the -11 - PCT/US2015/066112 WO 2016/100523 present teachings can be a time-dependent antibiotic such as beta-lactam antibiotic. Particular compounds of the present teachings include ceftriaxone and eriapenem. A “time-dependent antibiotic’’ refers to an antibiotic whose microorganism killing response is dependent on time, he,, its bactericidal activity continues as long 5 as the plasma concentration is greater than the minimum bactericidal concentration or the minimum inhibitory concentration (“MIC”). Unlike “concentration-dependent” antibiotics, a higher concentration of a time-dependent antibiotic does not result in increased effectiveness. Accordingly, for a time-dependent antibiotic, its plasma concentration should be maintained over the MIC for an organism to be 10 treated for as long as possible and ideally, the entire time interval between repetitive doses.

Examples of time-dependent antibiotics includes beta-lactams (“β-lactams”), clindamycin, macrolides such as erythromycin, clarithromycin and vancomycin, and oxazolidinones such as linezoiid. Examples of β-lactams include penicillin 15 derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems, in various embodiments, the β-iactam is ceftriaxone. In some embodiments, the β-lactam is a carbapenem, for example, imipenum, meropenem, ertapenem, doripenem, panipenem/betamipron, or biopenem. It should be understood that in the practice of the present teachings, although typically one time-dependent antibiotic is 20 administered in a triphasic dosing regimen, a combination of two or more time-dependent antibiotics can be administered simultaneously or concurrently in the triphasic dosing regimen of the present teachings.

The present teachings also include pharmaceutical compositions such as antibiotic compositions that include at least one compound described herein such as 25 a time-dependent antibiotic or a therapeutic combination, and one or more pharmaceuticaliy acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed. Alfonso R, 30 Gennaro, Lippincott Williams & Wilkins, Baltimore, MD (2000). - 12- PCT/US2015/066112 WO 2016/100523

As used herein, “therapeutic combination” refers to a combination of one or more active drug substances, i.e., compounds having a therapeutic utility such as antibiotics. Typically, each such compound, one of which is a time-dependent antibiotic, in a therapeutic combination can be present in a pharmaceutical 5 formulation comprising that compound and a pharmaceutically acceptable carrier.

The compounds in a therapeutic combination can be administered simultaneously, together or separately, or separately at different times, as part of a regimen of the present teachings.

As used herein, “pharmaceutically acceptable” refers to a substance that is 10 acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with an active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable, Supplementary active ingredients can also be incorporated into the pharmaceutical compositions, 15 Time-dependent antibiotics and therapeutic combinations administered in accordance with the present teachings can be useful for treating a pathological condition or disorder such as the presence of an undesirable microorganism in a patient, for example, a human. As used herein, “treating” refers to partially or completely alleviating and/or ameliorating the condition and/or symptoms thereof. 20 Time-dependent antibiotics and therapeutic combinations can be administered via a triphasic or hiphasie dosing regimen alone or in combination with other therapeutically-effective compounds or therapies for the treatment of a pathological condition or disorder. As used herein, “therapeutically-effective” refers to a substance or an amount that elicits a desirable biological activity or effect. 25 When administered for the treatment or inhibition of a particular disease state or disorder, it should be understood that an effective dosage can vary depending upon many factors such as the particular time-dependent antibiotic used, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a 30 time-dependent antibiotic can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms PCT/US2015/066112 WO 2016/100523 of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as weli as the size, age and response pattern of the patient, 5 In accordance with the present teachings, the time above the MIC a time- dependent antibiotie is in a patient’s system can be increased, for example, compared to known and conventional treatment regimens. The methods generally include administering the time-dependent antibiotic to a patient in two or three dosing phases over a period of less than 24 hours. In various embodiments, the total 10 time of administration can be about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-14 hours, or about 14-16 hours.

In various embodiments, methods of administering a time-dependent antibiotic to a patient can include administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic during a first dosing period, where the 15 fi rst dosing period is about 3% to about i 7% of a total time of administration; administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 66% to about. 94% of the total time of administration; and administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic 20 for a third dosing period, where the third dosing period is about 3% to about 17% of the total time of administration,

In some embodiments, methods of administering a time-dependent antibiotic to a patient can include administering to a patient a first dose of a time-dependent an tibiotic sufficient to provide a plasma concentration of the antibiotic above a 25 minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; administering to the patient a second dose of the antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, where administering the 30 second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and administering to the patient a third dose of the time- - 14 - PCT/US2015/066112 WO 2016/100523 dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), where administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration. 5 The sum of the first, second and third doses can equal a daily dose of the time-dependent antibiotic, in the methods of the present teachings, the total time of administration can be less than about 16 hours. For example, the total time of administration can be between about 6 to about 8 hours, between about 8 to about 10 hours, between about 10 10 to about 12 hours, between about 12 to about 14 hours, or between about 14 to about 16 hours, in various embodiments, the total time of administration can be about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

In certain embodiments, methods of administering a time-dependent 15 antibiotic to a patient can include administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic for a first dosing period, where the first dosing period is about 15 minutes to about 60 minutes; administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 4 hours to about 20 15.5 hours; and administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, where the third dosing period is about 15 minutes to about 60 minutes. in particular embodiments, methods of administering a time-dependent antibiotic to a patient can include administering to a patient a first dose of a time-25 dependent ant ibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the 30 minimum inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 4 hours - 15 - PCT/US2015/066112 WO 2016/100523 <.Λ ίο about 15.5 hours; and administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic during the first and second dosing periods, where administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes. The sum of the first, second and third doses can equal a daily dose of the time-dependent antibiotic. in some embodiments of a triphasic dosing regimen, the first phase (dosing period) and/or the second phase (dosing period) can include administering to a 10 patient about 20% to about 30%. or about 23% to about 27% of a daily dose of a time-dependent antibiotic. The third phase can include administering to a patient about 301½ to about 65%, about 40% to about 60%, or about 47% to about 53% of a daily dose of a time-dependent antibiotic.

In certain embodiments of a triphasic dosing regimen, the first dosing period 15 and/or the third dosing period can be between about 15 minutes to about 45 minutes, or between about 15 minutes to about 30 minutes. Depending on the total time of administration, the second dosing period can he about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 20 10.5 hours, about 11 hours, about 11.5 hours, or more.

In particular embodiments of the triphasic dosing regimens, the first dosing period and/or the third dosing period can be between about 4% to about 12%, between about 4% to about 10%, or between about 4% to about 8% of a total time of administration. The second dosing period can be between about 75% to about 94%, 25 between about 80% to about 93%, or between about 83% to about 92% of the total time of adm inistration.

In various embodiments of the triphasic dosing regimens of the present teachings, the second dose of the time-dependent antibiotic can be sufficient to maintain the plasma concentration of the time-dependent antibiotic above the 30 minimum inhibitory concentration for at least about 60%, about 70%, about 80%, about 90%, about 95%, or about 98% or more of the second dosing period. - 16- PCT/US2015/066112 WO 2016/100523

Ir, biphasic dosing regimens of the present teachings, methods of administering a time-dependent antibiotic to a patient can include administering to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic during a first dosing period, where the first dosing period is about 83% to about 96% 5 of a total time of administration; and administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 4% to about 17% of the total time of administration. in some embodiments of biphasic dosing regimens, methods of 10 administering a time-dependent antibiotic to a patient can include administering to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic for a first dosing period, where the first dosing period is about 5 hours to about 12 hours; and administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing 15 period is about 15 minutes to about one hour, in particular embodiments of biphasic dosing regimens, about 25% to about 50%, about 50% to about 75%, about 40%; to about 60%. or about 50% of a daily dose of a time-dependent antibiotic can be administered during the first dosing period and/or the second dosing period, 20 The methods of the present teachings can increase the daily time that the time-dependent antibiotic is above the minimum inhibitory concentration in the patient compared to administering intravenously or subcutaneously the daily dose of the time-dependent antibiotic over about 30 minutes. The methods can increase the daily time that the time-dependent antibiotic is above the minimum inhibitory 25 concentration in the patient compared to administering intravenously or subcutaneously 50% of the daily dose of the time-dependent antibiotic over about 30 minutes twice a day,

In various embodiments, the methods can maintain a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at 30 least 70% of the time over a 24-hour period. Because the dosing regimens of the present teachings generally can administer a daily dose or an amount sufficient for a - 17 - WO 2016/100523 PCT/US2015/066112 <«/ι 24-hour period, repeating the biphasic or triphasic dosing regimen (e,g,, steps (a) and (b) or steps (a)-(c), respectively) in 24-hour intervals can achieve a plasma concentration of the time-dependent antibiotic in the patient above the minimum inhibitory concentration for at least 70% of the time over a 48-hour period, over a 72-hour period, over a 96-hour period, or longer.

The methods of the present teachings can include administering subcutaneously to a patient a dose of a time-dependent antibiotic. The methods can include administering the time-dependent antibiotic or the antibiotic composition with a device in contact with the skin of the patient, such as a micropump, a patch 10 pump device, or an injection needle of such a device or an intravenous delivery device. A feature of the present teachings is the ability of a patient undergoing antibiotic treatment to be device-free, for as long as possible, while maintaining sufficient levels of the time-dependent antibiotic in the patient. Accordingly, the 15 methods of the present teachings can include (the step of) removing the device after the end of a daily dosing regimen (e.g., after step (c) of a triphasic dosing regimen, or after step (b) of a biphasic dosing regimen).

In the methods of the present teachings, the time-dependent antibiotic can be a β-lactam. In various embodiments, the β-lactam can be or includes ceftriaxone, in 20 some embodiments, the β-lactam can be or includes ertapenem.

As discussed herein, the pharmaceutical formulations or antibiotic compositions can be administered parenterally, including by infusion, injection or implantation, which includes subcutaneous administration as appropriate. For example, the time-dependent antibiotic or an antibiotic composition can be 25 administered by, for example, subcutaneous injection or delivery, or by intravenous injection or delivery.

The pharmaceutical forms suitable for injection can include sterile solutions, suspensions, or dispersions such as a sterile aqueous solution. The pharmaceutical form can be a sterile powder for the extemporaneous preparation of sterile injectable 30 solutions or dispersions, in certain embodiments, the pharmaceutical formulation is sterile and its viscosity permits it to flow through a syringe. The pharmaceutical - 38- PCT/US2015/066112 WO 2016/100523 formulation should be stable under the conditions of manufacture and storage. The pharmaceutical formulation can be preserved against the contaminating action of microorganisms such as bacteria and fungi, for example, by inclusion of a preservative. However, in some embodiments, the pharmaceutical formulation is 5 preservative-free. A sterile pharmaceutical formulation can be prepared using pharmaceuticaliy accepted practices, for example, filtration and/or heat.

The carrier of a pharmaceutical formulation can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and/or vegetable 10 oils. For example, solutions, mixtures, or suspensions of a time-dependent antibiotic can be prepared in water, which can be suitably mixed with a surfactant such as hydroxyl-propylcelluiose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Specific- examples of liquid carriers for parenteral administration include water, alcohols (including monohydric 15 alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.

The pharmaceutical formulations can Include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, 20 favoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Because the pharmaceutical formulations and their intended use is with patients such as humans, each of the ingredients or compounds of a pharmaceutical formulation described herein can be a pharmaceutically acceptable ingredient or compound. A number of devices have been proposed to facilitate self-administration of a pharmaceutical formulation including an antibiotic composition. The device typically includes a reservoir containing, for example, pre-loaded with, the pharmaceutical formulation to be administered, A micropump can provide precise subcutaneous administration of small quantities of a liquid pharmaceutical 30 formulation. Such micropumps can be compact and portable, Another type of device useful for subcutaneous delivery or administration of pharmaceutical - 19 - PCT/US2015/066112 WO 2016/100523 formulations is often referred to as a patch device or a patch pump device. Patch devices usually are attached directly to the skin of a patient. See, e.g., U.S. Patent Nos. 8,282,366 and 8,414,532 to Sensile Pat AG. After administration of the pharmaceutical formulation, the device can be removed from the skin of the patient. 5 Accordingly, in various embodiments of practicing the methods of the present teachings, a micropump or a patch pump device can include a reservoir containing an antibiotic composition; a subcutaneous injection needle configured for removable insertion into the skin of a patient; and a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with 10 the subcutaneous injection needle. The micropump or the patch pump device can include a control system configured to control the micropump to deliver the antibiotic composition from the reservoir through the subcutaneous injection needle to a patient according to any of the methods of the present teachings. The mieropump or the patch pump device also can include a housing for supporting the 15 reservoir, the subcutaneous injection needle, the micropump, and the control system, when present. The antibiotic composition contained within the reservoir can include at least one time-dependent antibiotic and a pharmaceutically acceptable carrier. After administration of the antibiotic composition according to the dosing regimens of the present teachings, the mieropump or patch pump device is typically removed 20 from the skin of the patient.

The control system can include a microprocessor programmed to carry out a method of the present teachings. The control system (or the device) also can include wireless communications hardware to permit remote monitoring, control, and/or maintenance of the device and its operation. 25 For example, the control system can include a radio frequency (RF) transceiver positioned in the housing of the device, which RF transceiver can communicate with an external control and display unit that enables the remote control and verification of the pump operation, for example, by a patient. The information transmitted by the control system can include an alarm signal arising 30 from faulty operation. The RF transceiver can use existing technology for keyed -20- PCT/US2015/066112 WO 2016/100523 digital transmission to ensure the absence of interference with other RF devices.

Such technology is widely available and is not further described herein.

The control system can include a radio frequency identification (RFID) reader, for example, connected to the microprocessor and in wireless communication 5 with an RFID transponder associated with the device, for example, its reservoir and/or micropump. RFID transponders are known passive devices used in a number of different applications and comprise a small chip and a coil to generate electrical energy for powering the transponder from the RF field. Such transponders can be used as identification tags, for example, to verify origination and/or authenticity of 10 the product and/or components thereof.

In any of the methods or systems of the present teachings, a patient can have a disease or condition that responds to time-dependent antibiotic treatment or therapy, for example, the time-dependent antibiotic can treat and/or ameliorate the symptoms of a bacterial infection. The disease or condition that responds to time-15 dependent antibiotics can include one or more of pneumonia, meningitis, influenza, pelvic inflammatory disease, and infections of the lungs, ears, skin, urinary tract, blood, bones, joints, and abdomen.

The following example Is provided to illustrate further and to facilitate understanding of the present teachings and are not in any way intended to limit the 20 invention. PCT/US2015/066112 WO 2016/100523

Example: Simulated Dosing Regimens For Administering .Ceftriaxone

SimuSations were performed based on literature review to define a pharmacokinetic mode! for subcutaneous and intravenous administration of 5 ceftriaxone. In the U.S., ceftriaxone is currently approved for IV and intramuscular administration. The pharmacokinetic model was then used to examine different administration routes and regimens to estimate time above MIC. A significant amount of pharmacokinetic (“PR”) data is available in the scientific literature for ceftriaxone, with various dosing regimens and routes of administration. Pharmacodynamic data such as MICs are also available in the literature. Overall, data and/or summary' results from relevant literature were employed to develop a model of subcutaneously-infused ceftriaxone. The final mode! was used to simulate different administration routes and dosing regimens 15 (e.g., known and conventional intravenous {“3V”) and subcutaneous (“SC”) dosing regimens compared to biphasic and triphasic dosing regimens of the present teachings administered subcutaneous (identified herein as “SCP”)) to evaluate time above MIC,

The dosing regimens evaluated are shown in Table 1. PCT/US2015/066112

Table 1. Dosing Regimens.

Number 1 E0UMV; fiosel2 ..: Dosei* Dose 3 ’ i IV 2 g, q24, 0.5 h None None 2 SC 2 g, q24, 0.5 h None None 3 IV 1 g, q!2, 0,5 h None None 4 sc 1 g, q 12. 0.5 h None None 5 SCP 1 g, q24, 5.5 h ; I g, q24, 0.5 h, 5.5 h none 6 SCP 1-5 g, q24, 5.5 h 0.5 g, q24, 0,5 h, 5.5 h none ? SCP 0.5 g, q24, 5.5 h 1.5 g, q24, 0.5 h , 5.5 h none 8 SCP 0.5 g, q24, 0.5 h 0,5 g, q24, 5.0 h, 0.5 h i I g, q24, 0,5 h, ; 5.5 h f 9............ SCP...... 0,5 g, q24, 0.5 h ; 0.5 g, q24, 11.0 h, 0.5 h 1 g, q24, 0.5 h, i; 31.5 h 10 Γ IV h None None WO 2016/100523 * NY” refers to traditional IV infusion; '‘SC” refers to traditional SC infusion; and “SCP'5 refers to SC infusion according to a biphasic or a triphasic dosing regimen according to the present teachings. 5 2 The values represent the amount, frequency, and duration of ceftriaxone administration, respectively. 3 The values represent the amount, frequency, duration, and start time of subsequent doses of ceftriaxone administration, respectively. MIC data for ceftriaxone were obtained from the Antimicrobial wild type 10 distributions of microorganisms, available from EUCAST (European Committee on Antimicrobial Susceptibility Testing) at muVNumheil i«lo ' MMfe;

Initially, common community-acquired bacteria were used for simulation of 15 MIC (e.g., Streptococcus pneumonia). However, as coverage for all regimens was very high (greater than 95% of time above MIC for nearly ail patien ts), it was elected to examine organisms that typically demonstrate lower sensitivity to ceftriaxone. Organisms chosen included one that was relatively sensitive (Staphylococcus aureus), one that was moderately resistant (Pseudomonas 20 aeruginosa), and one that typically showed high levels of resistance (Bacteroides fragilis). MIC’s for Staphylococcus aureus, Pseudomonas aeruginosa, and Bacteroides fragilis were randomly sampled from the distributions ofMICs from the -23 - PCT/US2015/066112 WO 2016/100523 reference given above. FIGS. 1A-1C show the histograms of the MIC empirical distributions used in the pharmacodynamics model. ΙΓΊ A review of the literature suggested that a two-compartment pharmacokinetics model with first order absorption adequately described the concentration-time profile of subcutaneously administered ceftriaxone. The absorption compartment was used for SC doses, whereas IV doses were administered to the central compartment. FIG. 2 is a schematic of the ceftriaxone pharmacokinetic model.

The basic model structure was based on Bomeret ah, “Comparative 10 pharmacokinetics of ceftriaxone after subcutaneous and intravenous administration,” Chemotherapy 31 (4):237-245 (1985) (“Borner”), However, the model by Borner was developed to describe free ceftriaxone concentrations, whereas the goal of the current simulations was focused on total ceftriaxone concentrations. A second study also indicated that a two-compartment model appropriately describes ceftriaxone 15 pharmacokinetics; however, this analysis was performed only in Japanese subjects. See. l ida et aL, “The pharmacokinetics of ceftriaxone based on population pharmacokinetics and the prediction of efficacy In Japanese adults,” Eur. J. Drug Me tab. Pkarmacokimt. 34(2):107-115 (2009). To ensure that simulations were applicable for the population planned for the simulations, these parameters were not 20 used in the final model.

Non-compartmental pharmacokinetic parameters based on total ceftriaxone concentrations were available from Harb et ah, “Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaiuronidase (rHuPH20) versus intravenous ceftriaxone administration in adult 25 volunteers,” Curr. Med. Res. Opin. 26(2):279-288 (2010) (“Harb”). These data were used to facilitate modification of the model by Borner. Harb was particularly useful because it included non-compartmental results for both SC and IV ceftriaxone. Briefly, parameters of the model based on Borner were adjusted manually so that non-compartmental parameters (AUC, Ci* and 1-½ (elimination half-life)) and the 30 standard deviation of the parameters were consistent with Harb. There were no covariates in the model. All between subject variability was described as PCT/US2015/066112 WO 2016/100523 unexplained between .subject variability in clearance (CL), central volume of distribution (Kη, K23), and absorption rate constant (Ka),

To confirm that the modified model was consistent with the observed data in Harb, non-compartmeniai parameters from simulated data (based on the modified 5 model) were compared to parameters from Harb using the same sampling design as in Harb with 16 samples collected out to 48 hours post dose.

Pharmacokinetic profiles were simulated for 200 subjects for each of the 10 dosing regimens in Table 1. Dosing regimens included traditional single-phase IV infusion administration as well as single-phase (rapid), two-phase and three-phase 10 SC infusion administration. More specifically, the two-phase SC dosing regimens of the present teachings (Dosing Regimens 5, 6 and 7) consisted of a zero order infusion for 5.5 hours, followed by an “end bolus” infusion over 0.5 hours. The three-phase SC dosing regimens of the present teachings (Dosing Regimens 8 and 9) consisted of an “initial bolus” infusion over 0.5 hours to achieve therapeutic 15 concentrations above MIC quickly. The initial infusion was followed by a zero-order infusion (5 or 11 hour duration, respectively), and a subsequent 0,5 hour “end bolus.” Because “true’5 values of concentrations were of interest, residual error was set to zero for all simulations.

Table 2 presents the final pharmacokinetics model parameters used for ail 20 simulations. As described previously, these parameters were optimized by manually adjusting the parameter until the non-compartmental parameter estimates were consistent with Harb,

Table 2, Parameters for Pharmacokinetics Model,

Parameter Expected value Rctvmm subject [ variance Clearance (L/h) 0.93 0.05 Centra] volume of distribution (L) 6 0.01 Absorption rate constant (Ka) (L/h) 0.61 0.55 1 K23 (L/h) 0.12 ΝΛ .........| K32 (L/h) 0.24 NA ] - 25 - PCT/US2015/066112 WO 2016/100523

Tabic 3 presents the non-compartmental parameters resulting from a simuiated one gram subcutaneous dose compared to resuits from Harb. Reasonable agreement is seen, both in the mean values and the variability (range or standard deviation). 5 Tablc3. Comparison of Noneomparimeutal Results. 1 Parameter 1 Harb results I Simulation results .jjj i max (h) I 3,02 (1,52-4.04), (mean, ! range) | 2.76 (1.39) (mean, SD) '·. · siu m ί * i: 82,2 (13.5) (mean, SD) :|... 90.7 (24.9} (mean. SD) j T (h) | 8.28 (5.95-10,9) (mean, 1 8,07 (1.52) (mean, SD) range)

Results for each of the pharmacokinetics simulations of Dosing Regimens 1 10 are shown in FIGS. 3-12, respectively. The upper plot of each figure shows the 10 traces for the median plasma concentration and the 95% prediction intervals over time (72 h). The lower plot of each figure shows the traces for the start time of the infusion and infusion rate over time (72 h).

Table 4 show's the median hours above MIC (of 72 hours), by organism.

Table 4. Median Hours (of 72 hours) Above MIC, by Organism,

Dosmg Regimen. S. aureus Μ. fragUls 1 71.99 42.62 46.09 A. 71.94 47.25 45.42 3 71.99 52.17 43.32 4 71.87 58.88 45,54 5 71.35 50.18 53.18 6 71.45 49.27 50.37 n / 70.97 45.85 47.08 8 71.75 56.44 43.84 9 71.76 60.17 70.29 10 71 9;·; 40.03 34.08

Table 5 shows the fraction of patients with greater than 70% of time above MIC, by organism. - 26 - PCT/US2015/066112 WO 2016/100523

Table S, Fraction of Patients with Greater Than 70% of Time Above MIC, by

Organism.

Dosing Regimen 1 *£ aureus ίί ν.' .Ϋνί' B. fragiiis ; 1........ 0.985 0.375 0.455 2 6.985 0,,415 0.465 s .........6.985................. 6,530 6.490 I “’Ϊ· ..................6.995............T 0.595 “A85 £ 0.975 0.490 o o 6 0.775 0.465 o L;* o o 7 0.985 0.425 6.490 s 6.995 .................6.585 6.475 9 :.· o 6.770 0.590 ίο 6.985 0,335 6.435

Overall, the subcutaneous dosing regimens of the present teachings improved 5 the time above MIC for all organisms, compared to the same total daily dose given once a day by IV or SC. More specifically, conventional rapid administration (IV or SC) and the SCP infusion regimens of the present teachings consistently resulted in plasma concentration above MIC for S. aureus (FIGS, 13 and 16). At the other extreme of resistance, in the case of B.jnigilis, only Dosing Regimens 5, 6 and 9 of 10 the present teachings of the 10 dosing regimens evaluated achieved greater than 50% of the simulated population above MIC for 70% of the treatment period, although Dosing Regimen 7 of the present teachings showed equal to or a higher percentage of the simulated population above MIC for 70% of the treatment period compared to conventional rapid administration (FIGS, 15 and 18). As for the results of the 15 moderately resistant organism, P, aeruginosa, the dosing regimens of the present teachings were notably superior, and in particular Dosing Regimen 9, to the other IV and SC infusion regimens (although Dosing Regimen 8 was slightly inferior to Dosing Regimen 4) (FIGS, 14 and 17).

Based on the simulation results, the three-phase or triphasic SCP infusion 20 regimens (Dosing Regimens 8 and 9) of the present teachings provided an additional benefit compared to a two-phase or biphasie infusion as the therapeutic concentrations were achieved quicker with an initial loading phase. However, with respect to the highly resistance organism (B, jragilis), both the biphasie and triphasic SCP infusion regimens generally were better than the conventional infusion PCT/US2015/066112 WO 2016/100523 u regimens. From a strictly pharmacodynamic perspective, the best coverage among the dosing regimens evaluated was the three-phase, 12-hour SCP infusion (Dosing Regimen 9). However, other considerations such as the specific time-dependent antibiotic administered, the organism to be treated, the condition or state of the infection or disease, as well as the size, age and response pattern of the patient, can factor into designing the optimal dosing regimen protocol. Nevertheless, the appropriate amount and timing of administration of the time-dependent antibiotic can be optimized to achieve the plasma concentrations or levels of the antibiotic above the MIC in the patient for the longest period of time. 10 In sum, subcutaneous administration, for example, using a wearable patch pump device, using slow and delayed infusion (biphasic or triphasic infusions over six to twelve hours) can result in improved time above MIC for three representative organisms (S. aureus, P. aeruginosa and B.fragilis) compared to conventional intravenous administration in accordance with the current prescribing information. 15 fn the simulations described herein, the dosing regimens of the present teachings improved the median time above MIC as well as the fraction of simulated patients who achieved at least 70% of the time above MIC for a 72-hour administration.

The present teachings encompass embodiments in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing 20 embodiments are therefore to be considered in all respects illustrative rather than limiting on the present teachings described herein. Scope of the present invention is thus indicated by the appended claims rather than by the foregoing description, and ail changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. 25 What is claimed is: 28 -

Claims

1. A method of administering a time-dependent antibiotic to a patient, the method comprising the steps of: (a) administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic during a first dosing period, wherein the first dosing period is about 3% to about i 7% of a total time of administration; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, wherein the second dosing period is about 66% to about 94% of the total time of administration; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 3% to about 17% of the total time of administration.

2, A method of administering a time-dependent antibiotic to a patient, the method comprising the steps of: (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; (h) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum, inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (h), wherein administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration; wherein the sum of the first, second and third doses equals a daily dose of the time-dependent antibiotic.

3, A time-dependent antibiotic for use in a method for the treatment of an infection or other disease or condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic during a first, dosing period, wherein the first dosing period is about 3% to about 17% of a total time of administration; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, wherein the second dosing period is about 66% to about 94% of the total time of administration; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 3% to about 17% of the total time of administration.

4. A time-dependent antibiotic for use in a method for the treatment of an infection or other disease or condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic· above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), wherein administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration; wherein the sum of the first, second and third doses equals a daily dose of the time-dependent antibiotic.

5. The method of any one of claims 1-4, wherein the total time of administration is less than about 16 hours.

6. The method of any one of claims 1-5, wherein the total time of administration is between about 6 to about 8 hours, between about 8 to about 10 hours, between about 10 to about 12 hours, between about 12 to about 14 hours, or between about 14 to about 16 hours,

7. The method of any one of claims 1-6, wherein the total time of administration is about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

8. A method of administering a time-dependent antibiotic to a patient, the method comprising the steps of; (a) administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic for a first dosing period, wherein the first dosing period is about 15 minutes to about 60 minutes; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, wherein the second dosing period is about 4 hours to about 15.5 hours; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 35 minutes to about 60 minutes.

9. A method of administering a time-dependent antibiotic to a patient, the method comprising the steps of: (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 4 hours to about i 5,5 hours; and (c) administering to the patient, a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (h), wherein administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes; wherein the sum of the first, second and third doses equals a daily dose of the time-dependent antibiotic,

10. A time-dependent antibiotic for use in a method .for the treatment of an infection or other disease or condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows; (a) administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic for a first, dosing period, wherein the first dosing period is about 15 minutes to about 60 minutes; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, wherein the second dosing period is about 4 hours to about 15.5 hours; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 15 minutes to about 60 minutes. i i. A time-dependent antibiotic for use in a method for the treatment of an infection or other disease or condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows; (a) administering to a patient a first dose of a time-dependent antibiotic suffic ient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the piasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 4 hours to about 15.5 hours; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), wherein administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes; wherein the sum of the first, second and third doses equals a daily dose of the time-dependent antibiotic.

12. The method of any one of claims 1-11, wherein the method increases the daily time that the time-dependent antibiotic is above the minimum inhibitory concentration in the patient compared to administering intravenously or subcutaneously the daily dose of the time-dependent antibiotic over about 30 minutes or administering intravenously or subcutaneously 50% of the daily dose of the time-dependent antibiotic over about 30 minutes twice a day,

13. The method of any one of claims 1-12, wherein the method maintains a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 70% of the time over a 24-hour period.

14. The method of any one of claims 1-12, comprising repeating steps (a)-(c) about 24 hours after beginning an immediately prior step (a), wherein the plasma concentra tion of the time-dependent antibiotic is maintained above the minimum inhibitory concentration for at least 70% of the time over a 48-hour period,

15. The method of claim 14, comprising repeating steps (a)-(c) a third time about 24 hours after beginning step (a) a second time, where the plasma concentration of the time-dependent antibiotic is maintained above the minimum inhibitory concentration for at least 70% of the time over a 72-hour period.

36. The method of any one of claims i-15, wherein administering to a patient comprises administering subcutaneously to a patient.

17. The method of any one of claims 1-16, wherein administering to a patient comprises administering with a device in contact with the skin of the patient,

18. The method of claim 17, wherein the device comprises a micropump or patch pump device.

19. The method of claims 17 or 18, comprising the step of removing the device after step (c).

20. The method of any one of claims 1-39, wherein the time-dependent antibiotic is a β-lactam.

21. The method of claim 20, wherein the β-iactam is ceftriaxone.

22. The method of claim 20, wherein the β-iactam is ertapenem,

23. The method of any one of claims 3-7 and 10-22, wherein the infection or other disease or condition comprises a bacterial infection.

24. The method of claim 23, wherein the bacterial infection comprises one or more of pneumonia, meningitis, influenza, peivie inflammatory disease, and infections of the lungs, ears, skin, urinary tract, biood, bones, joints, and abdomen.

25. A micropump or a patch pump device comprising: a reservoir containing an antibiotic composition, the antibiotic composition comprising at least one time-dependent antibiotic and a pharmaceutically acceptable carrier; a subcutaneous injection needle configured for removable insertion into the skin of a patient; a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the subcutaneous injection needle; a control system configured to control the micropump to deliver the antibiotic composition from the reservoir through the subcutaneous injection needle to a patient according to any one of claims 1-24; and a housing for supporting the reservoir, the subcutaneous injection needle, the micropump and the control system,

26, The micropump or the patch pump device of claim 25, wherein the control system comprises a microprocessor programmed to carry out a method of any one of claims 1-24,

27. The micropump or the patch pump device of claim 25 or 26, wherein the control system comprises wireless communications hardware.