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Ciprofloxacin Otiprio for Tympanostomy Tube Insertion ...p 68p 69 Three New Drugs for Multiple Myeloma ...online only ALSO IN THIS ISSUE Antimicrobial Prophylaxis for Surgery ▶ Antimicro

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1495

on Drugs and Therapeutics

Antimicrobial Prophylaxis for Surgery p 63

QuilliChew ER — Extended-Release Chewable Methylphenidate Tablets p 68

Ciprofloxacin (Otiprio) for Tympanostomy Tube Insertion p 69

Three New Drugs for Multiple Myeloma online only

63

on Drugs and Therapeutics

ISSUE

1433

Volume 56

ISSUE No

1495 QuilliChew ER — Extended-Release Chewable Methylphenidate Tablets Ciprofloxacin (Otiprio) for Tympanostomy Tube Insertion p 68p 69

Three New Drugs for Multiple Myeloma online only

ALSO IN THIS ISSUE

Antimicrobial Prophylaxis for Surgery

▶

Antimicrobial prophylaxis can decrease the

incidence of postoperative surgical site infection

after some procedures Since the last Medical Letter

article on this subject, consensus guidelines have

in specifi c surgical procedures are listed in the table

that begins on page 64

CHOICE OF AGENT — Antimicrobial prophylaxis for

surgery should be directed against the most likely

infecting organisms, but it does not need to eradicate

every potential pathogen to be effective Cefazolin

(Ancef, and others), a fi rst-generation cephalosporin

active against many staphylococci and streptococci,

can be used for most procedures

The second-generation cephalosporins cefoxitin

(Mefoxin, and others) and cefotetan (Cefotan, and

others) are recommended for procedures that involve

exposure to bowel flora, including Escherichia coli and

Bacteroides fragilis, but anaerobic resistance to these

drugs has increased.2 Ampicillin/sulbactam (Unasyn,

and generics), the broad-spectrum carbapenem

ertapenem (Invanz), or cefazolin plus metronidazole

(Flagyl, and others) may be considered, depending on

local susceptibility patterns.3

Most experts do not recommend routine use of

broad-spectrum antibiotics such as ertapenem or

extended-spectrum cephalosporins such as cefotaxime

(Claforan, and generics), ceftriaxone (Rocephin, and

generics), ceftazidime (Fortaz, and others), cefepime

(Maxipime, and generics), or ceftaroline (Teflaro) for

surgical prophylaxis because they are expensive,

some are less active against staphylococci than

fi rst- or second-generation cephalosporins, and their

spectrum of activity often includes organisms rarely

encountered in elective surgery.4

In patients who are colonized with

methicillin-resistant Staphylococcus aureus (MRSA) or in

institutions where surgical site infections are frequently due to methicillin-resistant staphylococci,

vancomycin (Vancocin, and others) could be

in addition to the routine prophylactic regimen recommended for the procedure Vancomycin is less effective than cefazolin for prevention of infections

due to methicillin-susceptible Staphylococcus

aureus (MSSA), it has a long infusion time, and

regular use possibly could lead to emergence of vancomycin-resistant organisms

Preoperative Screening and Decolonization –

Preoperative identification of patients who are nasal carriers of MRSA or MSSA and decolonization using

intranasal mupirocin (Bactroban Nasal, and others) and chlorhexidine (Peridex, and others) have been

shown to decrease surgical site infections following some procedures (primarily cardiac and orthopedic), but resistance to mupirocin could emerge if it is used routinely.6-8

TIMING AND DURATION — Administration of the

prophylactic antibiotic should begin within 60 minutes before the initial surgical incision to ensure adequate serum and tissue levels If vancomycin or a fluoroquinolone is used, the infusion should be started within 60-120 minutes before the initial incision because of the prolonged infusion times required for these drugs

A single prophylactic dose of an antimicrobial is usually suffi cient for most procedures; continuation

of prophylaxis for >24 hours after the procedure is not recommended There are no data to support continuation of prophylaxis after wound closure, even

if all indwelling drains and intravascular catheters have not yet been removed

Table 1 Antimicrobial Prophylaxis for Surgery

Type of Surgical Procedure Common Pathogens Antimicrobials Usual Adult Dosage 1

Cardiac

Coronary artery bypass grafting, Staphylococcus aureus, cefazolin 2,3 2 g IV 4,5

valve repairs, device implantation Staphylococcus epidermidis OR cefuroxime 2,3 1.5 g IV 5

Gastrointestinal

Esophageal, gastroduodenal Enteric gram-negative bacilli, cefazolin 3,7 2 g IV 4

Entry into the GI lumen or gram-positive cocci

patients at high risk for infection 6

Biliary tract Enteric gram-negative bacilli, cefazolin 3,7,9 2 g IV 4

Open or high-risk laparoscopic 8 enterococci, clostridia

Colorectal 10 Enteric gram-negative bacilli, cefazolin 2 g IV 4

Appendectomy, non-perforated Enteric gram-negative bacilli, cefoxitin or cefotetan 3,7 2 g IV

Genitourinary

Cystoscopy alone Enteric gram-negative bacilli, High-risk 14 only:

Cystoscopy with manipulation or Enteric gram-negative bacilli, ciprofloxacin 11 500 mg PO or 400 mg IV upper tract instrumentation 15 enterococci OR trimethoprim/ 160/800 mg (1 DS tab) PO

Open or laparoscopic surgery 16 Enteric gram-negative bacilli, cefazolin 3,7 2 g IV 4

1 Parenteral prophylactic antimicrobials can be given as a single IV dose begun within 60 minutes before the initial incision For procedures that exceed 2 half-lives of the drug or those with major blood loss, or in patients with extensive burns, additional intraoperative doses should be given at intervals of about 2 times the half-life of the drug (ampicillin/sulbactam q2 hours, cefazolin q4 hours, cefuroxime q4 hours, cefoxitin q2 hours, clindamycin q6 hours, vancomycin q12 hours) for the duration of the procedure in patients with normal renal function If vancomycin or a fluoroquinolone is used, the infusion should be started within 60-120 minutes before the initial incision to have adequate tissue levels at the time of incision and to minimize the possibility of an infusion reaction close to the time of induction of anesthesia.

2 Vancomycin (15 mg/kg IV) or clindamycin (900 mg IV) is a reasonable alternative for patients who are allergic to beta-lactams They only provide coverage against gram-positive organisms; for procedures in which enteric gram-negative bacilli are common pathogens, many experts would add an aminoglycoside (gentamicin, tobramycin or amikacin), aztreonam, or a fluoroquinolone.

3 A dose of vancomycin (15 mg/kg) can be given in addition to the recommended antimicrobial(s) in patients colonized with MRSA or in hospitals in which

methicillin-resistant S aureus and S epidermidis are a frequent cause of postoperative wound infection Vancomycin is less effective than cefazolin in

preventing surgical site infections due to methicillin-susceptible Staphylococcus aureus (MSSA) Vancomycin has activity only against gram-positive

bacteria; for procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (gentamicin, tobramycin or amikacin), aztreonam, or a fluoroquinolone Rapid IV administration of vancomycin may cause hypotension, which could be

especially dangerous during induction of anesthesia Even when the drug is given over 60 minutes, hypotension may occur; treatment with diphenhydramine

(Benadryl, and others) and further slowing of the infusion rate may be helpful An infusion rate of 10-15 mg/minute (≥1 h/1000 mg) has been recommended

(T Crawford et al Clin Infect Dis 2012; 54:1474)

4 Dose for patients who weigh <120 kg; the recommended dose is 3 g for those weighing ≥120 kg Morbidly obese patients may need higher doses.

5 Some experts recommend an additional dose when patients are removed from bypass during open-heart surgery.

6 Morbid obesity, GI obstruction, decreased gastric acidity or GI motility, gastric bleeding, malignancy or perforation, or immunosuppression.

7 For patients who are allergic to beta-lactams, clindamycin (900 mg IV) or vancomycin (15 mg/kg IV) with either gentamicin, aztreonam, or a fluoroquinolone

is a reasonable alternative Fluoroquinolones should not be used for prophylaxis in cesarean section.

8 Age >70 years, acute cholecystitis, non-functioning gallbladder, obstructive jaundice, common bile duct stones, duration >120 minutes, diabetes, pregnancy,

or immunosuppression.

9 Cefotetan, cefoxitin, and ampicillin/sulbactam are reasonable alternatives.

10 In addition to mechanical bowel preparation, 1 g of neomycin plus 1 g of erythromycin at 1 PM, 2 PM and 11 PM or 2 g of neomycin plus 2 g of metronidazole

at 7 PM and 11 PM the day before an 8 AM operation

CARDIAC SURGERY — A preoperative dose of an

antibiotic can decrease the incidence of infection

after cardiac surgery; appropriate intraoperative

redosing should be continued for the duration of the

procedure In a study in patients undergoing coronary

artery bypass grafting on cardiopulmonary bypass,

intraoperative continuous-infusion cefazolin was

superior to intermittent dosing every 2 hours.9

Antimicrobial prophylaxis is recommended before placement of electrophysiologic devices, ventricular assist devices, ventriculoatrial shunts, and arterial patches to prevent device-related infections Administration of an antimicrobial prior to implantation

of permanent pacemakers and cardioverter-defi brillators has been shown to signifi cantly reduce the incidence of wound infection, inflammation, and skin erosion.10

GASTROINTESTINAL SURGERY — Prophylaxis is

endoscopy or colonoscopy.11 Antimicro bial prophylaxis

is recommended for patients undergoing esophageal

or gastroduodenal procedures that involve entry into

the GI lumen, such as resection for gastric carcinoma,

percutaneous endoscopic gastrostomy (PEG) insertion,

pancreatic duodenectomy, and perforated ulcer

procedures For procedures that do not involve entry

into the GI tract, prophylaxis is recommended only for

patients at increased risk for infection, including those with GI obstruction, increased gastric pH, decreased

GI motility, gastric bleeding, malignancy, or perforation, morbid obesity, or immunosuppression

Because the risk of postoperative infection is high

in patients undergoing bariatric surgeries, such

as adjustable gastric banding, vertical banded gastroplasty, Roux-en-Y gastric bypass, and bilio-pancreatic diversion, antibiotic prophylaxis is used

Table 1 Antimicrobial Prophylaxis for Surgery (continued)

Type of Surgical Procedure Common Pathogens Antimicrobials Usual Adult Dosage 1

Gynecologic and Obstetric

Vaginal, abdominal, or Enteric gram-negative bacilli, cefazolin 3,7 2 g IV 4

laparoscopic hysterectomy anaerobes, Gp B strep, OR cefoxitin or cefotetan 3,7 2 g IV

Cesarean section same as for hysterectomy cefazolin 3,7 2 g IV 4

Abortion, surgical same as for hysterectomy doxycycline 300 mg PO 17

Head and Neck Surgery

Incisions through oral or Anaerobes, enteric gram- cefazolin 2 g IV 4

pharyngeal mucosa negative bacilli, S aureus + metronidazole 3,18 0.5 g IV 4

Neurosurgery

Craniotomy, spinal and CSF-shunting S aureus, S epidermidis, cefazolin 2,3 2 g IV 4

procedures, intrathecal pump Propionibacterium acnes

placement

Ophthalmic 19

S epidermidis, S aureus, neomycin-gramicidin- 1 drop q5-15 min streptococci, enterococci, polymyxin B, gatifloxacin, or x 5 doses

P acnes, Corynebacterium spp., moxifloxacin

Orthopedic

Spinal, hip fracture, internal fi xation, S aureus, S epidermidis, cefazolin 2,3,20 2 g IV 4

total joint replacement P acnes (shoulder)

Thoracic (Non-Cardiac)

Lobectomy, pneumonectomy, S aureus, S epidermidis, cefazolin 2.3 2 g IV 4

lung resection, thoracotomy streptococci, enteric gram- OR ampicillin/sulbactam 2,3,11 3 g IV

Vascular

Arterial involving a prosthesis, S aureus, S epidermidis, cefazolin 2,3 2 g IV 4

the abdominal aorta, or a enteric gram-negative bacilli

groin incision

Lower extremity S aureus, S epidermidis, cefazolin 2,3 2 g IV 4

amputation for ischemia enteric gram-negative bacilli,

11 Due to increasing resistance of Escherchia coli, local sensitivity profi les should be reviewed prior to use.

12 Where there is increasing resistance of gram-negative isolates to fi rst and second generation cephalosporins, a single dose of ceftriaxone plus metronidazole may be preferred over routine use of carbapenems

13 Ertapenem is FDA-approved for prophylaxis in colorectal surgery It was more effective than cefotetan in one study, but it was associated with an increased

risk of Clostridium diffi cile infection and other adverse effects (KM Itani et al N Engl J Med 2006; 355:2640) Routine use could promote carbapenem

resistance.

14 Urine culture positive or unavailable, preoperative catheter, transrectal prostatic biopsy, or placement of prosthetic material.

15 Shock wave lithotripsy, ureteroscopy.

16 Including percutaneous renal surgery, procedures with entry into the urinary tract, and those involving implantation of a prosthesis If manipulation of bowel

is involved, prophylaxis is given according to colorectal guidelines.

17 Divided into 100 mg before the procedure and 200 mg after.

18 For patients who are allergic to beta-lactams, clindamycin (900 mg IV) is a reasonable alternative.

19 Preoperative application of povidone-iodine to the skin and conjunctiva is recommended.

20 If a tourniquet is to be used during the procedure, the entire dose of antibiotic must be infused prior to its inflation.

routinely for these procedures, but no controlled trials

are available The appropriate antimicrobial regimen is

unclear, but higher doses of antibiotics may be needed

to achieve adequate serum and tissue concentrations

in morbidly obese patients.12

Antimicrobial prophylaxis is recommended before

biliary tract surgery for patients at high risk for

infection, including those >70 years old and those with

acute cholecystitis, a non-functioning gallbladder,

obstructive jaundice, or common bile duct stones

Antibiotic prophylaxis for endoscopic retrograde

cholangiopancreatography (ERCP) is recommended

only if complete biliary drainage is unlikely to be

achieved.11 Prophylactic antibiotics are generally not

necessary for low-risk patients undergoing elective

laparoscopic cholecystectomy.13

Antibiotic prophylaxis can decrease the incidence of

infection after colorectal surgery For most patients,

a combination of oral neomycin and either oral

erythromycin or oral metronidazole should be given

(after mechanical bowel preparation) in addition to IV

prophylaxis Combined IV and oral prophylaxis is more

effective than IV prophylaxis alone in preventing surgical

site infection.14 Ertapenem has been approved by the

FDA for prevention of infection after elective colorectal

procedures, but many experts advise against using it

routinely for this purpose; it may be considered for use

in situations where a patient or an institution is known

to have organisms resistant to other antimicrobials.14,15

Antimicrobial prophylaxis can decrease the incidence

of infection after surgery for acute appendicitis.16,17 It

has been shown to reduce infection rates in patients

undergoing mesh hernioplasty or herniorrhaphy; the

risk is higher with hernioplasty.18,19

GENITOURINARY SURGERY — Most experts do not

recommend antimicrobial prophylaxis before

cystos-copy without manipulation in patients with sterile urine

When cystoscopy with manipulation (dilation, biopsy,

fulguration, resection, or ureteral instrumentation) is

planned, the urine culture is positive or unavailable, or an

indwelling urinary catheter is present, patients should

either be treated to sterilize the urine before surgery or

receive a single preoperative dose of an agent that is

usually active against the likely microorganisms

Antimicrobial prophylaxis decreases the incidence

of postoperative bacteriuria and septicemia in

patients with sterile preoperative urine undergoing

transurethral prostatectomy and transrectal prostatic

biopsies.20-22 Prophylaxis is also recommended for

ureteroscopy, shock wave lithotripsy, percutaneous

renal surgery, and open laparoscopic procedures, and for placement of a urologic prosthesis (penile implant, artifi cial sphincter, synthetic pubovaginal sling, bone anchors for pelvic floor reconstruction).23

The effi cacy of fluoroquinolones for prophylaxis in urologic procedures is well established, but resistance has emerged.24 Local resistance patterns, particularly

of E coli, should guide appropriate selection of

antimicrobials for genitourinary procedures

GYNECOLOGIC AND OBSTETRIC SURGERY —

Antimicrobial prophylaxis decreases the incidence of infection after vaginal or abdominal hysterectomy.25

Prophylaxis is also recommended for laparoscopic hysterectomy Antimicrobials can prevent infection after elective and non-elective cesarean section; giving the dose prior to the initial skin incision appears to be more effective than giving it after cord clamping.26

Antimicrobial prophylaxis can also prevent infection following elective abortion.27

HEAD AND NECK SURGERY — Prophylaxis with

antimicrobials has decreased the incidence of surgical site infection after clean-contaminated oncologic head and neck operations that involve an incision through the oral or pharyngeal mucosa.28 Prophylaxis

is not recommended for tonsillectomy or nasal septoplasty.29,30

NEUROSURGERY — Antibiotic prophylaxis can

decrease the incidence of infection after craniotomy.31

It is also effective for spinal surgery The infection rate after conventional lumbar discectomy is low, but the consequences of postoperative infection at this site can be serious Infection rates are higher after prolonged spinal surgery or spinal procedures involving fusion or insertion of foreign material.32

Studies have shown lower infection rates with use of prophylactic antibiotics for implantation of permanent cerebrospinal fluid shunts and for placement of intrathecal pumps.33 The benefi ts of antimicrobial prophylaxis for ventriculostomy placement remain uncertain.34

OPHTHALMIC SURGERY — There is no consensus

supporting a particular choice, route, or duration of antimicrobial prophylaxis for ophthalmic procedures, but preoperative application of povidone-iodine to the skin and conjunctiva has been shown to lower the incidence of endophthalmitis.35 Other prophylactic strategies include pre- and postoperative topical antibiotic eye drops, addition of antibiotics to the irrigating solution, and subconjunctival injections Use of intracameral injections is limited by lack

of commercial availability and potential toxicity

prophylactic antibiotics are needed for procedures

that do not invade the globe

ORTHOPEDIC SURGERY — Antistaphylococcal drugs

administered prophylactically can decrease the

incidence of both early and delayed infection after joint

replacement.36 They also decrease the rate of infection

when hip and other closed fractures are treated with

internal fi xation by nails, plates, screws, or wires, and in

compound or open fractures.37-39 Whether prophylaxis

should be given as a single dose or as multiple doses

for up to 24 hours is unclear.38-40 Prophylaxis is also

recommended for orthopedic spinal procedures with

and without instrumentation.41 A retrospective review

of patients undergoing arthroscopic surgery concluded

that antibiotic prophylaxis is not indicated.42

THORACIC SURGERY — Antibiotic prophylaxis is

recommended for thoracic surgery, but supporting data

are sparse In one study, a single preoperative dose of

cefazolin before pulmonary resection led to a decrease

in surgical site infection, but not in pneumonia or

empyema.43 Insertion of chest tubes for non-traumatic

indications, such as spontaneous pneumothorax, does

not require antimicrobial prophylaxis

VASCULAR SURGERY — Preoperative prophylaxis

decreases the incidence of postoperative surgical

site infection after arterial reconstructive surgery

on the abdominal aorta, vascular operations on the

leg that include a groin incision, and amputation of

the lower extremity for ischemia.44,45 Many experts

also recommend prophylaxis for implantation of

any vascular prosthetic material, such as grafts for

vascular access in hemodialysis Prophylaxis is not

indicated for carotid endarterectomy or brachial

artery repair without prosthetic material Prophylactic

antibiotics are not routinely recommended for

bare-metal stenting, but risk factors that may justify their

use include repeat intervention within 7 days, prolonged

indwelling arterial sheath, prolonged procedure duration

(>2 hours), presence of other infected implants, and

immunosuppression Although the incidence of

infec-tion after stent graft procedures is low (<1%), use of

prophylactic antibiotics is justifi ed because the mortality

rate associated with graft infections is high (18-29%).46-48

OTHER PROCEDURES — Antimicrobial prophylaxis is

generally not indicated for cardiac catheterization,

plastic surgeries, arterial puncture, thoracentesis,

paracentesis, repair of simple lacerations, or outpatient

treatment of burns because the incidence of surgical site infections with all of these procedures is low Whether prophylaxis is needed in breast surgery (other than for breast cancer50) and other “clean” surgical procedures has been controversial Most experts generally do not recommend antibacterial prophylaxis for these procedures because of the low rate of infection and the potential for adverse effects with prophylaxis It may be considered for procedures

in which the consequences of infection can be serious, such as those involving placement of prosthetic material (e.g., saline implants, tissue expanders) ■

1 DW Bratzler et al Clinical practice guidelines for antimicrobial prophylaxis in surgery Am J Health Syst Pharm 2013; 70:195.

2 DR Snydman et al Update on resistance of Bacteroides fragilis group and related species with special attention to carbapen-ems 2006-2009 Anaerobe 2011; 17:147.

3 S Hawser et al Epidemiology and antimicrobial susceptibility

of Gram-negative aerobic bacteria causing intra-abdominal in-fections during 2010-2011 J Chemother 2015; 27:67.

4 Why not ertapenem for surgical prophylaxis? Med Lett Drugs Ther 2009; 51:72.

5 T Crawford et al Vancomycin for surgical prophylaxis? Clin In-fect Dis 2012; 54:1474.

6 C Hebert and A Robicsek Decolonization therapy in infection control Curr Opin Infect Dis 2010; 23:340.

7 LG Bode et al Preventing surgical-site infections in nasal carri-ers of Staphylococcus aureus N Engl J Med 2010; 362:9.

8 ML Schweizer et al Association of a bundled intervention with surgical site infections among patients undergoing cardiac, hip,

or knee surgery JAMA 2015; 313:2162.

9 BR Shoulders et al Impact of intraoperative continuous-infu-sion versus intermittent dosing of cefazolin therapy on the in-cidence of surgical site infections after coronary artery bypass grafting Pharmacotherapy 2016; 36:166.

10 JC de Oliveira et al Effi cacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defi brillators: re-sults of a large, prospective, randomized, double-blinded, pla-cebo-controlled trial Circ Arrhythm Electrophysiol 2009; 2:29.

11 ASGE Standards of Practice Committee et al Antibiotic prophy-laxis for GI endoscopy Gastrointest Endosc 2015; 81:81.

12 CE Edmiston et al Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Sur-gery 2004; 136:738.

13 RC Yan et al The role of prophylactic antibiotics in laparoscopic cholecystectomy in preventing postoperative infection: a meta- analysis J Laparoendosc Adv Surg Tech A 2011; 21:301.

14 RL Nelson et al Antimicrobial prophylaxis for colorectal sur-gery Cochrane Database Syst Rev 2014; 5:CD001181.

15 KM Itani et al Ertapenem versus cefotetan prophylaxis in elec-tive colorectal surgery N Engl J Med 2006; 355:2640.

16 BR Andersen et al Antibiotics versus placebo for prevention of postoperative infection after appendicectomy Cochrane Data-base Syst Rev 2005; 3:CD001439.

17 LM Mui et al Optimum duration of prophylactic antibiotics in acute non-perforated appendicitis ANZ J Surg 2005; 75:425.

18 Y Yin et al Antibiotic prophylaxis in patients undergoing open mesh repair of inguinal hernia: a meta-analysis Am Surg 2012; 78:359

19 FJ Sanchez-Manuel et al Antibiotic prophylaxis for hernia re-pair Cochrane Database Syst Rev 2012; 2:CD003769.

20 A Berry and A Barratt Prophylactic antibiotic use in transure-thral prostatic resection: a meta-analysis J Urol 2002; 167:571.

21 W Qiang et al Antibiotic prophylaxis for transurethral

pros-tatic resection in men with preoperative urine containing less

than 100,000 bacteria per ml: a systematic review J Urol 2005;

173:1175.

22 EL Zani et al Antibiotic prophylaxis for transrectal prostate

bi-opsy Cochrane Database Syst Rev 2011; 5:CD006576.

23 JS Wolf Jr et al Best practice policy statement on urologic

sur-gery antimicrobial prophylaxis J Urol 2008; 179:1379.

24 DA Williamson et al Escherichia coli bloodstream infection

af-ter transrectal ultrasound-guided prostate biopsy: implications

of fluoroquinolone-resistant sequence type 131 as a major

causative pathogen Clin Infect Dis 2012; 54:1406.

25 ACOG practice bulletin no 104: antibiotic prophylaxis for

gyne-cologic procedures Obstet Gynecol 2009; 113:1180.

26 ACOG committee opinion no 465: antimicrobial prophylaxis

for cesarean delivery: timing of administration Obstet Gynecol

2010; 116:791.

27 SL Achilles et al Prevention of infection after induced abortion:

release date October 2010: SFP guideline 20102 Contraception

2011; 83:295.

28 R Simo and G French The use of prophylactic antibiotics in

head and neck oncological surgery Curr Opin Otolaryngol Head

Neck Surg 2006; 14:55.

29 M Dhiwakar et al Antibiotics to reduce post-tonsillectomy

morbidity Cochrane Database Syst Rev 2012; 12:CD005607.

30 FM Gioacchini et al The role of antibiotic therapy and nasal

packing in septoplasty Eur Arch Otorhinolaryngol 2014; 271:879.

31 FG Barker 2nd Effi cacy of prophylactic antibiotics against

meningitis after craniotomy: a meta-analysis Neurosurgery

2007; 60:887.

32 EM Brown et al Spine update: prevention of postoperative

infection in patients undergoing spinal surgery Spine 2004;

29:938.

33 KA Follett et al Prevention and management of intrathecal drug

delivery and spinal cord stimulation system infections

Anes-thesiology 2004; 100:1582.

34 AM Sonabend et al Prevention of ventriculostomy-related

in-fections with prophylactic antibiotics and antibiotic-coated

external ventricular drains: a systematic review Neurosurgery

2011; 68:996.

35 Y Ahmed et al Povidone-iodine for endophthalmitis

prophy-laxis Am J Ophthalmol 2014; 157:503

36 B Al Buhairan et al Antibiotic prophylaxis for wound infections

in total joint arthroplasty: a systematic review J Bone Joint

Surg Br 2008; 90:915.

37 L Prokuski Prophylactic antibiotics in orthopaedic surgery J

Am Acad Orthop Surg 2008; 16:283.

38 WJ Gillespie and GH Walenkamp Antibiotic prophylaxis for

sur-gery for proximal femoral and other closed long bone fractures

Cochrane Database Syst Rev 2010; 3:CD000244.

39 JP Southwell-Keely et al Antibiotic prophylaxis in hip fracture

surgery: a metaanalysis Clin Orthop Relat Res 2004; 419:179.

40 GP Slobogean et al Single- versus multiple-dose antibiotic

prophylaxis in the surgical treatment of closed fractures: a

meta-analysis J Orthop Trauma 2008; 22:264.

41 WO Shaffer et al An evidence-based clinical guideline for

anti-biotic prophylaxis in spine surgery Spine J 2013; 13:1387.

42 JM Bert et al Antibiotic prophylaxis for arthroscopy of the knee:

is it necessary? Arthroscopy 2007; 23:4.

43 R Aznar et al Antibiotic prophylaxis in non-cardiac thoracic

sur-gery: cefazolin versus placebo Eur J Cardiothorac Surg 1991;

5:515.

44 AH Stewart et al Prevention of infection in peripheral arterial

reconstruction: a systematic review and meta-analysis J Vasc

Surg 2007; 46:148.

45 S Homer-Vanniasinkam Surgical site and vascular infections:

treatment and prophylaxis Int J Infect Dis 2007; 11:S17.

46 JA Sutcliffe et al Antibiotics in interventional radiology Clin

Radiol 2015; 70:223.

47 WM Bosman et al Infections of intravascular bare metal stents:

a case report and review of literature Eur J Vasc Endovasc Surg 2014; 47:87.

48 AM Venkatesan et al Practice guidelines for adult antibiotic prophylaxis during vascular and interventional radiology pro-cedures Written by the Standards of Practice Committee for the Society of Interventional Radiology and Endorsed by the Cardiovascular Interventional Radiological Society of Europe and Canadian Interventional Radiology Association [corrected]

J Vasc Interv Radiol 2010; 21:1611.

49 TI Wright et al Antibiotic prophylaxis in dermatologic surgery: advisory statement 2008 J Am Acad Dermatol 2008; 59:464.

50 DJ Jones et al Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery Cochrane Database Syst Rev 2014; 3:CD005360.

Pronunciation Key

Methylphenidate : meth" il fen' i date QuilliChew : quil" ih choo'

QuilliChew ER — Extended-Release

Chewable Methylphenidate Tablets

▶

The FDA has approved a once-daily, extended-release chewable tablet formulation of methylphenidate

(QuilliChew ER – Pfi zer) for treatment of

attention-defi cit/hyperactivity disorder (ADHD) It is the fi rst long-acting chewable formulation of the drug to be marketed in the US Immediate-release chewable

methylphenidate tablets (Methylin, and generics) have

been available since 2003.1

METHYLPHENIDATE — Short-acting methylphenidate

formulations are effective for treatment of ADHD, but their 3-5 hour duration of action usually requires mid-day dosing in school, which children may fi nd disruptive or stigmatizing Long-acting methylphenidate preparations have therefore become the mainstay

of clinical practice Most long-acting formulations are available only as tablets or capsules that many children fi nd diffi cult to swallow Some capsules can

be opened and their contents sprinkled on applesauce All methylphenidate products are Schedule II controlled substances

THE NEW FORMULATION — QuilliChew ER is available

as tablets containing 15% methylphenidate HCl and 85% methylphenidate bound to sodium polystyrene sulfonate particles; they contain a mixture of 30% immediate-release and 70% extended-release methylphenidate In a pharmacokinetic study in healthy adults comparing a single 40-mg dose of

QuilliChew ER with two 20-mg doses of

immediate-release chewable methylphenidate, the AUC of

methylphenidate with QuilliChew ER was within the

80% to 125% bioequivalence acceptance standard, but the Cmax was 20% lower and the AUC was 11% lower than those with immediate-release methylphenidate.2

Ciprofloxacin (Otiprio) for

Tympanostomy Tube Insertion

▶

The FDA has approved ciprofloxacin 6% otic

suspension (Otiprio – Otonomy) for single-dose

prophylaxis in children with bilateral otitis media with effusion who are undergoing tympanostomy tube placement It is the first drug to be approved for this indication in the US Otic formulations

of the fluoroquinolone antibiotics ofloxacin

(Floxin Otic, and generics) and ciprofloxacin (plus dexamethasone; Ciprodex) have been available for

years for treatment of acute otitis media in children with tympanostomy tubes; an otic suspension containing ciprofloxacin and fluocinolone acetonide

(Otovel) has recently been approved for the same

indication and will be reviewed in a future issue

TYMPANOSTOMY TUBE INSERTION — The primary

surgical intervention for recurrent acute otitis media and otitis media with effusion in children 6 months

to 12 years old is tympanostomy tube insertion (TTI).1 About 667,000 TTIs are performed annually in the US in children <15 years old.2 TTI reduces middle ear effusion and improves hearing in patients with otitis media with effusion Whether the procedure prevents recurrences of acute otitis media is less clear.3 Otorrhea, primarily due to a bacterial infection, is the most common complication of TTI Tympanostomy tubes can be kept in place for several months or years

Pronunciation Key

Otiprio : oh ti' pree oh

Table 1 Some Long-Acting Methylphenidate Formulations

Drug Formulations Initial/Usual 1 Cost 2

Dexmethylphenidate

Focalin XR 5, 10, 15, 20, 25, 30, 5 mg qAM/ $289.70

(Novartis) 35, 40 mg ER caps 3,4 10-20 mg qAM

generic 5, 10, 15, 20, 30, 40 mg 218.30

ER caps 3,4

Methylphenidate

Metadate CD 10, 20, 30, 40, 50, 20 mg qAM/ 227.00

(UCB) 60 mg ER caps 3,5 30 mg qAM

Ritalin LA 10, 20, 30, 40 mg 10-20 mg qAM/ 242.80

(Novartis) ER caps 3,4 30 mg qAM

generic 20, 30, 40 mg ER caps 3,4 121.20

Concerta 18, 27, 36, 54 mg 18 mg qAM/ 291.30

(Janssen) ER tabs 7 36 mg qAM

Daytrana 10, 15, 20, 30 mg 10 mg qAM/ 303.10

(Noven) transdermal patches 8 30 mg qAM

Quillivant XR 25 mg/5 mL ER 20 mg qAM/ 216.80

(Pfi zer) oral suspension 9 30-40 mg qAM

Aptensio XR 10, 15, 20, 30, 40, 50, 10 mg qAM/ 195.00

(Rhodes) 60 mg ER caps 3 30 mg qAM

QuilliChew ER 20, 30, 40 mg 20 mg qAM/ 270.00

(Pfi zer) chewable tabs 30 mg qAM

ER = extended-release

1 Dosage for children ≥6 years old

2 Approximate WAC for 30 days’ treatment at the lowest usual pediatric

dos-age WAC = wholesaler acquisition cost or manufacturer’s published price to

wholesalers; WAC represents a published catalogue or list price and may not

represent an actual transactional price Source: AnalySource® Monthly May

5, 2016 Reprinted with permission by First Databank, Inc All rights reserved

©2016.www.fdbhealth.com/policies/drug-pricing-policy.

3 Capsules can be either swallowed whole or the contents sprinkled on

applesauce, but should not be crushed or chewed

4 Should not be taken with antacids or other drugs that decrease gastric acidity.

5 Should be taken before breakfast.

6 Only the generic product distributed by Actavis is bioequivalent to the brand

name product.

7 Must be swallowed whole, and not be crushed or chewed

8 The patch should be applied 2 hours before an effect is needed and removed

9 hours after application It may be removed earlier than 9 hours if needed.

9 Quillivant XR must be reconstituted prior to administration and is stable for

up to 4 months It is available in bottles containing 60, 120, 150 or 180 mL

Each bottle is packaged with a bottle adapter and dosing syringe.

CLINICAL STUDIES — Approval of the new formulation

was based on the results of an unpublished,

randomized trial (summarized in the package insert)

in 90 children 6-12 years old with ADHD who were

titrated to an optimal dose (max 60 mg/day) of

QuilliChew ER over 6 weeks, followed by 1 week of

treatment with either the active drug or placebo

After the 1-week treatment period, the children

were evaluated using the SKAMP-Combined score,

which measures ADHD symptoms in a laboratory

school setting, at 7 time points between 0.75 and

13 hours post-dose SKAMP-Combined scores were

signifi cantly better with the active drug than with

placebo at 0.75, 2, 4, and 8 hours post-dosing, but

not at 10, 12, or 13 hours No head-to-head trials are

available comparing the new formulation to other

formulations of methylphenidate or other stimulants

DOSAGE AND ADMINISTRATION — The recommended

starting dosage of QuilliChew ER in patients ≥6 years

old is 20 mg once daily in the morning with or without food The daily dose can be titrated at weekly intervals

by 10, 15, or 20 mg (20- and 30-mg tablets are scored)

to a maximum dose of 60 mg

CONCLUSION — QuilliChew ER, a once-daily

methyl-phenidate chewable tablet, provides another option for children with ADHD who are unable to swallow tablets

or capsules How it compares to other long-acting methylphenidate products in effi cacy and adverse effects remains to be determined ■

1 Drugs for ADHD Med Lett Drugs Ther 2015; 57:37.

2 R Abbas et al Single-dose pharmacokinetic properties and relative bioavailability of a novel methylphenidate extended-release chewable tablet compared with immediate-extended-release methylphenidate chewable tablet Clin Ther 2016 March 24 (epub).

DOSAGE AND ADMINISTRATION — The recommended

dosage of Otiprio is 0.1 mL (6 mg) administered

intratympanically into each affected ear following suctioning of the middle ear effusion

CONCLUSION — Ciprofloxacin 6% otic suspension

(Otiprio), administered intratympanically once into

each ear during placement of tympanostomy tubes in children with bilateral otitis media with effusion, can reduce the incidence of postsurgical otorrhea, and it appears to be safe Its long-term safety and its effect

on bacterial resistance are unknown Comparative trials with systemic or other topical antimicrobials are lacking ■

1 AS Lieberthal et al The diagnosis and management of acute otitis media Pediatrics 2013; 131:e964.

2 RM Rosenfeld et al Clinical practice guideline: tympanostomy tubes in children Otolaryngol Head Neck Surg 2013; 149:S1.

3 IF Wallace et al Surgical treatments for otitis media with effu-sion: a systematic review Pediatrics 2014; 133:296.

4 X Wang et al OTO-201: nonclinical assessment of a sustained-release ciprofloxacin hydrogel for the treatment of otitis media Otol Neurotol 2014; 35:459.

5 EA Mair et al Safety and effi cacy of intratympanic ciprofloxacin otic suspension in children with middle ear effusion undergoing tympanostomy tube placement: two randomized clinical trials JAMA Otolaryngol Head Neck Surg 2016 March 17 (epub).

6 EA Mair et al Randomized clinical trial of a sustained-exposure ciprofloxacin for intratympanic injection during tympanostomy tube surgery Ann Otol Rhinol Laryngol 2016; 125:105.

Table 1 Some Otic Fluoroquinolone Products

Ciprofloxacin 6% – Otiprio2 (Otonomy) 60 mg/1 mL single-use vial 3 0.1 mL in each ear once, intratympanically $283.20 Ciprofloxacin 0.3%/dexamethasone 0.1% – 7.5 mL bottle 4 drops in affected ear bid x 7 days 192.90

Ciprofloxacin 0.3%/fluocinolone acetonide 0.025% – 0.25 mL single-dose vial 5 0.25 mL in affected ear bid x 7 days

Ofloxacin 0.3% 4 – generic 5, 10 mL bottles 5 drops in affected ear bid x 10 days 16.80

N.A = Product is not yet available.

1 Approximate WAC for the smallest-size bottle or vial WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly May 5, 2016 Reprinted with permission

by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

2 FDA-approved for the treatment of children with bilateral otitis media with effusion who are undergoing tympanostomy tube placement.

3 Includes suffi cient syringes and needles to treat both ears.

4 FDA-approved for treatment of acute otitis media in children with tympanostomy tubes.

5 Sold in cartons containing 14 single-dose vials.

PHARMACOKINETICS — Otiprio is a thermosensitive

suspension that is liquid at room temperature, but

gels at body temperature or when warmed In animal

models, a single dose of Otiprio produced a higher

Cmax and AUC of ciprofloxacin than a pulsed course

of Ciprodex; release of ciprofloxacin in the middle ear

continued for as long as 2 weeks.4

CLINICAL STUDIES — Approval of Otiprio was based

on the results of 2 prospective, sham-controlled

trials in a total of 532 children (median age 1.5

years) with bilateral otitis media with effusion who

were randomized to TTI alone or TTI plus Otiprio

The drug was administered as a single dose in each

ear intraoperatively The primary endpoint was the

percentage of treatment failures, defi ned as otorrhea ≥3

days after surgery, need for antibiotics for any reason

at any time post-surgery, or a missed visit or failure

to follow-up At day 15, the percentage of treatment

failures was 24.6% in the Otiprio group vs 44.8% with

TTI alone in the fi rst study and 21.3% vs 45.5% in the

second study; in both studies the differences were

statistically signifi cant Otorrhea occurred in 7% of

patients treated with Otiprio in both trials compared to

11% and 27% of those treated with TTI alone.5

In a randomized, double-blind trial in 83 children with

bilateral middle ear effusion undergoing TTI, treatment

failures occurred in 14.3% and 15.8% of patients

treated with 4 mg and 12 mg of Otiprio, respectively,

and in 45.5% and 42.9% of those treated with placebo

or a sham procedure.6

ADVERSE EFFECTS — In the clinical trials, the only

adverse effects that occurred at a higher rate with

Otiprio than with sham treatment were nasopharyngitis

(5% vs 4%), irritability (5% vs 3%), and rhinorrhea (3% vs

2%) The effect of Otiprio administration on emergence

of bacterial resistance is unknown

Online Only Article

Three New Drugs for Multiple Myeloma

www.medicalletter.org/TML-article-1495d

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e70

on Drugs and Therapeutics

The FDA recently approved ixazomib (Ninlaro –

Takeda), daratumumab (Darzalex – Janssen Biotech),

and elotuzumab (Empliciti – BMS) for treatment of

relapsed and/or refractory multiple myeloma

dexamethasone with lenalidomide, dexamethasone, and placebo in 722 patients who had relapsed and/or refractory multiple myeloma The median duration of progression-free survival, the primary endpoint, was signifi cantly longer with ixazomib (20.6 months vs 14.7 months) The overall response rate was 78% with ixazomib and 72% with placebo.6

Adverse Effects – Diarrhea was the most common

non-hematologic adverse event; grade 3 diarrhea occurred in 23 patients (6%) taking ixazomib and in

9 (3%) taking placebo Hematologic events included grade 3 and 4 thrombocytopenia (12% and 7%) and neutropenia (18% and 5%), and grade 3 anemia (9%)

Drug Interactions – Coadministration of strong CYP3A

inducers with ixazomib should be avoided.7

DARATUMUMAB (DARZALEX) — Daratumumab, an

intravenous human monoclonal antibody that targets the transmembrane glycoprotein CD-38, which is overexpressed on myeloma cells, is approved for use in patients with multiple myeloma who received

≥3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory drug or who are double-refractory to a proteasome inhibitor and an immunomodulatory drug

Clinical Studies – Approval of daratumumab was based

on the results of 2 open-label monotherapy trials in 42 and 106 heavily pretreated patients; overall response rates were 36% and 29%, respectively The median duration of progression-free survival was 5.6 and 3.7 months In the smaller study, 65% of responders did not have disease progression at one year.8,9

Adverse Effects – Serious adverse effects, which

occurred in 33% of patients, included infusion reactions, pneumonia, hypertension, and grade 3-4 anemia, lymphopenia, neutropenia, and thrombocytopenia

ELOTUZUMAB (EMPLICITI) — Elotuzumab, the second

intravenous monoclonal antibody to receive approval for use in patients with relapsed or refractory multiple myeloma (1-3 prior therapies), targets signaling lymphocytic activation molecule family member 7 (SLAMF7), which is expressed on myeloma cells

Three New Drugs for Multiple

Myeloma

▶

Pronunciation Key Ixazomib: ix az' oh mib Ninlaro : nin lar' oh

Daratumumab: dar" a toom' ue mab Darzalex : dar' zah lex

Elotuzumab: el" oh tooz' ue mab Empliciti : em plis city

STANDARD TREATMENT — Use of drug regimens that

include the proteasome inhibitor bortezomib (Velcade)

plus either the immunomodulating drug thalidomide

(Thalomid) or lenalidomide (Revlimid), a thalidomide

analog, instead of chemotherapy has led to improved

response rates and survival in patients with multiple

myeloma

Carfi lzomib (Kyprolis), a second proteasome inhibitor,

is an alternative for treatment of refractory multiple

thalidomide analog, is an alternative for patients

with disease progression who have received at

least two prior therapies including lenalidomide

histone deacetylase inhibitor, in combination with

bortezomib and dexamethasone is another option for

patients who have received at least two prior therapies

including bortezomib and an immunomodulatory

drug.3 Many patients discontinue these drugs due to

lack of response or toxicity; most who respond initially

subsequently relapse, and with each relapse the

disease becomes more resistant to treatment.4

IXAZOMIB (NINLARO) — Ixazomib, the only oral

proteasome inhibitor available in the US, is approved

by the FDA for use in combination with lenalidomide

and dexamethasone for treatment of patients with

multiple myeloma who were previously treated with at

least one other regimen.5

Clinical Studies – Approval of ixazomib was based

on the results of a randomized, double-blind

trial comparing ixazomib plus lenalidomide and