Antimicrobial Stewardship

Principles and Practice

Kerry LaPlante, Cheston Cunha, Haley Appaneal, Louis Rice, Eleftherios Mylonakis, Kerry LaPlante, Cheston Cunha, Haley Morrill, Louis Rice, Eleftherios Mylonakis

• Publisher: CAB International
• Year: 2016
• ISBN:
  9781786390530
• Topic: Medicine
• Subtopic: Medical Microbiology & Parasitology

In an age where antimicrobial resistance amongst pathogens grows more prevalent, particularly in the hospital setting, antimicrobial stewardship is an evidence-based, proven measure in the battle against resistance and infection. This single comprehensive, definitive reference work is written by an international team of acknowledged experts in the field. The authors explore the effective use of coordinated antimicrobial interventions to change prescribing practice and help slow the emergence of antimicrobial resistance, ensuring that antimicrobials remain an effective treatment for infection. Amongst the first of its kind, this book provides infectious disease physicians, administrators, laboratory, pharmacy, nursing and medical staff with practical guidance in setting up antimicrobial stewardship programs in their institutions with the aim of selecting the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration.

1 Principles of Antimicrobial Stewardship

CHESTON B. CUNHA^*

Rhode Island Hospital, Providence, Rhode Island, US

^* E-mail: [email protected]

Introduction

Antimicrobial Stewardship (or Antibiotic Stewardship) Programs (ASPs) have become the mechanism to optimize antimicrobial therapy within hospitals. There are many components of an ASP and these require the support and enthusiastic participation of the Infectious Disease Division, one or more Infectious Disease-trained Doctors of Pharmacy (PharmD), the Pharmacy Department, Microbiology Laboratory, and Infection Control (IC). These components should be organized under an ASP Program Director, an Infectious Disease clinician, with the requisite interpersonal, diplomatic, and organizational skills to assure ASP implementation and coordination to achieve its goals (Doron and Davidson, 2011; Hand, 2013) There is no pro forma structure for ASP programs as each hospital has its own ASP challenges. Each ASP, under the leadership and guidance of the Infectious Disease ASP Director, should tailor the ASP to the needs of the institution, i.e., some hospitals have problems with multidrug-resistant (MDR) Gram-negative bacilli, others have methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) concerns, and still others have problems with Clostridium difficile infections (Cunha et al., 2013). An essential element in a successful ASP is medical staff education. Medical staff education efforts need to be ongoing and periodically to focus on different topics so as to continually reinforce basic ASP principles. Aside from the major ASP problem areas among all institutions, each hospital, in this era of limited economic resources, certainly needs and can justify an ASP on the basis of cost savings alone. The economic advantages of a well configured and executed ASP cannot be overestimated. Therefore, whether the hospital has major ASP challenges with the nosocomial problems mentioned or not, the economic benefits of ASPs should not be underestimated (Fraser et al., 1997).

ASP Principles of Optimal Antibiotic Therapy

There are several key tenets of ASPs, which begin with optimal antibiotic utilization. The inappropriate or unnecessary utilization of antibiotics to treat either nonbacterial infections, e.g., viral infections, or those with fever and leukocytosis and mimicking a bacterial infection. Many antibiotic days are wasted treating “fever and leukocytosis” of nonbacterial origin and this is a needless waste of institutional resources. Aside from wasting valuable hospital resources, unnecessary antibiotic treatment also comes with the potential perils of unwanted side effects, e.g., hematologic adverse events (AEs) or antibiotic-related complications, e.g., C. difficile. Another area where antimicrobial therapy is unwarranted and potentially harmful is in the unnecessary treatment of “colonizers” in respiratory secretions, nonpurulent wounds, or urine in those with indwelling urinary catheters. Treating colonization is unnecessary and, in general, it is more difficult to eradicate than infection due to the same organism. The problem with needlessly “covering” colonizers in body fluids is that these organisms are often of the MDR variety and the prolonged treatment associated with trying to eradicate such pathogens is frequently complicated by the subsequent development of further antimicrobial resistance (Lutters et al., 2004).

The next consideration in selecting appropriate antibiotics is to take into account the spectrum of activity of the antibiotic against the known or presumed pathogen, which is related to the flora of the anatomical site of infection. All too often, clinicians use “broad spectrum” antimicrobial therapy in a “shotgun” approach regardless of anatomical location. The pathogens responsible for various intra-abdominal infections (IAIs) depend on the resident flora, which becomes the pathogenic flora in different locations in the gastrointestinal (GI) tract. Gastric and small bowel pathogens are different from biliary pathogens, which are yet again different from liver/colon pathogens. The antibiotic chosen should have the appropriate spectrum of activity and a high degree of activity against the presumed pathogens from the anatomical site of infection. The use of an antibiotic with an incorrect spectrum of activity results in suboptimal therapy or in the selection of organisms not covered by the antibiotic, e.g., MRSA, VRE (Weiss et al., 2011).

Pharmacokinetic (PK) principles are important in dosing, but are critical in assessing antibiotic penetration at the site of infection. Tissue serum PK principles, i.e., serum/tissue concentration gradient, lipid solubility, pK_a, local pH, and estimated local tissue concentrations should be considered by the Infectious Disease consultant. Infectious disease consultation should be obtained in such difficult cases because of the interaction of multifactorial factors based upon PK principles. However, prescribing without the knowledge of the importance of PK factors may predispose to either therapeutic failure or antibiotic resistance at the site of infection (Cunha et al., 2013).

It should be obvious that the shortest duration of antimicrobial therapy that eliminates the infection should be used, although in practice quite the opposite frequently occurs. All too often antibiotics are continued for additional days after infection has resolved. Shorter durations of therapy are clearly associated with decreased costs to the institution. In patient terms, a shorter course of therapy means a shorter length of stay (LOS) with less antibiotic exposure and less potential for AEs as well as increased antibiotic resistance potential (Pinzone et al., 2014; Pogue et al., 2014).

ASP Strategies for Optimal Antibiotic Therapy

Restricted formulary

The single most important component in optimizing antimicrobial therapy is formulary restriction. Formulary restriction limits antibiotic selection to preferred antibiotics based on their “low resistance potential,” safety profile, and C. difficile potential. It is well known that the use of certain antibiotics predisposes to certain pathogens, e.g., intravenous vancomycin exerts a selective pressure on the enterococcal fecal flora, resulting in the emergence of VRE. Because there are fewer options to treat VRE than vancomycin-susceptible enterococci (VSE), it makes sense in an ASP program to educate the staff in minimizing the use of antibiotics that promote the emergence of VRE in the fecal flora at the expense of a decreased VSE population. Similarly, with MRSA, the use of some antibiotics is associated with an increased MRSA colonization, e.g., ceftazidime, and the control of MRSA begins by avoiding antibiotics that predispose to increased MRSA prevalence. The other part of MRSA containment in hospital is based on effective IC containment measures. Patients with MRSA admitted from the community introduce MRSA to hospital, and containing the intrahospital spread of MRSA from colonized/infectious patients depends entirely upon effective IC containment measures (Hayman and Sbravati, 1985; Pulcini and Gyssens, 2013; Reed et al., 2013).

Minimizing emergence of multidrug-resistant Gram-negative bacilli

Another important ASP goal is to minimize the emergence of MDR Gram-negative bacilli (GNBs). Different hospitals have different problems with different organisms and the approach should be tailored to local epidemiologic concerns. In general though, the ASP operating principle is that antibiotics with a “low resistance potential,” i.e., the development of resistance is fairly independent of volume and duration of use, are relatively unlikely to result in MDR GNBs. In contrast, other antibiotics with a “high resistance potential,” even with limited use, have been associated with the emergence of MDR GNBs, e.g., imipenem, ceftazidime, gentamicin/tobramycin, ciprofloxacin. Within each antibiotic class, there are one or more “low resistance potential” alternatives for use by medical staff, e.g., instead of imipenem, meropenem, doripenem, or ertapenem may be used, in place of ceftazidime, cefepime or amikacin may be used, and in place of ciprofloxacin, levofloxacin or moxifloxacin may be utilized (Cunha, 1998, 2000, 2003; Pulcini et al., 2014).

Major Problems of ASPs

Antibiotic resistance

Major control of antibiotic resistance depends not on antibiotic class, antibiotic volume (tonnage), or duration of antibiotic use, but rather primarily on the widespread use of “high resistance potential” antibiotics, e.g., ciprofloxacin (re: Streptococcus pneumoniae, Pseudomonas aeruginosa) vs. levofloxacin or moxifloxacin; imipenem (re: P. aeruginosa) vs. meropenem, doripenem, gentamicin, or tobramycin (re: P. aeruginosa) vs. amikacin; ceftazidime (re: P. aeruginosa) vs. cefepime or other 3rd generation cephalosporins; macrolides (re: S. pneumoniae) vs. doxycycline.

The antibiotics with “low resistance potential” cited above should be used preferentially over their “high resistance potential” counterparts. Another aspect of controlling resistance has to do with untoward collateral effects not causing resistance per se but related to causing changes in the flora from susceptible to more resistant organisms; e.g., the use of vancomycin does not cause an increase of enterococci resulting from colonization by VRE, but the intravenous use of vancomycin inhibits/eliminates VSE, which are normally the predominant species in bowel flora, so resulting in an increase in the number or emergence of more VRE. Similarly, the widespread use of some antibiotics predisposes to other unrelated resistant organisms; e.g., the use of ceftazidime inhibits/decreases methicillin-susceptible S. aureus (MSSA) in respiratory secretions in ventilated patients, leading to colonization of respiratory secretions by MRSA (Cunha, 2000, 2003).

It is a common misconception that antibiotic resistance is related to a high volume or duration of use of common antibiotics. This misconception of resistance is that over time, e.g., years of use, resistance is inevitable, leading to a lack of effective antibiotics over time. Even modest use or modest use of antibiotics over decades will lead to resistance or worsening resistance, but this occurs only with “high resistance potential” antibiotics. High volume use over years of “low resistance potential” antibiotics, e.g., ceftriaxone, doxycycline, amikacin, or nitrofurantoin, has not led to meaningful resistance problems. Unless these concepts are understood and implemented, the success of any ASP in trying to control antibiotic resistance will be limited accordingly (Cunha, 1998, 2001, 2003). Formulary restriction helps selective antibiotic prescribing to minimize the emergence of resistant pathogens, i.e., VRE, MRSA, and MDR GNBs. If, in the rare cases when there are situations when only a “high resistance potential” antibiotic is requested for a specific one time use, then this is within the purview of the ASP Stewardship Director.

If the approach of the ASP to try to control antibiotic resistance is by restricting the use of certain drug classes, e.g., 3rd generation cephalosporins, carbapenems, or quinolones, such efforts are doomed to failure unless it is understood that individual agents, within each...