Antibiotic use in Hospitals

                                           Dr. KS Dhillon

Introduction

The last 60 plus years have witnessed the golden age of antibiotic discovery and their widespread use in hospitals. Many of the antibiotics available are regarded as very effective, safe, and relatively inexpensive. They have saved millions of lives. This availability of many antibiotics, however, has led to their misuse, leading to bacterial resistance.

There is a need to optimize antimicrobial use so as to slow the spread of resistant pathogens.

There is a dire need for hospitals to implement antimicrobial stewardship programs with the aim of improving antimicrobial use to optimize infection cure rates and minimize harm [1].

Most often efforts to evaluate antimicrobial stewardship programs’ effect on hospital antibiotic use focus on volume rather than prescribing quality [2,3,4]. It is, however, not known whether the volume of antimicrobial use correlates with the appropriateness of antibiotic use [5].

Prescribing decisions for patients in hospitals are associated with several factors, including allergies, comorbidities, adverse effects, and drug interactions.

Evaluating the appropriateness of hospital antimicrobial use is challenging. 

Evaluation of the appropriateness of antibiotic use is lacking in most hospitals. Hospital antimicrobial stewards usually perform intensive, small-scale antibiotic use evaluations to answer specific questions about the appropriateness of antibiotic use. Larger scale evaluations are usually more difficult to conduct.

Inappropriate antibiotic use in hospitals

Antibiotic use in hospitals is common and unfortunately frequently inappropriate. For several decades now it has been known that up to 50% of antimicrobial use is inappropriate [6].

Hecker et al [7] carried out a prospective observational study to evaluate the current pattern of misuse (unnecessary use) of antimicrobials in hospitalized patients. The study included all adult nonintensive care inpatients for whom new antimicrobials were prescribed during a 2-week period. They found that a total of 1941 antimicrobial days of therapy were prescribed for 129 patients. Thirty percent of the therapy was deemed unnecessary.

Administration of antimicrobials for longer than the recommended duration (192 days of therapy) was the most common reason for unnecessary therapy (33%). Other reasons included administration of antimicrobials for noninfectious or nonbacterial syndromes (32%) and treatment of colonizing or contaminating microorganisms (16%). The use of antianaerobic agents accounted for 35% of the unnecessary antimicrobial therapy, and these agents were frequently prescribed when equally efficacious alternative agents with minimal antianaerobic activity were available.

Magill et al [8] carried out a study to assess the appropriateness of antimicrobial use in US hospitals. Their aim was to evaluate the appropriateness of antimicrobial use for patients who were hospitalized for treatment of community-acquired pneumonia (CAP) or urinary tract infection (UTI) present at admission or for patients who had received fluoroquinolone or intravenous vancomycin treatment [8].

They found that overall, treatment was unsupported (inappropriate) for  55.9% of the patients. It was unsupported in 27.3% of the patients who received vancomycin, 46.6% in those who received fluoroquinolones, in 76.8% of those with a diagnosis of UTI, and in 79.5% in those with a diagnosis of CAP. The common reasons for unsupported treatment included excessive duration (59.2% patients with CAP) and lack of documented infection signs or symptoms (50.1% patients with UTI). 

The Australian Commission on Safety and Quality in Health Care in 2018 carried out a Hospital National Antimicrobial Prescribing Survey (NAPS) throughout Australia in both government and private hospitals. The survey showed that antimicrobials with the highest rates of inappropriate prescribing were: cefalexin, cefazolin, azithromycin, amoxicillin-clavulanic acid, and metronidazole. The survey also showed that the five most common indications for prescribing antimicrobials were surgical prophylaxis, community-acquired pneumonia, medical prophylaxis, cystitis, and cellulitis/erysipelas.  The highest proportions of prescriptions assessed as inappropriate were for chronic obstructive pulmonary disease (COPD), surgical prophylaxis, non-surgical wound infections, community-acquired pneumonia, and cystitis [9].

Trivedi et al [10] carried out a multicenter assessment of antibiotic appropriateness in 47 ICUs in the USA. The study included 667 patients in 47 ICUs. Three hundred and two patients (54%) were on antibiotics. The incidence of inappropriate antibiotic use was found to be 31%. The reasons for inappropriate antibiotic use included no infection or nonbacterial syndrome (22%), unnecessarily broad-spectrum (29%), and duration longer than necessary (21%). 

Generally, suboptimal or inappropriate antibiotic prescribing includes overly broad coverage, excessively long treatment, duplicate treatment, failure to de-escalate on the basis of microbiology test results, antimicrobial use when antimicrobials are not required and selection of antimicrobial where the dose, route, or duration is unlikely to treat the pathogen or the likely pathogen [9].

Rising threat of antimicrobial resistance

When antibiotics were first discovered they were called "miracle" drugs which saved millions of lives. Now we face a dramatic challenge as a result of two combined problems. First, bacteria are becoming extremely resistant to existing antibiotics, particularly, Gram-negative rods which are resistant to most of the currently available antibiotics in some settings. Second, there are no new antibiotics in the pipeline [11]. 

In the last few years several new powerful compounds active against Gram-positive cocci have become available, but this is not so for Gram-negative bacteria and there are almost no new antibiotic class active against multiresistant Gram-negative rods. None can be anticipated in the near future. Many doctors are likely to face a therapeutic dead-end in the treatment of certain types of severe bacterial infections. Such a situation will take us back to the pre-antibiotic era of the 1930s and early 1940s [12].

Over the last few years, several alarming facts regarding antimicrobial resistance (AMR) have become known [12]. These include:

• There has been an increase in global resistance rates in many bacterial species such as staphylococci, gonococci, enterococci,  enterobacteria (E. coli, Salmonella, and Shigella), Pseudomonas, Acinetobacter, and Mycobacterium tuberculosis.
• The burden of bacteremias due to E. coli (most common human pathogens) is increasing in Europe, partly due to resistant strains.
• New mechanisms of resistance have emerged and have disseminated. These include extended-spectrum beta-lactamases (ESBL) and carbapenemases. There now exist new resistance genes such as the New Delhi metallo-beta-lactamase 1 (NDM-1) and other carbapenemases in Enterobacteriacae. These "superbugs" are resistant to most available antibiotics and can disseminate around the world very rapidly. 
• Although there has been a rapid increase in the multi-resistance of Gram-negative rods, there has been a steady decrease in methicillin-resistant Staphylococcus aureus (MRSA) rates in many countries due to successful infection control programmes.  In other countries, resistance to both Gram-positive and Gram-negative bacteria is very high. There also other countries with vancomycin-resistant enterococci.
• There is a propensity to use last-line therapy (e.g., carbapenems) to treat infections. This is triggered by a fear of infections caused by ESBL-producing Enterobacteriaceae. These antibiotics should, in fact, be preserved as the last weapons for use against multiresistant Gram-negative bacterias.
• Due to the lack of alternative drugs, old drugs with poor safety and efficacy profiles and uncertain pharmacokinetic/pharmacodynamic characteristics (e.g., colistin) are used.
• Multiresistant bacteria in critically ill patients cause high morbidity and mortality. The European Centre for Disease Prevention and Control (ECDC) reported that in Europe 25,000 people die each year from antibiotic-resistant bacteria [13]. In the USA, there are 90,000 MRSA infections with an estimated 19,000 deaths annually [14].
• Serious financial consequences of bacterial resistance. The healthcare costs and productivity losses due to bacterial resistance is at least 1.5 billion euros each year in Europe [13]. The annual cost of AMR in hospitals in the USA is estimated at more than US$ 20 billion [15]. 

Morbidity, mortality, and the associated economic burden from AMR is very likely to increase dramatically during the next decade [16]. Due to financial crises in many countries in the world, massive cuts in healthcare expenditure and medical research can result in further spread of multiresistant bacteria in hospitals around the world.

The major cause of this frightening evolution is the massive overuse of antibiotics worldwide over the past decades. Excess antibiotics are used particularly for common colds and upper respiratory tract syndromes that are mostly of viral origin. Self-medication, an important driver of antibiotic overuse, is common in many developing countries where antibiotics can be bought over the counter in pharmacies. 

These resistant bacteria can be exchanged via travel activities and patient transfers leading to a rapidly growing "resistance globalization" [12].

At the same time, the antibiotic pipeline is drying up for the following reasons. Firstly it is difficult to find new antibiotics with novel mechanisms of action and secondly a high cost/benefit and risk/benefit ratio discourage pharmaceutical companies from investing in the research and development of new antibiotics. 

Improved diagnosis, education, and legislation can reduce antibiotic consumption. A sustained, multifaceted, community-level intervention can help reduce overall antibiotic use [17]. 

Patients can and should have a very active role in making healthcare safer. In many countries, national campaigns have been launched to educate patients and physicians about antimicrobial misuse and the threat of resistance.

Every hospital should have an antibiotic stewardship program. These programs are dedicated to improving antibiotic use and are commonly referred to as Antimicrobial Stewardship Programs (ASPs). They can both optimize the management of infections and reduce adverse events associated with antibiotic use.

It is important to implement antibiotic stewardship programs around the world. There should be a multidisciplinary approach aimed at the optimal selection, dosage, and duration of antimicrobial treatment that would result in the best clinical outcome for the treatment and prevention of infection with least toxicity to the patient, and least impact on subsequent bacterial resistance. 

Besides the diagnosis, the reason for the prescription and the planned duration of therapy should be indicated on every patient chart. 

An international programme should be able to markedly decrease the overall consumption of antibiotics in humans. There is a need for a strong and sustained cooperation between healthcare professionals and antibiotic users.  All antibiotic prescribers must work together to ensure the success of these programmes.

Strategies for correct antibiotic prophylaxis [18]

Antibiotics alone cannot prevent surgical site infections. Attention to infection and prevention control strategies including correct hand hygiene practices are important strategies to prevent surgical site infections. Other strategies include meticulous surgical techniques and minimization of tissue trauma, clean hospital and operating room environments, proper instrument sterilization processes, targeted glycemic control, and appropriate management of surgical wounds.

Prophylactic antibiotics should be used for operative procedures that have a high rate of postoperative surgical site infection, or when implants are inserted.

Prophylactic antibiotics should be effective against both aerobic and anaerobic bacteria most likely to contaminate the surgical site such as Gram-positive skin commensals or normal flora colonizing the mucosa that is to be incised.

Prophylactic antibiotics should be administered within 120 min prior to the incision. However, for most antibiotics, it is recommended that the first dose should be administered within 30–60 min before the surgical incision is made. This is to ensure an adequate serum and tissue concentration of antibiotics during the period of potential contamination. Obese patients will require higher doses of antibiotics.

A single dose of antibiotic is usually sufficient. Additional antibiotic doses need to be administered intraoperatively for procedures that last more than 2–4 hours and when there is significant blood loss (more than 1.5 L).

There is no evidence that postoperative antibiotic prophylaxis is of any value. Every institution should have guidelines for proper surgical prophylaxis.

Strategies for correct antibiotic therapy [18]

The source of infection should be identified and controlled as soon as possible. Empirical antibiotic therapy should be started after the infection is detected. Microbiological data (culture and sensitivity results) will only be available after 48–72 hours to guide the targeted therapy.

In patients who are critically ill, empiric broad-spectrum therapy which will cover all likely pathogens should be started as soon as possible once the infection is recognized. This empiric antimicrobial therapy should be narrowed once the culture and sensitivity results are available and there is adequate clinical improvement. 

Empirical therapy is chosen based on local epidemiology, clinical severity, individual patient risk factors for multidrug-resistant bacteria, and infection source.

Specimen, for culture and sensitivity, from the site of infection should always be taken for patients with hospital-acquired or with community-acquired infections at risk for resistant pathogens. This would be in patients with previous antimicrobial therapy, prior infection, or colonization with multidrug-resistant pathogens. 

Blood cultures should be taken before the administration of antibiotics in critically ill patients.

The dosages of antibiotics should be optimized to make sure that pharmacodynamic-pharmacokinetic targets are achieved.

The need for and appropriateness of the antibiotic treatment should be reassessed on a daily basis.

Once the source of infection has been controlled, short courses of antibiotic therapy are as effective as longer courses regardless of the fact that signs of inflammation are still present. 

For intra-abdominal infections, 4 days of antibiotics are as effective as 8 days in moderately ill patients [19]. For bloodstream infections, 5 to 7 days of antibiotics are as effective as 7 to 21 days for most patients [20]. For ventilator-associated pneumonia, 8 days of antibiotics are as effective as 15 days [21,22].

When there is failure of antibiotic therapy in patients having active infection a re-operation to clear the infection would be required.

Use of biomarkers such as procalcitonin may be useful to guide the duration and/or cessation of antibiotic therapy in critically ill patients.

The infection prevention and control (IPC) measures combined with ASPs should be implemented in clinical departments. These programs and interventions require regular, systematic monitoring to assess compliance and efficacy.

Antibiotic consumption should be monitored and feedback provided to all ASP team members on a regular basis (e.g. every 3 to 6 months). Data on resistance surveillance and outcome measures should also be provided.

Conclusion

We have overused and abused antibiotics not only in humans but also in animals with huge variations between countries [23]. Now regular and precise barometers to survey resistance levels and antibiotic consumption are available to us [24]. Bacterial resistance to antibiotics has reached levels that place the human race in real danger. There is a worldwide need for immediate, vigorous, and coordinated measures to be taken to save and protect the erosion of existing antibiotics and at the same time facilitate the discovery of new and potent antibiotics, active in particular against Gram-negative bacilli [25,26]. To achieve this there is a need for profound change in the way we diagnose and treat bacterial infections [27]. There is a dire and urgent need for educational programmes targeting both healthcare professionals and consumers, including children. The real key to success is strong cooperation and complicity between healthcare professionals (including researchers) and consumers. 

Reference

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