Antibiotics - Microbes - US Dilemma

Dr.Khaled AlazzazyMBBCH,

Dip. Internal Medicine, Dip.Cardiology,

MRCP (UK) SPECIALIST INTERNAL MEDICINE

DEPUTY HEAD OF ICU AL-ZAHRA PRIVATE HOSPITAL- SHARJAH

Disclosure:

non

Case scenario

A 62 years old female Pt. presented with SOB, was found to have pulmonary edema due to decompensated heart failure EF 45%.

H/O DM2, HTN, IHD. not compliant with medications No evidence of current myocardial Ischemia Bp 150/95 Received Frusemide IV, Nitrates, NIV. Other heart failure measures Urinary bladder was catheterized for 3 days . Was discharged from hospital on 4th day with no C/O.

After another 4 days she came back with tachypnea, Dyspnea and fever.

O/EFever 39C, Bp 85/50 Pulse 130 bpm sinus. O2 sat 91% room air.RR 29 / min.ECG: sinus tachy. onlyDrowsy, cold clammy skin, capillary hypo perfusion.Chest : Just few scattered secretions

ABG: PH 7.29 Pco2 26 Po2 69 Hco3 18 O2sat 96 %WBCs 19,000, CRP 250 , Procal. 3

Diagnosis?

1-Decompensated heart failure again!2-Septic shock.3-Drug induced hypotension.4-Cardiogenic shock.

Septic Shock Septic Shock

Simply!

IV lines (2 Large ones) IVF, C/S and Lactate level + CBC, CRP, Procalcitonin, RFT, LFT, Coagulation. IV antibiotics within 1-3 hours( ceftazidime,Cefepime, Pipra/Tazobactam, Carbapenem)(Meropenem was started 1 g IV infusion over 3 hours / 8 hours)

Why She had developed Septic Shock?

Pneumonia?UTI?Septicemia?

Urinary Catheter insertion

Evidence!

Urine and Blood cultures came back with Gram Negative rods; E.coli. Sensitive to ;-Amikacin-Ceftazidime-Meropenem-Cefepime

Hospital Acquired Infection(HAI) Aka Nosocomial Infections.

Is it nosocomial infection or not?

HAI

Definition

HAI or Nosocomial infections can be defined as thoseoccurring within 48 hours of hospital admission OR 3 days of discharge OR 30 days of an operation.

HAI Definition

HAI infection” can be defined as:

An infection acquired in hospital by a patient who was admitted for a reason other than that infection (1).

An infection occurring in a patient in a hospital or other healthcare facility in whom the infection was not present or incubating at the time of admission.

This includes infections acquired in the hospital but appearing after discharge, and also occupational infections among staff of the facility (2).

1. Ducel G et al. Guide pratique pour la lutte contre l’infection hospitalière. WHO/BAC/79.1.2. Benenson AS. Control of communicable diseasesmanual, 16th edition. Washington, American Public Health Association, 1995.

So it was a Nosocomial infection!

HAI Is it a big deal?

Hospital acquired infections (HAIs) is a major safety concern for both health care providers and the patients.

Considering morbidity, mortality, increased length of stay and the cost, efforts should be made to make the hospitals as safe as possible by preventing such infections.

Indian J Crit Care Med. 2014 Mar; 18(3): 149–163

Nosocomial Infections

In UK, They affect 1 in 10 patients admitted to hospital each year. results in 5000 deaths with a cost a billion pounds. 2.5-timeslonger in hospital, incurring additional costs of £3000 more than an uninfected patient Intensive care units (ICU) have the highest prevalence of hospital-acquired infections . The European Prevalence of Infection in Intensive Care Study (EPIC), demonstrated that; The nosocomial infection prevalence rate in ICU was 20.6%

Nosocomial infections, Oxford Journals Medicine & Health BJA: CEACCP Volume 5, Issue 1Pp. 14-17

Nosocomial InfectionsIN USA It is estimated that in 2002, A total of 1.7 million hospital-acquired infections occurred (4.5 per 100 admissions), and almost 99,000 deaths resulted from or were associated with a hospital-acquired infection.

making hospital-acquired infections the sixth leading cause of death in the United States.

The estimated costs to the U.S. health care budget are $5 billion to $10 billion annually.Approximately one third or more of hospital-acquired infections are preventable.

N Engl J Med. 2010 May 13; 362(19): 1804–1813. doi:10.1056/NEJMra0904124

.

Nosocomial infection European CDC 2008

In Europe Approximately 4.1 million patients are estimated to acquire a healthcare-associated

infection in the EU each year.

The number of deaths is estimated to be at least 37 000 and these infections are thought to contribute to an additional 110 000 deaths each year.

The most frequent infections are urinary tract infections, followed by respiratory tract infections, infections after surgery, bloodstream infections, and others (including diarrhea due to Clostridium difficile). Methicillin-resistant Staphylococcus aureus (MRSA) is isolated in approximately 5% of all healthcare-associated infections.

http://ecdc.europa.eu/en/healthtopics/Healthcare-associated_infections/Pages/index.aspx#sthash.umXzAeOl.dpuf

Nosocomial infections Components

Phlebotomy Handbook: Blood Collection Essentials, Seventh EditionDiana Garza • Kathleen Becan-McBride

Nosocomial Infections Predisposing factors Nosocomial infections, Oxford Journals Medicine & Health BJA: CEACCP Volume 5, Issue 1Pp. 14-17

Related to underlying health status

Related to acute disease process

Related to invasive procedures

Related to treatment

Advanced age Surgery Endotracheal or nasal intubation Blood transfusion

Alcoholism Burns Extracorporeal renal support Recent antimicrobial therapy

Heavy smoking Trauma Surgical drains Immunosuppressive treatments

Chronic lung disease Tracheostomy Stress-ulcer prophylaxis

Diabetes Urinary catheter Recumbent position

Nasogastric tube Parenteral nutrition and Length of stay

Nosocomial Infections main Types

Pneumonia; VAP, HCAP Blood stream infections, CRBSI Urinary tract infections (UTI) Surgical site infections (SSI) Others e.g. diarrhea (Hospital-acquired infections are most commonly associated with invasive medical devices or surgical procedures.Lower respiratory tract and bloodstream infections are the most lethal; however, urinary tract infections are the most common)

N Engl J Med. 2010 May 13; 362(19): 1804–1813. doi:10.1056/NEJMra0904124.

Which Organism?!

HAI

HAIThe Proportion of the Microorganisms Isolated as Causative Agents for Hospital-Acquired Infections in Zahedan, 2013-2014

Acinetobacter species were the most common type of pathogen isolated from HAI patients with bloodstream infection and pneumonia . E. coli was the prominent causative agent for urinary tract infections in HAI cases

Nosocomial infection G-Negative bacteria.

Recent data from the U.S. National Healthcare Safety Network indicate that; Gram-negative bacteria are responsible for more than 30% of hospital-acquired infections. They are predominate in cases of VAP (47%) Urinary tract infections (45%). In intensive care units (ICUs) in the United States, gram-negative bacteria account for about 70% of these types of infections, Similar data are reported from other parts of the world.

N Engl J Med. 2010 May 13; 362(19): 1804–1813. doi:10.1056/NEJMra0904124

Nosocomial Frequent organisms in Europe

The most frequently isolated microorganisms in HAIs were: Escherichia coli (15.9%), Staphylococcus aureus (12.3%), Enterococcus species (9.6%), Pseudomonas aeruginosa (8.9%), Klebsiella species (8.7%), coagulase-negative staphylococci (7.5%), Candida species (6.1%), Clostridium difficile (5.4%), Enterobacter species (4.2%), Proteus species (3.8%) and Acinetobacter species (3.6%).

http://ecdc.europa.eu/en/healthtopics/Healthcare-associated_infections/point-prevalence-survey

HAI G- Negative organism problem!

Infections caused by gram-negative bacteria have features that are of particular concern. These organisms are highly efficient at up-regulating Or acquiring genes that code for mechanisms of antibiotic drug resistance, Especially in the presence of antibiotic selection pressure. Furthermore, they have available to them a plethora of resistance mechanisms, Often using multiple mechanisms against the same antibiotic Or using a single mechanism to affect multiple antibiotics

Hospital-Acquired Infections Due to Gram-Negative Bacteria

Anton Y. Peleg, M.B., B.S., M.P.H. and David C. Hooper, M.D.

N Engl J Med. 2010 May 13; 362(19): 1804–1813.

HAI G-Negative Bacteria

Mechanisms of Resistance in Gram-Negative Bacteria, and the Antibiotics Affected

Hospital-Acquired Infections Due to Gram-Negative Bacteria, Anton Y. Peleg, M.B., B.S., M.P.H. and David C. Hooper, M.D.N Engl J Med. 2010 May 13; 362(19): 1804–1813

HAI G-Negative bacteria perfect storm!

Due to antimicrobial resistance and decline in production of new antibiotics; treatment of that kind of infection has become medical problem.

Several factors have contributed to this decline, Such as:- -increasing challenges of screening for new compounds, -the high capital costs and long time required for drug development, -the growing complexity of designing and performing definitive clinical trials, -the concern about reduced drug longevity due to the emergence of resistance. As a consequence, a perfect storm has been created with regard to these infections:

increasing drug resistance in the absence of new drug development.

HAI What is the plan?!

Prevention.

Prevention.Prevention. Treatment.

HAI Prevention General rules

General rules:- Hand hygiene: Poor hand hygiene is responsible for 40% of infections transmitted in hospitals. Protective garments: are necessary for health providers exposed to body fluids, for example sweat,

oropharyngeal fluids, blood or urine. (Gloves and aprons). High efficiency particulate air (HEPA) filter masks for sputum smear positive patients with

tuberculosis, particularly for cough-inducing procedures. Antimicrobial impregnated catheters can reduce catheter related infections Strict, aseptic technique is paramount in the insertion of intravascular catheters isolation rooms for patients with MRSA, C. difficile, VRE and resistant Gram-negative infections. High-quality cleaning and disinfection of all patient-care areas is important, especially surfaces close

to the patient (e.g. bedrails, bedside tables, doorknobs and equipment).

HAI World Health Organization's five moments for hand hygiene.

Before touching a patient. Before aseptic procedures. After body fluid exposure/risk. After touching the patient. After touching the patient's surrounding. (Remember there are two moments before and three moments after touching the patient).

HAI Prevention Special Rules

Strategies to reduce VAP Avoid intubation whenever possible. Consider noninvasive ventilation whenever possible. Prefer oral intubations to nasal unless contraindicated. Keep head elevated at 30-45° in the semi-recumbent body position. Daily oral care with chlorhexidine solution of strength 0.12%. Daily sedation vacation if feasible and assessment of readiness to extubate. Avoid re intubation whenever possible. Routine change of ventilator circuits is not required. Monitor endotracheal tube cuff pressure (keep it >20 cm H2 O) to avoid air leaks around the cuff, which can allow entry of bacterial

pathogens into the lower respiratory tract. Prefer endotracheal tubes with a subglottic suction port to prevent pooling of secretions around the cuff leading to micro aspiration. Closed endotracheal suction systems may be better than the open suction. Periodically drain and discard any condensate that collects in the tubing of a mechanical ventilator.

Indian J Crit Care Med. 2014 Mar; 18(3): 149–163.

HAI Prevention Special Rules

Strategies to reduce UTI Insert catheters only for appropriate indications Follow aseptic insertion of the urinary catheter Maintain a closed drainage system Maintain unobstructed urine flow. At all times the urinary catheter should be placed and taped above the thigh and the

urinary bag should hang below the level of the bladder The urinary bag should never have floor contact Changing indwelling catheters or drainage bags at fixed intervals is not recommended. Change only if there are clinical

indications such as infection or obstruction, or when the closed system is compromised Remove the catheter when it is no longer needed.

Indian J Crit Care Med. 2014 Mar; 18(3): 149–163

HAI Prevention Special Rules Indian J Crit Care Med. 2014 Mar; 18(3): 149–163

Strategies to reduce CRBSI ( Catheter Related Blood Stream Infection):- Use maximal sterile barrier precautions (cap, mask, sterile gown and sterile gloves) and a sterile full-

body drape while insertion. Clean skin with more than 0.5% chlorhexidine preparation with alcohol (usually 2% chlorhexidine with

70% w/v ethanol) before insertion. Use impregnated CVCs when the catheter is expected to remain in place for more than 5 days and only

if the bloodstream infection rates are high. Use either sterile gauze or sterile, transparent, semipermeable dressing to cover the catheter site . Peripheral lines should not be replaced more frequently than 72-96 h. Routine replacement of CVCs is not required. If intravenous fluids are used, change no <96-h intervals and at least every 7 days. Needleless connectors should be changed frequently (every 72 h). Replace disposable or reusable transducers at 96-h intervals.

HAI Special rules CRBSI Indian J Crit Care Med. 2014 Mar; 18(3): 149–163

Daily:- -Evaluate the catheter insertion site daily and palpate for tenderness. -Insertion date should be put on all vascular access devices. -Use 2% chlorhexidine wash daily for skin cleansing to reduce CRBSI. -Assess the need for the intravascular catheter daily and remove when not required. -Replace administration sets every day in patients receiving blood, blood products, or fat emulsions Whole day:- -Cap stopcocks when not in use. -Clean injection ports with an appropriate antiseptic (chlorhexidine,povidone-iodine,or70% alcohol). -Accessing the port only with sterile devices.

HAI Treatment

Antimicrobial is the corner stone in treating pt. with HAI Use of appropriate and early antibiotics improves morbidity and mortality. Appropriate antibiotic use requires a thorough knowledge of their mode of Action. Previous antibiotic history, local bacterial resistance profile. Local pathogen prevalence and Local antibiotic policy. Antibiotics should be administered at the right dose and for the appropriate duration. Empirical use of antibiotic is often necessary as laboratory results are often not available for

48 h.

HAI Empirical Antimicrobial choice

Antibiotic-resistant organisms are more commonly associated with inappropriate therapy

Empirical broad-spectrum antimicrobial regimen that includes agents not previously administered, especially for Gram-negative coverage, to minimize the occurrence of inadequate antimicrobial treatment.

M.Kollef , Clin Infect Dis 2000 ; 31(suppl 4) : S131-S138

HAI Antimicrobial choice

It should be active against Gram-positive aerobesBacillus spp., Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus spp., Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase negative and positive), Staphylococcus spp, Streptococcus pneumoniae (penicillin susceptible and resistant), Streptococcus pyogenes, Streptococcus spp.

Meronem SmPC

HAI Antimicrobial choice

It should be active against Gram-negative aerobesAcinetobacter spp., Campylobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including β-lactamase positive, penicillin resistant and spectinomycin resistant strains), Klebsiella pneumoniae, Klebsiella spp., Moraxella catarrhalis, Proteus spp., Pseudomonas aeruginosa, Pseudomonas spp., Salmonella spp., Serratia spp, Shigella spp.,

HAI Antimicrobial choice

It Should be active against Anaerobic bacteriaBacteroides spp., Bifidobacterium spp., Clostridium perfringens, Clostridium spp., Peptostreptococcus spp., Propionibacterium Spp.

Meronem SmPC

HAI Antimicrobial choice; ESBL

Extended-spectrum beta-lactamases (ESBL) are enzymes that confer resistance to most beta-lactam antibiotics, including penicillins, cephalosporins, and the monobactam aztreonam.

Infections with ESBL-producing organisms have been associated with poor outcomes. Community and hospital-acquired ESBL-producing Enterobacteriaceae are prevalent worldwide. Two enzymes ( TEM1&2) are the most common plasmid-mediated beta-lactamases in gram-negative

bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, and Neisseria gonorrhoeae.

TEM-1 and TEM-2 are not effective against higher generation cephalosporins (when these antibiotics were first introduced), such as cefotaxime, ceftazidime, ceftriaxone, or cefepime.

Carbapenems are the best antimicrobial agent for infections caused by such organisms.

http://www.uptodate.com/contents/extended-spectrum-beta-lactamases

HAI Increasing Cephalosporins Resistance Overview of Nosocomial Infections Caused by Gram-Negative Bacilli Robert A. Weinstein, Section Editor, Robert Gaynes, Jonathan R. Edwards, and National Nosocomial Infections Surveillance System

Results of intensive care unit surveillance revealing rates of antimicrobial resistance to third-generation cephalosporins among Klebsiella pneumoniae isolates (which includes isolates that were either intermediately susceptible or resistant) and Escherichia coli isolates—National Nosocomial Infections Surveillance system, 1986–2003. The proportions of K. pneumoniae and E. coli that were resistant were significantly higher in 2003, compared with 1986 (P < .001 for both, by the Cochran-Armitage χ2 test for trend).

Results of intensive care unit surveillance revealing the proportions of Pseudomonas aeruginosa isolates that were resistant to imipenem and ceftazidime—National

Nosocomial Infections Surveillance system, 1986–2003.

© 2005 by the Infectious Diseases Society of America

Results of intensive care unit surveillance revealing the proportions of Acinetobacter isolates that were resistant to amikacin, imipenem, and ceftazidime—National Nosocomial Infections Surveillance system, 1986–2003.

© 2005 by the Infectious Diseases Society of America

Carbapenems versus other beta-lactams in the treatment of hospitalized patients with infection: a mixed treatment comparison. Edwards SJ, Clarke MJ, Wordsworth S, Welton NJ

Authors' objectives To compare meropenem versus cefepime and piperacillin/tazobactam in treating hospitalised patients with infection, using a mixed treatment

comparison.

Results of the review Thirty-four RCTs were included in the review (number of patients unclear). Four trials compared ertapenem versus piperacillin/tazobactam. One

trial compared cefepime versus imipenem/cilastatin. Twenty six trials compared imipenem/cilastatin versus meropenem. Three trials compared imipenem/cilastatin versus piperacillin/tazobactam. There were no trials that compared: ertapenem versus cefepime, imipenem/cilastatin or meropenem; meropenem versus cefepime or piperacillin/tazobactam; and cefepime versus piperacillin/tazobactam.

Meropenem had the highest clinical response rate, with a probability of 91.6% that this was the best treatment in the network of comparisons (OR 1.52, 95% credible interval 1.23 to 1.87). Meropenem was also the best treatment in terms of bacteriological response (OR 1.45, 95% credible interval 1.15 to 1.80) and overall reduced risk of serious adverse events (OR 0.88, 95% credible interval 0.76 to 1.02), including those that led to withdrawal (OR 0.73, 95% credible interval 0.42 to 1.20) and those that were gastro-intestinal related (OR 0.76, 95% credible interval 0.56 to 1.02). Ertapenem was preferable in terms of all-cause mortality (OR 1.15, 95% credible interval 0.39 to 2.67). The authors also presented probability rankings as part of the analysis (reported in the paper).

Authors' conclusions Meropenem had substantial advantages over cefepime and piperacillin/tazobactam in the treatment of

hospitalised patients with infection. University of York, Center of reviews and dissemination

Meropenem versus Pip/Tazo and Cefepime in Vitro

Meropenem is more effective 'in vitro' than other broad spectrum antibiotics against ESBL-producing Enterobacteriaceae

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H.Goossens and B.Grabein, Diagn Microbiol Infect Dis 2005 ; 53 : 257-264

Let us see what happened to the Lady!

After 3 days the lady has no fever, started to feel better and she is hemodynamically stable on IVF , no Vasopressor support. Still CRP is 120 WBCS dropped from 19,000 to 12,000 Procal., 0.5

What is your plan?

1-De-escalate 2-Continue the same3-Add another antibiotic4-Stop antibiotic5-Convert to oral route

STREAMLINING OR DE-ESCALATING OF THERAPY

STREAMLINING OR DE-ESCALATING OF THERAPY Empiric antimicrobial regimens are often broad in spectrum to maximize the chance of providing activity against the infecting organism. This strategy refers to narrowing the spectrum of an empiric antimicrobial regimen and can include: Adjusting an empiric antibiotic regimen on the basis of culture results and other data. Discontinuing empiric therapy if testing subsequently fails to demonstrate evidence of an infectious process.

ANTIMICROBIAL STEWARDSHIP TOOLKIT BEST PRACTICES FROM THE GNYHA/UHF ANTIMICROBIAL STEWARDSHIP COLLABORATIVE

De-escalation. Why?!

The use of broad-spectrum antimicrobial may increase the risk of antimicrobial resistance.

The De-escalation strategy has the potential to improve pt. without compromising pt.’s safety.

It was associated with decreased in mortality, hospitalization and cost.

Protocol on antimicrobial Stewardship Program in Health care facilities.

DOSE OPTIMIZATION

Dose optimization includes strategies to ensure that specific characteristics of the drug (e.g., concentration or time-dependent killing, toxicities), infectious agent (minimum inhibitory concentration [MIC]), patient (e.g., weight, renal function), and site of infection are taken into account.

Such strategies may improve rates of cure and minimize risk of toxicity. These strategies include: Prolonged or continuous dosing of beta-lactams Once-daily dosing of aminoglycosides Appropriate dosing of vancomycin Weight-based dosing of certain antimicrobials Dose-adjustments for patients with renal dysfunction who are receiving antimicrobials that are

cleared by the kidneyANTIMICROBIAL STEWARDSHIP TOOLKIT BEST PRACTICES FROM THE GNYHA/UHF ANTIMICROBIAL STEWARDSHIP COLLABORATIVE

Extended versus continuous IVI of B-Lactams

Definitions. Intermittent infusion administration: Infusion lasting 30-60 minutes. Extended infusion administration: Infusion lasting 3-4 hours Continuous infusion administration: Continuous over 24 hours at fixed rate

Benefits. -Studies have shown that extended / continuous infusion of B-Lactam increases the chance of maintaining serum drug concentration above the MIC of the pathogen over 24 hours .

-Prospective and retrospective clinical trials have demonstrated higher clinical cure rate, shorter length of stay and mortality benefits.

Johns Hopkins Hospital Antimicrobial Stewardship Program

Revised 12/6/2010

Extended versus continuous IVI of B-Lactams

Examples:-

Continuous infusion over 24 hours; Cefepime, Ceftazidime, Pipracillin, Piperacillin/Tazobactam.

Extended Infusion over ; Meropenem over 3 hours Q 8 hr.

Johns Hopkins Hospital Antimicrobial Stewardship Program

Revised 12/6/2010

Things to Remember!

One in ten patients will acquire a nosocomial infection. ( Cost lives and Billions of Dollars) A third of nosocomial infections are preventable. Hand washing is the best preventative measure against the spread of infection; gloves are not a

substitute for hand washing. Use VAP, CRBSI, UTI Strategies Inadequate antibiotic therapy is associated with poor outcome and emergence of bacterial

resistance. For B-Lactams; Extended/ Continuous infusion is superior to intermittent infusion ( Higher cure

rate, Decreases hospital stay and mortality). Optimization of the antibiotic dose is crucial specially in Pt. with disturbed renal and liver

function. De-Escalate once the C/S is known if possible. Stop antibiotics whenever there is no response or no need.