Antibiotics in critically ill patients

Question 1

How quick do you need to be in humans to give antibiotics once there is hypotension caused by septic shock?

Answer 1

Within 1 hour! Has strong relationship with improved patient outcome (2006 study)
Survival rate around 80% if within 1 hour
Survival decreased by nearly 8% for every hour delay of appropriate ABs
Patients not receiving appropriate ABs until >36 hrs had 5% survival rate

Buuut other studies have failed to show similar results
Theory now is administering early ABs is a marker of overall care (ie prompt with all other treatment as well, so might not be the ABs that are the vital factor)

Question 2

What do the surviving sepsis campaign guidelines say about antibiotics?

Answer 2

Include one or more drugs that have activity against the likely pathogens (cannot always confirm which and/or delay in results) and penetrate into the tissues presumed to be the source of sepsis
Loading dose when possible
Ensure AB potency by using bactericidal drugs, using combination therapy with differing mechanisms of action etc
Prompt and adequate source control

Question 3

Which bacteria are common for respiratory infections in horses (pneumonia/pleuropneumonia)?

Answer 3

Often mixed, gram positive/negative/anaerobic
Streptococci equi zooepidemicus very common aerobe isolated
Other aerobes most frequently isolated - Pasteurellacea, E. coli, Klebsiella
Anaerobes - Bacterioides, Clostridium (isolated in 68% of horses in one study)

Question 4

Idiopathic peritonitis study in Sweden - which antibiotic were they mostly sensitive to?

Answer 4

64% isolates sensitive to penicillin
So they treated with penicillin alone and had survival to discharge 94%

Need to look at own hospital data..

Question 5

What toxic side effect can fluoroquinolones cause in foals?

Answer 5

Cartilage defects

Question 6

Why use IV antibotic first, followed by oral/IM?

Answer 6

Achieve high concentration in tissues quicker as oral etc has slower absoprtion
Often expensive to continue IV, so switch to oral

E.g. IV metronidazole, followed by oral/rectal

Question 7

Bactericidal or static drugs for critical patient?

Answer 7

Cidal where possible as static relies on immune system, which may be compromised in critical patient

Question 8

Why are penicillin and gentamicin synergistic?

Answer 8

Penicillin damages cell wall and increases influx of gentamicin

Question 9

Does using one antibiotic reduce risk of antibiotic resistance?

Answer 9

SOmetimes
But some antibiotics develope resistance quickly on their own and this might be slowed by adding another antibiotic (e.g. rifampin develops resistance quickly)

Question 10

Which combinations of antibiotics are antagonistic? (ie don’t use them together..)

Answer 10

Penicillin and tetracyclines (tetracycline inhibits growth of bacteria, but penicillin needs the growth to attack cell wall) - ie bacteriostatic vs bactericidal

Question 11

When to stop antibiotics for critical patient?

Answer 11

Hard to say!
Some recent studies have shown a longer course doesn’t necessarily have better outcomes

Poss use inflammatory markers, haemogram, just once horse is ‘well’?

Probably short course fine for many things, exceptions e.g. endocarditis which requires long course

Question 12

Does a shorter or longer course of antibiotics have a bigger effect on antibiotic resistance?

Answer 12

Stopping the antibiotics early won’t cause antibiotic resistance (nonsense!), but a long course will have a risk of this

Question 13

Mortality rates for bacterial pneumonia and pleuropneumonia in horses?

Answer 13

Up to 45%

Question 14

Which antibiotics to use for bacterial pneumonia/pleuropneumonia?

Answer 14

No studies comparing ABs for LRT infections in horses
Pen/gent is expected to be efficacious in the majority of cases and is commonly used
Could add metronidazole if anaerobes cultured (anaerobes have been associated with poorer prognosis), but probably unnecessary unless indicated by sensitivity results because most anaerobes will be sensitive to penicillin

Remember in vitro sensitivity does not tell you if the antibiotic can reach the pulmonary epithelial lining fluids (PELF) or into the alveolar macrophages

So penicillin logical as Strep equi zoo frequently isolated, and also good activity against most anaerobes.. but its concentration within the PELF after systemic administration has not been determined in horses
- Ampilcillin (15mg/kg IV) and pivampicillin (19.9mg/kg PO) recently shown to result in drug concentrations in PELF above the MIC of susceptible bacteria for at least 12 hours - supports the use of these drugs for bacterial LRT infections

Gentamicin used commonly, but is reported to have poor lung penetration and found to have low PELF concentrations in healthy horses folloiwng IV 6.6mg/kg - the increased vascular permeability during inflammation may result in increased diffusion into infected tissues, however (no studies in horses with pulmonary inflammation though)
- gent concentrations are decreased when mixed with purulent material in human and lab studies, though (thought due to binding to the drug)

Gent concentrations in PELF were around 12 times higher than IV when given as an aerolisation, and remained higher for up to 8 hours

Ceftiofur and cefquinome licensed for LRT bacterial infections in horses and lung concs have been reported
- But 1mg/kg IV cefquinome did not have a detectable PELF concentration after 8hrs, so the recommended q24hrs may not be sufficient even for highly susceptible pathogens
- Ceftiofur achieved pulmonary concs that were slightly lower than plasma concs and has been shown to be effective for naturally occurring resp disease
- Ceftiofur sodium is not inactivated by inflammatory environments
- In some countries can get crystalline free acid version of Ceftiofur which requires less frequent administration and has been shown to be effective for Strep equi zoo: 2 doses 4 days apart, then weekly IM doses resulted in PELF concs above the MIC to inhibit the growth of at least 90% of common LRT pathogens
- Not a first line treatment in non life threatening infections, but may be valuable treatment option for pleuropneumonia when supported by appropriate sentivity testing
- Inhaled cephalosporins may maximise clinical efficacy and minimise risk of antimicrobial resistance
- Cefquinome reached high PELF concentrations following jet nebulisation, but not detectable after 4hrs, so frequent treatment may be required

Oxytetracycline:
- Not used unless supported by sensitivity data, because high proportion of S zoo and E coli isolates are resistant

Enrofloxacin:
- Good gram negative coverage (limited gram positive) and may overcome limitations of aminoglycosides when treating purulent LRT infections
- But critically important AB, so not first line without sensitivity testing
- 5mg/kg IV q24hrs enrofloxacin reaches concs within lung tissue greater than MIC of common equine pathogens
- less affected by purulent material or anaerobic enviro than aminoglycosides
- Found to have 21% treatment failure in horses if used as sole therapy, so use in combo with a drug effective against gram positives
- aerolising can help efficacy and reduce resistance concerns
- Marbofloxacin concs in BALF following nebulisation (300mg/horse) were 5.5 times higher than a 2.2mg/kg IV dose

If using oral antibiotics for more chronic cases, base off of sensitivity:
- Doxycycline can achieve good concs in PELF, but mixing in feed may limit effectiveness due to low bioavailability
- TMPS often used for resp disease, but PELF concs have been shown to be below the MIC of common equine pathogens and was found to be unable to clear S zoo infection in a tissue cage model, compared to penicillin (likely due to high levels of p-aminobenzoix acid in purulent materal, inhibiting the drug’s ability to cause bacterial cell death)
- So TMPS not recommended for purulent LRT disease

Question 15

Which doses of penicillin G potassium/sodium and procaine penicillin G have been shown to result in serum concentration above the MIC of susceptible bacteria?

Answer 15

Penicillin G ptoassium/sodium: 20-50,000 U/kg IV q6hrs

Procaine penicillin G: 22,000 U/kg IM q12hrs

Question 16

Why are macrolides rarely used in adult horses?

Answer 16

Oral macrolides have been associated with severe and often fatal colitis in adult horses

(used in foals in combo with rifampin for Rhodococcus pneumonia)

Question 17

What are typical bacteria involved in primary and secondary abdominal abscesses in horses?

Answer 17

Primary are typically associated with single aetiological agents, such as:

Adults:
- Strep equi equi
- Corynebacterium pseudotuberculosis

Foals:
- Rhodococcus equi

Secondary, caused by trauma, ulceration or perforation of the intestinal tract etc, can be a wide variety of gram positives and negatives, as well as anaeroves

Question 18

What is the prognosis for survival in horses with addominal abscesses?

Answer 18

60-70% with long term antimicrobial therapy

But more recent study of 61 horses only had 25% survival

Question 19

Which antibiotics to use for abdominal abscesses in horses? How long for?

Answer 19

Only available evidence is case reports and series

Penicillin, ceftiofur, ampicillin, gent, chloramphneicol, TMPS, enrofloxacin, mactolides and rifampin have all been used successfully in some cases (but the pharmocological characteristics of some of these drugs suggest poor in vivo efficacy)

Pen and gent - poor tissue and abscess penetration and reduced activity in acid environment

Potentiated sulphonamides - widespread tissue distribution due to high lipid solubility, but inactivated by pus and necrotic material, so poor choice in treatment of abscesses

Rifampin, macrolides, enrofloxacin, chloramphenicol, metronidazole - likely to be more efficacious due to high lipid solubility, good tissue penetration, and activity in acidic environments

Culture often not available due to inaccessible location of abscess

1-6 months of procaine penicillin G has been successful for Strep and C.pseudotuberculosis abscesses, despite its theoretical limitations

Rifampin has also been successfully used, but must be used in combo with another AB class due to the rapid development of resistance if used as a sole agent (e..g used with a macrolide for Rhodococcus resp disease in foals, but no studies for abdominal abscesses)
- Combo of rifampin and ceftiofur has been recommended as an appropriate treatment for abdo abscesses in adults, but there are no reports to support any particular AM combination and therefore can’t really use a critically important AB first line

If secondary abscess, need AMs active against gram positives and negatives, aerobes and anaerobes:
- Aminoglycosides not appropriate as monotherapy as low tissue penetration and poor clinical outcome in humans
- Tetracyclines have broad spectrum of activity and good tissue distribution, but widespread resistance to both oxytetracycline and doxy have been reported (so need sensitivity data to support use)
- Chloramphenicol is broad spectrum with good tissue penetration, but licencing restriction sin some countries preclude its use
- Penicillin or rifampin can provide gram positive coverage
- Enrofloxacin has excellent gram negative activity, but is critically important
- Penicillin is expected to be efficacious against majority of anaerobes, but metronidazole may provide a broader coverage due to its activity against Bacteroides fragilis

Question 20

Which antibiotics to use for a foal with Rhodococcus respiratory disease?

Answer 20

Rifampin, in combination with a macrolide (rifampin develops quick resistance if used as a sole agent)

Macrolides is critically important, but still recommended for foals with R equi pneumonia, based on in vitro activity data and studies

Question 21

How to determine duration of AM treatment for abdominal abscess?

Answer 21

Response to therapy
Ultrasonography monitoring
Rectal exams
Serial measurements of inflammatory markers, e.g. fibrinogen

Earlier reports describe treatment of up to 6 months

More recent reports suggest a shorter period, median 29-35 days

Question 22

Did studies find any difference in infectious disease rate between neonatal foals treated prophylactically with antibiotics vs those that weren’t?

Answer 22

No difference

Question 23

Why is it difficult to determine whether to use antibiotics in compromised neonates? Should we limit ABs?

Answer 23

It is close to impossible to definitively differentiate sepsis from noninfectious causes of weakness in foals, such as perinatal asphyxia syndrome (PAS) and prematurity

And conditions can occur concurrently

Potentially severe consequences of withholding or delaying AM therapy in the face of sepsis, so unrealistic to propose limiting initial AM usage in this critical patient group at the moment

More achievable goal may be to decrease the length of AM treatments and making sensible AM choices

Question 24

Has AB resistance been found in neonatal foals?

Answer 24

Yes
Decreased suseptibility og Enterobacteriacea and other bacteria has been found to ceftifur and gentamicin in septic foals

Increasing MIC values for several bacteria also found for amikacin, gentamicin and ceftiofur = early warning signs for developing resistance

Question 25

When to stop antibiotics for a compromised neonatal foal?

Answer 25

After 2-5 days, once the foal has recovered from the inital insult and clinical evidence of persisting infection is absent

Such a short course needs the AB to be bactericidal with rapid onset at optimal dose (often need increased doses than in adults)

Ensure normal IgG levels before stop ABs

(e.g. in human infants advise is to stop ABs after 48hrs in culture negative infants with no signs of infection and normal screening lab exams, whilst continuing if they are culture positive or have signs compatible with infection beyond 48hrs)

Question 26

Can SAA or fibrinogen be used to determine when to stop ABs for compromised neonatal foal?

Answer 26

Fibrinogen has long half life of 4-5 days, so concern that using this leads to overtreatment and unnecessary contnuation of treatment

SAA has short half life of 1.5 hours (in mice), but if SAA is low this doesn’t rule out sepsis, as study found 11/36 foals with sepsis to have SAA <25 on admission

Question 27

Best choice for initial AB therapy of compromised neonate?

Answer 27

Unknown…

Pen/gent has been used successfully for long time, but resistance against gent is increasing

Amikacin with ampicillin has been recommended based on recent sensitivity data

Some clinicians favour cephalosporins as monotherapy - cefquinome is licensed for treatment of neonatal sepsis

Cephalosporins supposedly have reduced risk of nephrotoxicity in foals with unknown/impaired renal fucntion

But increased occurence of Enterococcus with unpredicitable sensitivity and frequent resistance to cephalosporins means their use may not be advisable for much longer

Question 28

What is the recommendation of AB use for colic surgery?

Answer 28

Evidence in people that AM prophylaxis decreases the risk of post op infectious complications after intestinal surgery

Not enough evidence in horses for firm recommendations. Given unknown pre-op if will be clean or clean-contaminated, it seems prudent to give pre-op ABs within 1hr of incision and repeat during surgery if required. The little evidence available suggests unnecessary to extend beyong 3 days post-op in most cases. And unknown whether 3 days is beneficial over <24hrs.

Question 29

Effect of antibiotics on the normal GI flora?

Answer 29

Decrease in GI ceullulolytic bacteria and lactobacilli
Increased shedding of Salmonella and C difficile

Question 30

Which AB is the treatment of choic for Clostridial enterocolitis? Duration?

Answer 30

Metronidazole - evidence to support increased survival if used
Appears to be a low rate of resistance, so still appropriate choice
Ideal duration is unknown - typically ranges from 3 to 5 days
Experimentally infected foals cleared the infection within 48-72hrs after initiation of treatment (study did not have untreated control group though)

Question 31

Ab of choice for equine neorickettsiosis (Potomac Horse Fever)? Duration?

Answer 31

Oxytetracycline for 5 days
Early treatment is associated with improved outcome

Question 32

Ab choice for Equine Proliferative Enteropathy caused by Lawsonia intracellularis? Duration?

Answer 32

Good outcome if treated
Lipophilic ABs, such as macrolides, either alone or in combo with rifampin, chloramphenicol, oxytet or doxyxyxline for 2-3 weeks are recommended

Question 33

Should ABs be used for Salmonella?

Answer 33

Not routinely
Oxytet shown to prolong shedding and various ABs shown to not affect the presence of Salmonella in naturally infected horses

Stronger evidence in humans of no clinical benefit of ABs for nonsevere Salmonella

Higher risk patients at risk of bacteraemia is more complicated - if invasive infection identified then fluoroquinolones and 3rd gen cephalosporins are recommended first line in horses, but C+S advised due to increasing resistance

Question 34

Should you use ABs for a compromised foal with diarrhoea?

Answer 34

Broad spectrum ABs have long been recommended due to vulnerable immune system and possibility of bacterial translocation

2 studies found bacteraemia in 49-63% of blood cultures in foals with diarrhoea, but unknown if ABs influence outcome

Oral or IV ABs appear justified - B lactam and aminoglycoside or a cephalosporin whilst awaiting C+S results