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Antibiotics for Intra-abdominal Infections

Advances in bacteriology and the introduction, of antibiotics with limited activity against obligate anaerobes (e.g., aminoglycosides, cephalosporins), has refocused the attention on the anaerobic nature of secondary peritonitis during the 1960's and 1970's. This prompted experimental studies that identified E. coli and B.fragilis as the main target organism for therapy.  Both are also the most frequent isolates from intra-abdominal infections.
Today the practice of early empirical administration of antibiotics targeted against these bacteria is being challenged by a more sophisticated calculated design of antibiotic therapy that is based on concentration dynamics at the site of infection, e.g peritoneal fluid in the abdominal cavity.
In addition, the choice and timing of administartion, the need for intra-operative cultures and the duration of postoperative administration remain controversial and is often influenced by the pharmaceutical industry that often were designed as low-mortality studies to suggest that therapy with a broad-spectrum antibiotic that includes incomplete activity against obligate anaerobes might be equal, or superior to agents fully effective against both facultative and obligate anaerobes.  Patients in such series have been cured of infection with antibiotics resistant to bacteria suggesting that in many instances the source control operation alone was curative.
This confirms the pre-antimicrobial era revelation that operative source control alone reduces the mortality rate from 90% to 40%; – without any anti-infective agent at all (Krischner, M. Langbeks Archiv Chirurgie, 1923).


Value of Controlled Trials

abstud
Mortality in clinial studies with focus on surgical versus antbiotic therapy during same treatment periods

The true mortality of intra-abdominal infection reported in surgical series contrasts sharply to industry driven antibiotic trials that consistently excludes severe intra-abdominal infections and therefore makes these trials meaningless for antibiotic choices
Unfortunately, the numerous prospective randomized studies about antibiotic management of peritonitis exclude the sickest patients by study design.  Low mortality penetrating trauma cases that represent peritoneal contamination rather than intra-abdominal infection dilute results.  Consequently, the average mortality rate is only 3.5% in the antibiotics studies (see table).  This sharply contrasts with the 33%, 33%, 21%, 32% and 29% mortality rates of 113, 393, 271, 569 and 929 of non-selected cases and treated during the same period, respectively. 


Killing Target Bacteria

gram stain

PIC of Gram stain of peritoneal fluid from a patient with peritonitis

In spite of the numerous options advertised, antibiotic therapy for secondary peritonitis is simple.  The emerging concepts suggest that less, in terms of the number of drugs and the duration of treatment, is better.  To hit the primary endotoxin producing target organism, an antibiotic is required that kills strains (of the target species) at the site of infection e.g. peritoneum with a peritoneal fluid concentration of sufficiently level and duration until the next administration.
Subinhibitory concentration in the peritoneum compartment must be avoided because strains with higher MIC’s can survive and pose a major resistance problem down the road.<>

For a synopsis of antibiotic therapy of calculated design, click here to paper calcuated antibiotic therapy>

Cephalosporins and Penicillins

These beta-lactam antibiotics have a very similar pharmacokinetic behavior. After IV injection two procersses dominate kinets: 1. Diffusion from the central compartmet into the (global) peripheral compartment until concentrtation equilibrum berween compartments is reached. 2. Simulatneous elimination from the peripheral compartment into the central compartment and clearance from the central compartment via mainly renal or hepatic routes. In the example below antibiotic movements are shown graphically. It also shows that certain concentration of drugs are available for a give time only depending ont the elimination processes. These concentration must surpass the concentrations at which bacteria cannot survive for antibiotic therapy to be effective.

Killing Target Bacteria


Cefotaxime kinetics 3333

Diffusion of cfotaxime between central and peripheral compartments"

Third Generatios Cephalosporind


Third generation cephalosporins such as cefotaxime, ceftizoxime, cefmenoxime, moxalactam and ceftriaxone were the first ß-lactam antibiotics with a 100% activity against target organism E.coli at tissue levels . In 104 studies none of 10478 strains of E.coli tested had a minimal inhibitory concentration (MIC) in excess of the concentrations achieved in the peritoneum with a two gram dose. (Figure) None of the penicillins, even when combined with ß-lactamase inhibitors achieves similar results with doses used in clinical practice.


Pathogens killed at tissue levels

MIC e-coli

EC


pic b fragilis MIC

BF


Third Generatios Cephalosporindos


Third generation cephalosporins such as cefotaxime, ceftizoxime, cefmenoxime, moxalactam and ceftriaxone were the first ß-lactam antibiotics with a 100% activity against target organism E.coli at tissue levels . In 104 studies none of 10478 strains of E.coli tested had a minimal inhibitory concentration (MIC) in excess of the concentrations achieved in the peritoneum with a two gram dose. (Figure) None of the penicillins, even when combined with ß-lactamase inhibitors achieves similar results with doses used in clinical practice.



Aminoglycosides


The once popular 'triple' regimen of the 1970's (ampicillin, an aminoglycoside, and metronidazole or clindamycin) has become obsolete.  Aminoglycosides are significantly more nephrotoxic than for example the third generation cephalosporins, are inefficient in the low pH of the infected peritoneal environment, and are no longer the first choice of antibiotics in the initial treatment of IAI.  The enterococcus, which is frequently isolated in experimental and clinical peritonitis, is almost clinically non-significant except its role as a co-factor for B.fragilisin the formation of abscesse.  Thus it does not require a 'coverage' with ampicillin if the obligate anaerobes (e.g.B. fragilis are adequately 'covered' by metronidazole or clindamycin.


Carbapenems


Imipenem, a carbapenem derivative, has broad activity against facultative and obligate Gram-negative anaerobes and excellent Gram-positive activity (excepting methicillin-resistant Staphylococci.  Its Achilles tendon is its marginal activity against Proteus mirabilisat peritoneal fluid levels following the 500 mg dose.
Proteus mirablils is another, gram negative target organisms causing lethal sepsis. Following the 1-gram dose, a much higher proportion of this pathogen is covered at the site of infection.


It is therefore better to give 1000 mg iv every 8 hours instead of 500 mg every 6 hours to the majority of patients that have an age related diminished elimination of the drug. The benefits of success far outweigh the risk for seizures with that dosage.


Imipenem is formulated with cilastatin, a renal dehydropeptidase inhibitor which prevents renal tubal epithelial metabolism of the drug. It also prevents tubular cell damage by preventing accumulation of toxic byproducts of the many drugs given to an intensive care patient. This nephroprotective effect of the imipenem/cilastatin combination should favor its clinical use. 


Meropenem is a synthetic agent with a typical broad carbapenem antibacterial spectrum.  Several clinical trials in which serious intra-abdominal infections were treated with meropenem dosed at 1 g every 8 hours have shown considerable efficacy. It is not combined with a dipetidase inhibitor.



Fluoroquinolones


The currently marketed fluoroquinolones are active against facultative and aerobic Gram-negative bacteria. Streptococci and Enterococci show in vitro susceptibility to quinolones but other, more effective agents are available.
Staphylococcus aureus and coagulase-negative Staphylococci have become progressively more resistant to fluoroquinolones. These drugs should be considered only as a last resort for treatment of infections caused by multiply antibiotic-resistant Gram-positive strains, and only in combination with other anti-staphylococcal drugs.
A primary virtue of the quinolones is a very large volume of distribution meaning that high concentrations are available in tissue when related to the dose given. Because of their relatively small molecular size and absence of localized electrical charges, these agents penetrate well into interstitial fluid and achieve high tissue levels, in excess of those seen with other, larger molecules.
A major benefit of currently available quinolones, as compared with β-lactam agents, is continuing activity against Enterobacterand other species which have inducible -lactamases. Another advantage of quinolone therapy ,the potential for oral treatment of serious Gram-negative infections, does not aplly often to patients with intra-abdominal infections. There are a variety of clinical situations, however, in which prolonged therapy is considered appropriate. These include hepatic abscesses and nosocomial pneumonia.
The next generation of quinolones is have substantially expanded spectra of activity including many ciprofloxacin-resistant Gram-negatives, Gram-positives, and many anaerobic organisms, including Bacteroides fragilis. These agents also appear to have considerable potential for both gene damage and photosensitization, and their futures remain unclear.


Quinolone-metronidazole ombination


As clinical experience has accumulated, quinolone antibiotics appear to be potentially useful for serious systemic infections. These agents act by inhibiting DNA replication, and have shown similar activity to imipenem in clinical trials for pneumonia and intra-abdominal infection. Available quinolones have little anti-Bacteroides fragilis activity and should be combined with metronidazole in intra-abdominal infection



Duration of antibiotics


The trend to continue administration of antibiotics for fixed periods is no longer justified.  A recommendation of the Surgical Infection Society that the conditions representing ‘simple’ (simple cholecystitis, appendicitis, etc.) intra-abdominal infection do not require therapeutic postoperative antibiotics is an important rule towards limiting the currently prevailing practices of excessive antibiotic prescription.  Further changes in the current practices may be possible to minimize postoperative administration by intra-operative stratification of the extent of infection, tailoring the duration of therapy to operative findings, which will also limit the need for oral continuation of intravenous antibiotics.


Antibiotic therapy should be started as early as possible after diagnosis as it also helps to reduce endotoxemia. Specific, directed treatment is not possible, however, because the infecting microorganisms and their sensitivities are not precisely known and microbiologist were unable to develop a test that provides instant identification and and required inhibitory concentrations.
Consequently, the choice of antimicrobial must be based on other criteria. Antimicrobial therapy should be directed against the most frequently expected pathogens and achieve an antimicrobially active concentration of drug at the site of infection. The potential for adverse interaction of antibiotics with host defenses, and possible toxic effects such as the ototoxicity of aminoglycosides, must also be considered. Controlled clinical trial reports of antimicrobial efficacy are often of little help; the most severely diseased patients have been excluded from most trials. Necrotizing fasciitis and other forms of extension of infection to the surgical wound represent catastrophic failures of antimicrobial treatment.
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