TMP/SMX, Nitrofurantoin, Fosfomycin Flashcards
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Resistance
1) overproduction of PABA
2) ↓ affinity of enzyme dihydrofolate synthetase for
sulfonamide
3) ↓ affinity of dihydrofolate reductase for trimethoprim
4) ↓ cell permeability (plasmid mediated)
trimethoprim/Sulfamethoxazole
(Cotrimoxazole) (TMP/SMX)
what effect together?
❑ fixed ratio oral or IV results in ideal serum ratio of 1:20
❑ (SS tablet 80mg TMP / 400 mg sulfamethoxazole)
(DS tablet 160mg TMP / 800 mg sulfamethoxazole)
❑ synergistic / bactericidal
❑ reduced risk of resistance
Effect of sum of them together is greater than sum of them alone
TMP/SMX Spectrum
gram postiitve
S. aureus 98% 2020 (99% 2014)
MRSA 94% 2020 (97% 2014)
CoNS 81% 2020 (74% 2014)
S. pneumoniae 86% 2020 (89% 2014), 74% 2011
• not effective against Streptococcal pharyngitis
caused by S. pyogenes
• (Not effective against enterococci)
Not as good as coagulase neg staph
Not as good for pneumoniae but still reasonable
Not good for pyogenes
Not good against group A strep SSTI
TMP/SMX Spectrum
gram neg
❑ H. influenzae 67% 2020 (77% 2012) ❑ E.coli 79% 2020 (78% 2012)* ❑ K. pneumoniae 94% 2020 (96% 2012) ❑ Proteus mirabilis 82% 2020 (71% 2014) ❑ S. marcesens 100% 2020 (100% 2012) ❑ Enterobacter spp (87% 2020, 97% 2012) ❑ Acinetobacter 94% 2019 (UAH) ❑ Citrobacter freundii 90% 2020 ❑ Stenotrophomonas maltophilia 98% 2020 (UAH)
❑ not effective against P. aeruginosa
AMP-C making SPICE-A organisms are treated
TMP/SMX Spectrum
anaerobes?
without cell wall organisms?
fungi?
❑ Active against M. catarrhalis,L. monocytogenes, &
Legionella
❑ Not reliable against M. pneumoniae or Chlamydia
❑ Not active against anaerobes
❑ Active against Pneumocystis jiroveci and Nocardia
TMP/SMX Pharmacokinetics
IV or oral?
metabolized by CYP?
❑ well absorbed orally
❑ well distributed to many tissues, pleural fluids, peritoneal
fluids, and CSF (variable - SMX 25-30%, TMP ~ 40%)
❑ variable protein binding (SMX 70%, TMP 44%)
❑ extensively metabolised in liver (acetylation, glucuronidation)
• both SMX and TMP metabolized by CYP 2C9 and 3A4
❑ Both excreted in urine (metabolites and unchanged) – dosage adjustment required in renal impairment
Good bioavailability
Comp levels to IV
TMP/SMX Adverse Effects
GI
hematologic
❑ GI (nausea, vomiting, diarrhea) jaundice, hepatic necrosis
Hematologic
❑ anemia, agranulocytosis,
❑ thrombocytopenia,
❑ hemolytic anemia (G6PD deficiency)
(hematologic effects may be more severe in elderly and patients with HIV disease)
❑ Teratogenicity in pregnancy (contraindicated in 1
st and 3rd trimesters)
❑ kernicterus, infants (displacement of bilirubin from binding sites)
❑ photosensitivity - protect from sun
TMP/SMX Adverse Effects
which class of rxns more common
❑ Sulfonamide antibacterials can rarely cause
IgE-mediated reactions
❑ More commonly cause maculopapular rashes
❑ Maculopapular rashes occur at a rate of 1-3% in the
non-HIV population, but higher incidence in HIV patients
class 4
❑ Stevens-Johnson syndrome, erythema nodosum,
erythema multiforme
❑ vasculitis
❑ interstitial nephritis, tubular necrosis
hyperkalemia
TMP/SMX
HIV Patients
❑ Hypersensitivity reactions develop in only ~ 1-3 % of
patients not infected with HIV, but 40-50% in HIV
❑ some literature as high as 20 - 80% patients infected with HIV
❑ ? Due to altered drug metabolism, reduced glutathione levels, or both
❑ Graded challenge with sulfamethoxazole may permit its use again (75% in one study)
❑ Patients may tolerate TMP/SMX with rapid induction of tolerance (desensitization)
❑ Patients with HIV more likely to develop anemia
associated with TMP/SMX
TMP/SMX testing for hypersensitibity
❑ Specific determinants of sulfonamide
hypersensitivity not known - no test available
❑ Repeated administration is not recommended after any life-threatening reaction (anaphylaxis, drug-induced
hemolytic anemia, thrombocytopenia, neutropenia,
immune-complex reactions, Stevens-Johnson Syndrome and toxic epidermal necrolysis)
- agents that are used preferentially in certain agents, but there are other agents available and can switch
Sulfonamide Antibiotic
Cross-Reactivity with
Non-Antibiotic Sulfonamide Drugs
(sulfa allergy)
although all sulfonamides contain an NH2
-SO2 moiety, sulfonamide antibiotics also contain an aromatic amine at the N4 position and a substituted ring at the N1 position”
❑ “these groups are believed to be essential for
various types of allergic reactions to sulfonamide
antibiotics”.
HCTZ, furosemide, COX2 inhibitors are diff from sulfamethoxazole
Cross-reactivity with
Sulfonamide Antibacterials and
Sulfonamide Non-antibacterials
is there evidence to suggest cross-reactivity b/w sulfonamide abx and non-sulfonamide abx?
“ There is an association betweenhypersensitivity after the receipt of sulfonamide antibiotics and a subsequent allergic reaction after the receipt of a sulfonamide non-antibiotic, but, this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.”
“ There is no evidence to suggest allergic cross-reactivity between sulfonamide antibiotics and non-antibiotic sulfonamides”
confirm speciifc sulfa drug pt was allergic to
By comparison the OR for an allergic reaction after the receipt of a Rx for penicillin in those with a prior rxn to sulfonamides
compared to those without such a reaction was 7.8
These results suggest subsequent reaction
to nonantibiotic sulfonamides is probably a
predispostion to allergic reactions in general”
