my $str      = 'Fsih my test variable is fsihd or is it gfsih or gfsih
+d fsih';
#                                        1111            2222     3333
+  4444
my $substr   = 'fsih';
my $replace  = 'fish';
my $instance = 3;  # 3rd

print("$str\n");

my $pos = -length($substr);

for (;;) {
   last if !$instance--;
   $pos = index($str, $substr, $pos + length($substr));
   last if $pos < 0;
}

substr($str, $pos, length($substr), $replace)
   if $pos >= 0;

print("$str\n");
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Update: Fixed off-by-one error.